Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]=[CH:6][CH:7](OC)OC)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>C(#N)C.O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]2=[N:24][CH:7]=1)[CH3:2]
Reactant: Nc1ccccn1
Reactant: CCOC(=O)C=CC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)Cc1cnc2ccccn12
Temperature: 25 °C
Yield: 73.4 %

Procedure:
Heat a mixture of 4,4-dimethoxy-but-2-enoic acid ethyl ester (43.5 g, 250 mmol) and p-toluenesulfonic acid (4.75 g, 25 mmol) in acetonitrile (240 mL) and water (15 mL) at reflux for 2 hours. Cool the reaction mixture to room temperature and add 2-aminopyridine (18.8 g, 200 mmol). Heat the mixture at reflux for 16 hours then cool to room temperature. Dilute the reaction mixture with ethyl acetate (1200 mL) and wash sequentially with saturated aqueous sodium bicarbonate (600 mL×3) and saturated aqueous sodium chloride (600 mL×2). Dry the organic phase over sodium sulfate and concentrate under reduced pressure to provide the desired compound as a brown oil (30 g, 73%).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH:9]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[S:14][C:13]=2[C:12](B(O)O)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:9]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[S:14][C:13]=2[C:12]([C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[NH2:4])=[CH:11][CH:10]=1
Reactant: Nc1ccccc1Br
Reactant: OB(O)c1cccc2c1sc1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Nc1ccccc1-c1cccc2c1sc1ccccc12
Yield: 78.9 %

Procedure:
The 300 ml round-bottom flask equipped with reflux condenser and magnetic stirrer was charged with 2-bromoaniline (8.00 g, 46.5 mmol), 4-dibenzothiopheneboronic acid (10.5 g, 46.5 mmol), potassium carbonate (20 g, saturated solution in water), tetrakis(triphenylphoshine)palladium (0) (500 mg) and 100 ml of toluene. The reaction mixture was refluxed overnight under nitrogen atmosphere, filtered through silica plug and evaporated. Product was purified by column chromatography on silica gel, eluent hexane/ethyl acetate 4/1 mixture, providing 2-(dibenzo[b,d]thiophen-4-yl)aniline (10.1 g) as yellow oil.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][CH2:27][CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C.ClCCl>[Cl:26][CH2:27][CH2:28][CH2:29][S:30]([N:23]1[CH2:24][CH2:25][CH:20]([C:11]2[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[NH:13][N:12]=2)[CH2:21][CH2:22]1)(=[O:32])=[O:31]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Reactant: O=S(=O)(Cl)CCCCl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Yield: 66.5 %

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (Example 2) (140 mg, 0.437 mmol) was reacted with 3-chloropropane sulfonyl chloride (58 uL, 0.480 mmol) in the presence of diisopropylethyl amine (305 uL, 1.75 mmol) and DMAP (53 mg, 0.437 mmol) in dichloromethane (5 mL) to give the title compound (134 mg, 77%)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=4)[CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[C:15]([CH3:43])[C:14]=3[CH:44]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([NH:25][C:26]4[CH:27]=[CH:28][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=4)[CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[C:15]([CH3:43])[C:14]=3[CH:44]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OCc4ccc(Cl)nc4)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(OCc3ccc(Cl)nc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
Ethyl 3-{[(4-{[{5-[(6-chloropyridin-3-yl)methoxy]-3-methyl-1-benzofuran-2-yl}(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (0.32 g) synthesized in the above-mentioned (1) was dissolved in ethanol (3 mL), 1N aqueous sodium hydroxide solution (1.0 mL) was added to the solution at room temperature and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (1.0 mL) was added to the residue. The precipitate was washed with water to give the title object compound (0.26 g, 85%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1C(C2C=CC=CC=2[N+]([O-])=O)C(C(OC2CCCC2)=O)=C(C)[NH:15][C:16]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C>[CH2:1]([O:8][C:9](=[O:10])/[CH:11]=[C:16](\[NH2:15])/[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1=C(C(=O)OCc2ccccc2)C(c2ccccc2[N+](=O)[O-])C(C(=O)OC2CCCC2)=C(C)N1
Solvent: CCO
Product: C/C(N)=C/C(=O)OCc1ccccc1
Yield: 73 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 2'-nitrobenzylideneacetoacetic acid cyclopentyl ester and 75 mmols of β-aminocrotonic acid benzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-cyclopentyloxycarbonyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid benzyl ester of melting point 111° C (from ethanol).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:27][CH2:28][CH3:29])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH2:13][C:14]2[N:15]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:16]=[CH:17][N:18]=2)=[CH:7][CH:6]=1)[CH3:2].[NH:30]1[CH:34]=[CH:33][N:32]=[C:31]1[C:35](O)=[O:36].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[OH-].[Na+]>ClCCl>[CH2:1]([O:3][CH:4]([O:27][CH2:28][CH3:29])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:12]([CH2:13][C:14]2[N:15]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:16]=[CH:17][N:18]=2)[C:35]([C:31]2[NH:30][CH:34]=[CH:33][N:32]=2)=[O:36])=[CH:9][CH:10]=1)[CH3:2]
Reactant: O=C(O)c1ncc[nH]1
Reactant: CCOC(OCC)c1ccc(CNCc2nccn2COCC[Si](C)(C)C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(OCC)c1ccc(CN(Cc2nccn2COCC[Si](C)(C)C)C(=O)c2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.4 %

Procedure:
To a solution of the compound 16 (1.93 g), 1H-imidazole-2-carboxylic acid (773 mg) and diisopropylethylamine (2.97 g) in dichloromethane (15 mL), O-(7-azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (2.62 g) was added under ice cooling. The reaction mixture was stirred at room temperature for 4 hours. To the reaction mixture, an aqueous 1N sodium hydroxide solution (30 mL) was added. The aqueous layer was extracted twice with dichloromethane (50 mL). The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel chromatography (ethyl acetate:methanol=1:0→10:1) to obtain the title compound (977 mg) having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH:30]1([CH2:36][CH2:37]O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.Cl.[K+].[Br-]>C(Cl)(Cl)Cl>[CH:30]1([CH2:36][CH2:37][O:24][C:23]([C:18]2([C:20]([O:22][CH2:9][CH2:8][CH:4]3[CH2:5][CH2:6][CH2:7][CH2:2][CH2:3]3)=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: OCCC1CCCCC1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccc2c(c1)OC(C(=O)OCCC1CCCCC1)(C(=O)OCCC1CCCCC1)O2)NCC(O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-cyclohexylethanol according to the procedure of Example 30 as an off-white foam (HCl salt); 1H NMR (CDCl3) δ 0.80-1.80 (m, 26H), 1.32 (d, J=6.3 Hz, 3H), 2.80 (m, 1H), 3.18 (m, 2H), 3.48 (m, 2H), 4.32 (t, J=6.9 Hz, 4H), 5.45 (bd, J=9.7 Hz, 1H), 6.80 (m, 3 H), 7.25 (m, 2H), 7.45 (s, 1H), 8.70 (bs, 1H), 10.0 (bs, 1H); IR (KBr): 1765 cm-1 (C=O); MS (CI) m/z 642 (MH+); [α]D25 -24° (c, 1.0, CHCl3). Anal. Calcd. for C36H48ClNO7 ·HCl: C, 63.71; H, 7.13; N, 2.06; Cl, 10.45. Found: C, 63.07; H, 7.54; N, 2.07; Cl, 12.81.
Reaction SMILES: [Cl-].[C:2]1([I+:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:15]([Si](C)(C)C)[S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17]>C(Cl)Cl>[O-:18][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:17])=[O:15].[C:9]1([I+:8][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Cl-]
Agent: c1ccc([I+]c2ccccc2)cc1
Solvent: ClCCl
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 22 °C

Procedure:
Into a 500 mL flask was placed 300 mL of distilled methylene chloride (distilled from P2O5) and 5.0 g (16 mmol) of commercial diphenyliodonium chloride (Aldrich Chemical Co.). The heterogeneous mixture was stirred vigorously in a water bath at 22° C. and 3.19 ml (3.91 g, 17.6 mmol) of trimethylsilyl triflate was added. The solid dissolved almost immediately but a precipitate reappeared after 5 m. The reaction was stirred for 15 h and the solvent removed on the rotary evaporator. The residue was triturated with ether to yield 6.5 g (96%) of the iodonium triflate 1 (mp 165°-8° C.). The material tested negative for chloride with silver nitrate-ethanol. The aryl iodonium triflates 3 and 4 were produced in a similar fashion.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.FC(F)(F)S(O[Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])(=O)=O.O>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([O:13][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[C:9]([F:11])([F:12])[F:10])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: OC(c1ccnc(Br)c1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(c1ccnc(Br)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 9.5 h
Yield: 89.1 %

Procedure:
In dichloromethane (50 mL) was dissolved 1-(2-bromopyridin-4-yl)-2,2,2-trifluoroethanol (5.00 g, 19.5 mmol) obtained in Step 1. Triethylamine (10.2 mL, 73.2 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (7.41 mL, 32.3 mmol) were added under ice-cooling and the mixture was stirred at room temperature for 9.5 hours. Water was added to the reaction mixture. Extraction with ethyl acetate and drying over anhydrous magnesium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give 2-bromo-4-(1-(tert-butyldimethylsilyloxy)-2,2,2-trifluoroethyl)pyridine (6.43 g, 89% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH:14](=O)[CH:15]([CH3:17])[CH3:16].[BH3-]C#N.[Na+]>>[CH2:14]([N:8]1[C:7]2[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[O:11][CH2:10][CH2:9]1)[CH:15]([CH3:17])[CH3:16]
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2
Reactant: CC(C)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)CN1CCOc2cc([N+](=O)[O-])ccc21
Yield: 100.6 %

Procedure:
This compound was prepared by General Method 3 (EXAMPLE 1) from 3,4-dihydro-7-nitro-2H-1,4-benzoxazine (EXAMPLE 1) (550 mg, 3.0 mmol), isobutyraldehyde (1.65 g, 22.8 mmol) and NaBH3CN (959 mg, 15 mmol) to afford 713 mg (99%) of 3,4-dihydro-4-isobutyl-7-nitro-2H-1,4-benzoxazine, an yellow solid. Data for 3,4-dihydro-4-isobutyl-7-nitro-2H-1,4-benzoxazine: Rf 0.75 (3:2 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 7.78 (dd, 1H, J=9.0, 2.6), 7.66 (d, 1H, J=2.6), 6.55 (d, 1H, J=9.2), 4.21 (t, 2H, J=4.5), 3.52 (t, 2H, J=4.6), 3.16 (d, 2H, J=7.4), 3.12 (hept, 1H, J=6.9), 0.97 (d, 6H, J=6.7).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[NH2:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:39])=[C:36]([OH:38])[CH:37]=1>C1COCC1>[OH:38][C:36]1[CH:37]=[C:32]([NH:31][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]5[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])[CH:33]=[CH:34][C:35]=1[CH3:39]
Reactant: Cc1ccc(N)cc1O
Reactant: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)n(C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(C)c(O)c3)cc2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 54 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 25, 100 mg, 0.248 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methylphenol (33.7 mg, 0.248 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 54% (68 mg, 0.134 mmol) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][C:10]2[C:11](C(N)=O)=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].Br[N:27]1C(=O)CCC1=O.[OH-].[Na+]>CO.O.[NH4+].[Cl-]>[CH2:1]([C:3]1[C:8]([O:9][C:10]2[C:11]([NH2:27])=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1ncccc1Oc1cc(Sc2ccccn2)cnc1C(N)=O
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCc1ncccc1Oc1cc(Sc2ccccn2)cnc1N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.6 %

Procedure:
3-(2-Ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinamide (71 g, 201 mmol) was dissolved in MeOH (1 L). 1-Bromopyrrolidine-2,5-dione (46.6 g, 262 mmol) was added and the reaction was stirred at ambient temperature for 5 minutes and then cooled in an ice bath. Sodium hydroxide (41.9 g, 1048 mmol) dissolved in water (200 mL) was added slowly and the reaction was stirred at ambient temperature for 1 hour, refluxed for 8 hours and then cooled to ambient temperature overnight. The reaction was diluted with 2.5 L water and 0.5 L NH4Cl and stirred for 30 minutes. The precipitate was filtered and dried to afford 3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (52.6 g, 162 mmol, 80.5% yield) as a tan solid.
Reaction SMILES: Cl[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[CH3:17][CH:18]([NH2:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:20][CH:18]([CH3:19])[CH3:17])[O:8][C:7]=2[CH:9]=1)(=[O:15])=[O:14]
Reactant: CC(C)N
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CCl)OC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)NCC1OCc2ccc(S(C)(=O)=O)cc2O1
Temperature: 25 °C
Yield: 56.3 %

Procedure:
A mixture of 2-(chloromethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (0.1 g, 0.38 mmol), propan-2-amine (1.30 ml, 152 mmol), potassium carbonate (80 mg, 0.57 mmol), some few crystals of sodium iodide in ACN (3 ml) was heated in a micro wave oven at 170° C. for 40 min. After cooling to ambient temperature the volatiles were evaporated in vacuum. The oily residue was chromatographed twice on a silica column with EtOAc/MeOH (7:1) as eluent. Collection of the fractions containing pure product and evaporation of the solvent afforded the title compound (61 mg, 55%). MS m/z (rel. intensity, 70 eV) 285 (M+, 1), 123 (11), 86 (15), 77 (16), 72 (bp).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][OH:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1>O1CCCC1.CN(C)C=O>[CH2:10]([O:11][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[CH2:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCCCCCCCCCOC1CCCCO1
Reactant: OCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1ccc(CCOCCCCCCCCCOC2CCCCO2)cc1
Reaction time: 16 h
Yield: 39 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 264 mg, 6.6 mmol) was added at 0° C. to a solution of 2-phenylethanol (807 mg, 6.61 mmol) in tetrahydrofuran (8.6 mL) and N,N-dimethylformamide (3.4 mL), then after 1 h a solution of 2-(9-bromo-nonyloxy)-tetrahydro-pyran (2.44 g, 7.93 mmol) in N,N-dimethylformamide (1.5 mL) was added dropwise. The solution was allowed to reach room temperature over 16 h, then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) produced 2-(9-phenethyloxy-nonyloxy)-tetrahydro-pyran (898 mg, 39%). Colorless oil, m/e=366.2 ([M+NH4]+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[C:33]2[S:37][CH3:38])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:20])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N:32]4[CH:36]=[CH:35][N:34]=[C:33]4[S:37][CH3:38])[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CSc1nccn1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(N(C)C)cc2NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1nccn1-c1cccc(C2=Nc3cc(N(C)C)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (5-dimethylamino-2-{3-[3-(2-methylsulfanyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example M62) (450 mg, 0.78 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (253 mg).
Reaction SMILES: [C:1]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[P:20](Cl)([O:37][C:38]1[C:43]([C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:42][C:41]([CH3:48])=[CH:40][C:39]=1[C:49]([CH3:52])([CH3:51])[CH3:50])[O:21][C:22]1[C:27]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:26][C:25]([CH3:32])=[CH:24][C:23]=1[C:33]([CH3:36])([CH3:35])[CH3:34].Cl>O1CCCC1.C(#N)C>[P:20]([O:17][C:14]1[CH:13]=[CH:12][C:11]([C:1]([C:4]2[CH:5]=[CH:6][C:7]([O:10][P:20]([O:37][C:38]3[C:39]([C:49]([CH3:52])([CH3:51])[CH3:50])=[CH:40][C:41]([CH3:48])=[CH:42][C:43]=3[C:44]([CH3:47])([CH3:46])[CH3:45])[O:21][C:22]3[C:23]([C:33]([CH3:34])([CH3:35])[CH3:36])=[CH:24][C:25]([CH3:32])=[CH:26][C:27]=3[C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:8][CH:9]=2)([CH3:3])[CH3:2])=[CH:16][CH:15]=1)([O:37][C:38]1[C:43]([C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:42][C:41]([CH3:48])=[CH:40][C:39]=1[C:49]([CH3:52])([CH3:51])[CH3:50])[O:21][C:22]1[C:27]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:26][C:25]([CH3:32])=[CH:24][C:23]=1[C:33]([CH3:36])([CH3:35])[CH3:34]
Reactant: Cc1cc(C(C)(C)C)c(OP(Cl)Oc2c(C(C)(C)C)cc(C)cc2C(C)(C)C)c(C(C)(C)C)c1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1cc(C(C)(C)C)c(OP(Oc2ccc(C(C)(C)c3ccc(OP(Oc4c(C(C)(C)C)cc(C)cc4C(C)(C)C)Oc4c(C(C)(C)C)cc(C)cc4C(C)(C)C)cc3)cc2)Oc2c(C(C)(C)C)cc(C)cc2C(C)(C)C)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
A solution of 0.9 grams of 4,4'-isopropylidenebisphenol (0.004 mol) in 50 ml of dry tetrahydrofuran was added to a reaction vessel equipped with stirring and heating means. While stirring the 4,4'-isopropylidenebisphenol solution under nitrogen, 0.19 gram (0.008 mol) of sodium hydride, as a 50 weight percent dispersion mineral oil was added to the 4,4-isopropylidenebisphenol solution and the resulting mixture was stirred at 55° C. for one hour. The reaction mixture was cooled to room temperature and a solution of bis(2,6-di-t-butyl-4-methylphenyl) phosphorochloridite (4.0 grams, 0.008 mol) in 25 ml of tetrahydrofuran was added to the reaction mixture and the mixture was stirred for three hours. The reaction product was then acidified with 1N HCl and filtered. The filtrate was heated to remove the solvent, and an oily reaction product was obtained. This oil was stirred with 50 ml of acetonitrile for one hour. The resulting white powder was recovered by filtration and dried. The product yield of tetrakis(2,6-di-t-butyl-4-methylphenyl)-4,4'-isopropylidenebisphenyl diphosphite was 3.72 grams. The molecular weight, FD/MS was 1164. NMR data obtained was, (CDCl3): 1.44 (S, 72H), 2.23 (S, 12H), 6.01 (d, J=8.4, 4H), 6.69 (d, J=8.4, 4H), 7.02 (S,8H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]2[C:20](O)=[O:21])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.ClC(OCC)=O.[CH2:36]([NH:38][CH:39]([CH3:41])[CH3:40])[CH3:37]>O1CCCC1>[CH2:36]([N:38]([CH:39]([CH3:41])[CH3:40])[C:20]([C:12]1[N:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:19]2[C:14]([CH:13]=1)=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:21])[CH3:37]
Reactant: CCNC(C)C
Reactant: COc1ccc(-n2c(C(=O)O)cc3ccccc32)cc1OC
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(C(=O)c1cc2ccccc2n1-c1ccc(OC)c(OC)c1)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-(3,4-Dimethoxyphenyl)indole-2-carboxylic acid (2.0 g, 6.8 mmol) was stirred in tetrahydrofuran (10 ml). Triethylamine (1 ml, 7.5 mmol) was added and the mixture was cooled to 0° C. Ethyl chloroformate (0.7 ml, 7 mmol) was added dropwise, followed by stirring for 30 minutes. N-ethyl isopropylamine (0.6 g, 7 mmol) in tetrahydrofuran was added, followed by stirring for 30 minutes and refluxing for 6 hours. The tetrahydrofuran was evaporated in vacuo, and the residue was dissolved in toluene. The toluene solution was washed with water, dried, evaporated in vacuo, applied onto a flash chromatography column (silica gel, 30 g) and eluted with toluene/acetone (9.5:0.5). The desired fractions were concentrated and the residue triturated with diisopropyl ether to give 1-(3,4-dimethoxyphenyl)indole-2-carboxylic acid N-ethyl isopropyl amide as white crystals which were then filtered and dried. Yield: 50 mg (2% of theoretical). Rf : 0.53 (toluene/acetone 7:3). The H-NMR spectra was consistent with the assigned structure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:12]([CH3:14])([CH3:13])[N:11]([O:15]CC2C=CC=CC=2)[C:10]1=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:12]([CH3:14])([CH3:13])[N:11]([OH:15])[C:10]1=[O:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N(OCc2ccccc2)C1(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1C(=O)N(O)C1(C)C
Yield: 100.4 %

Procedure:
(±)-3-[(t-Butyloxycarbonyl)amino]-4,4-dimethyl-1-(phenylmethoxy)-2-azetidinone (8.07 g, 25 mmol) was hydrogenated at atmospheric pressure and ambient temperature in 40 ml of methanol with 0.6 g of 10% palladium on charcoal as catalyst for 2 hours. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated to yield 5.78 g of the title compound as a solid.