Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].OC1C=C(N[C:23]2[C:28]3=[CH:29][C:30](C)=[CH:31][N:27]3[N:26]=[CH:25][N:24]=2)C=CC=1C>C(O)(C)C.C(Cl)Cl>[N:26]1[N:27]2[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]([NH:13][C:10]2[CH:11]=[C:12]3[C:7]([CH2:6][CH2:5][N:4]3[C:1](=[O:3])[CH3:2])=[CH:8][CH:9]=2)=[N:24][CH:25]=1
Reactant: CC(=O)N1CCc2ccc(N)cc21
Reactant: Cc1cc2c(Nc3ccc(C)c(O)c3)ncnn2c1
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(=O)N1CCc2ccc(Nc3ncnn4cccc34)cc21
Yield: 4 %

Procedure:
Example 10 was prepared as a white solid in 4% yield from Compound A of Example 1 and 1-acetyl-6-aminoindoline as described for Compound B of Example 1, using 10% isopropanol/methylene chloride for extraction, and with purification by chromatography on silica gel with ethyl acetate. (M+H)+=294.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:10]1([N:13]2[C:21]3[C:16](=[CH:17][C:18]([CH2:22][NH:23][S:24]([C:27]4[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][C:28]=4[CH3:37])(=[O:26])=[O:25])=[CH:19][CH:20]=3)[CH:15]=[N:14]2)[CH2:12][CH2:11]1>>[CH:10]1([N:13]2[C:21]3[C:16](=[CH:17][C:18]([CH2:22][N:23]([C:3]4[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=4)[S:24]([C:27]4[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][C:28]=4[CH3:37])(=[O:26])=[O:25])=[CH:19][CH:20]=3)[CH:15]=[N:14]2)[CH2:12][CH2:11]1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(cnn3C3CC3)c2)c(C)c1
Reactant: Fc1ncc(Cl)cc1Cl
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(cnn3C3CC3)c2)c2ncc(Cl)cc2Cl)c(C)c1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 3,5-dichloro-2-fluoropyridine and methyl 4-(N-((1-cyclopropyl-1H-indazol-5-yl)methyl)sulfamoyl)-3-methylbenzoate (step-2 of Example 33).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][C:25]1=[O:29]>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:24]4[CH2:28][CH2:27][CH2:26][C:25]4=[O:29])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C1CCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3)CC2)c(C)c1

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (568 mg) described in Preparation Example 113 and pyrrolidin-2-one (0.12 mL) and by the reaction and treatment in the same manner as in Example 1, the title compound (427 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:43][S:40]([C:37]3[CH:36]=[CH:35][C:34]([C:33]([F:32])([F:45])[F:44])=[CH:39][CH:38]=3)(=[O:41])=[O:42])=[O:24])=[CH:16][CH:15]=2)[N:3]=1
Reactant: NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(C(F)(F)F)cc3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 4-(trifluoromethyl)benzenesulfonamide: 1H-NMR (CDCl3) δ 8.06 (2H, d, J=7.7 Hz), 7.80 (2H, d, J=8.2 Hz), 7.47-7.21 (9H, m), 6.10 (1H, br.s), 3.50-3.43 (2H, m), 2.86 (2H, t, J=6.3 Hz), 2.32 (3H, s), 2.23 (3H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]1[N:12]=[N:13][N:14]([C:16]2[CH:32]=[CH:31][C:19]([C:20]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]3)=[O:21])=[CH:18][CH:17]=2)[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH3:30][N:28]([CH3:29])[CH:25]1[CH2:26][CH2:27][N:22]([C:20](=[O:21])[C:19]2[CH:31]=[CH:32][C:16]([N:14]3[CH:15]=[C:11]([C:5]4[C:4]5[C:8](=[CH:9][CH:10]=[C:2]([CH:3]=[C:4]([CH3:8])[CH3:5])[CH:3]=5)[NH:7][N:6]=4)[N:12]=[N:13]3)=[CH:17][CH:18]=2)[CH2:23][CH2:24]1
Reactant: CN(C)C1CCN(C(=O)c2ccc(-n3cc(-c4n[nH]c5ccc(Br)cc45)nn3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)=Cc1ccc2[nH]nc(-c3cn(-c4ccc(C(=O)N5CCC(N(C)C)CC5)cc4)nn3)c2c1
Temperature: 80 °C
Yield: 90.5 %

Procedure:
A mixture of 1-{4-[4-(5-bromo-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoyl}-N,N-dimethylpiperidin-4-amine (160 mg; 0.32 mmol; 1.0 eq.), 1-{4-[4-(5-bromo-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoyl}-N,N-dimethylpiperidin-4-amine (160 mg; 0.32 mmol; 1.0 eq.), PdCl2dppf (24 mg; 0.03 mmol; 0.1 eq.) and potassium carbonate (224 mg; 1.62 mmol; 5.0 eq.) in dioxane (1 mL) and water (1 mL) was heated at 80° C. O/N in a sealed tube. The reaction mixture was then filtered through a celite pad and filtrate was extracted twice with DCM. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM:MeOH, gradient form 90:10 to 50:50) gave the title compound as a brown powder (68 mg, 45%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26]>CN(C=O)C>[C:15]([C:7]1[C:8]([C:11]([F:12])([F:14])[F:13])=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])[C:2]([CH3:1])=[CH:10]2)#[N:16]
Reactant: COC(=O)C(C)Br
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)n1c(C)cc2c(C(F)(F)F)c(C#N)ccc21
Temperature: 90 °C
Yield: 100.9 %

Procedure:
A mixture of 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (see, for example, US2008139631A1) (0.300 g, 1.338 mmol), cesium carbonate (0.654 g, 2.007 mmol) and methyl 2-bromopropanoate (0.223 mL, 2.007 mmol) in DMF (3 mL) was heated at 90° C. for 1 h. Upon cooling, the reaction mixture was partitioned between Et2O (30 mL) and water (25 mL). The organic phase was washed with water (20 mL) and brine (10 mL). The combined aqueous phases were washed with Et2O (2×25 ml). The organic phases were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel eluting with 5-40% EtOAc-hexane gradient to give methyl 2-[5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]propanoate (0.419 g, 94% yield): MS (ESI): m/z 311 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:17]>C(Cl)(Cl)Cl>[CH3:11][O:10][C:8]([C:3]1[C:2]([CH3:1])=[N+:7]([O-:17])[CH:6]=[CH:5][N:4]=1)=[O:9]
Reactant: COC(=O)c1nccnc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ncc[n+]([O-])c1C
Temperature: 70 °C

Procedure:
In a 1-L flask, the methyl 3-methylpyrazine-2-carboxylate (step 1, 16.08 g, 106 mmol) was suspended in CHCl3 (300 mL). 3-chlorobenzoperoxoic acid (Aldrich, 24.62 g, 143 mmol) was added. The reaction mixture was heated to 70° C. for 16 h. The reaction mixture was quenched with saturated NaHCO3 (200 mL). The layers were separated, and the aqueous layer was further extracted with DCM (2×100 mL). The combined organic layers were dried over MgSO4, and the filtrate was concentrated to afford the title compound. MS m/z=169 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[Br:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1>>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([O:29][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:33][CH:32]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Reactant: Oc1ccc(Br)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(Br)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-bromophenol: ESMS m/e: 553.0 (M+H)+.
Reaction SMILES: Cl.Cl.[C:3]([NH:7][C:8](=[O:22])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:10]=1)([CH3:6])([CH3:5])[CH3:4].C(N(C(C)C)C(C)C)C.[N+:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)([O-:34])=[O:33]>ClCCl>[C:3]([NH:7][C:8](=[O:22])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:39](=[O:40])[C:38]3[CH:37]=[CH:36][C:35]([N+:32]([O-:34])=[O:33])=[CH:43][CH:42]=3)[CH2:20][CH2:21]2)[CH:10]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1
Reaction time: 0.17 h
Yield: 94.9 %

Procedure:
N-tert-Butyl-3-(piperazin-1-ylmethyl)benzamide dihydrochloride (0.50 g, 1.44 mmol) was suspended in stirred dichloromethane (20 mL) at 0° C. (ice-bath) under an argon atmosphere. N-ethyl-N-isopropylpropan-2-amine (1.0 mL, 5.75 mmol) was added slowly. After 10 minutes stirring, the resulting solution was treated with a suspension of 4-nitrobenzoyl chloride (0.267 g, 1.44 mmol) In dichloromethane (10 ml). The ice-bath was removed and stirring continued for 1 hour. The solution was diluted with dichloromethane (70 mL) and washed with water (×4). The organic phase was dried on magnesium sulfate, filtered and concentrated under vacuum to give the title compound (0.58 g) as a yellow foam.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][CH2:10][NH:11][CH3:12])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][NH:31][CH:32]=2)O1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:29]=[N:30][NH:31][CH:32]=3)=[CH:3][CH:4]=2)[CH2:9][CH2:10][NH:11][CH3:12])=[CH:14][CH:15]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CNCCC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Product: CNCCC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1

Procedure:
[3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propyl]-methyl-amine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-B3) Rt 2.63 [M+H]+ 326.00. 1H NMR (Me-d3-OD) δ 237-2.47 (2H, m), 2.66 (3H, s), 2.91 (2H, t), 4.05 (1H, t), 7.25-7.34 (6H, m), 7.54 (2H, d), 7.92 (2H, s), 8.51 (1H, br s—due to formic acid).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]([NH:32][C:33](=[O:35])[CH3:34])([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:14])[CH3:13])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.C([SiH](CC)CC)C>[C:1]([O:4][CH2:5][CH2:6][C:7]([NH:32][C:33](=[O:35])[CH3:34])([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:14])[CH3:13])(=[O:3])[CH3:2]
Reactant: CCCCCCCC(=O)c1ccc(CCC(CCCOC(C)=O)(CCOC(C)=O)NC(C)=O)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCc1ccc(CCC(CCCOC(C)=O)(CCOC(C)=O)NC(C)=O)cc1
Temperature: 0 °C
Yield: 64.3 %

Procedure:
To a solution of 3-acetamido-6-acetoxy-3-[2-(4-octanoylphenyl)ethyl]hexyl acetate (720 mg) in trifluoroacetic acid (15 ml), triethylsilane (0.53 ml) was added at room temperature. After stirring for an hour, the reaction solution was poured into ice-water and potassium carbonate was carefully added to the mixture to neutralize. The mixture was extracted with ethyl acetate and the extract was washed with water and a saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled away and the residue obtained was purified by silica gel chromatography (eluent; hexane-ethyl acetate=1:1) to give the subject compound (450 mg) as a colorless oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:42][C:43](O)=[O:44])[CH:28]=[CH:29][C:30]=1[NH:31][C:32]([NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH3:41])=[O:33].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>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:43](=[O:44])[CH2:42][C:27]3[CH:28]=[CH:29][C:30]([NH:31][C:32]([NH:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[CH3:41])=[O:33])=[C:25]([O:24][CH3:23])[CH:26]=3)=[CH:17][CH:16]=2)[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)[CH3:2]
Reactant: CCOC(=O)CC1(c2ccc(N)cc2)Cc2ccccc2C1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(c2ccc(NC(=O)Cc3ccc(NC(=O)Nc4ccccc4C)c(OC)c3)cc2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
A solution of [2-(4-amino-phenyl)-indan-2-yl]-acetic acid ethyl ester (0.158 g, Reference Example 10) in dimethylformamide (2 mL) was treated with a solution of [3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetic acid (0.169 g) in dimethylformamide (2 mL) which had been treated with diisopropylethylamine (1.3 mL) and a solution of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.223 g) in dimethylformamide (2 mL). After stirring at room temperature for 2 hours the reaction mixture was evaporated and the residue was partitioned between ethyl acetate (30 mL) and hydrochloric acid (30 mL, 0.5N). The organic phase was washed with hydrochloric acid (30 mL, 0.5N), then with saturated sodium hydrogen carbonate solution (30 mL), then dried over magnesium sulfate and then evaporated. The residual beige coloured solid was subjected to chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane (2:1, v/v) to give the title compound (0.06 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1>ClCCl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
Pyridinium p-toluenesulfonate (7.65 g, 30.45 mmol) was added to a clear solution of methyl 3-hydroxypropanoate (63.4 g, 609.00 mmol) and 3,4-dihydro-2H-pyran (78 mL, 852.60 mmol) in dichloromethane (650 mL) at room temperature under nitrogen to give a cloudy solution. This was allowed to stir at room temperature overnight. The reaction mixture was washed with water (250 mL) and brine (250 mL) before drying (MgSO4) and evaporating to an oil. This crude product was purified by flash silica chromatography, elution gradient 15 to 30% EtOAc in heptane. Pure fractions were evaporated to dryness to afford methyl 3-(tetrahydro-2H-pyran-2-yloxy)propanoate (67.7 g, 59.0%) as a colourless oil: 1H NMR Spectrum: (CDCl3) 1.47 (4H, dddd), 1.55-1.84 (2H, m), 2.55 (2H, t), 3.33-3.53 (1H min), 3.53-3.7 (4H, n), 3.78 (1H, ddd), 3.93 (1H, dt), 4.42-4.72 (1H, m); Mass Spectrum [MH]+=189.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][C:4]=1[C:13]([F:16])([F:15])[F:14])[CH3:2].[Br:17][C:18]1[C:23]([NH2:24])=[CH:22][C:21]([Cl:25])=[CH:20][N:19]=1>N1C=CC=CC=1>[Br:17][C:18]1[C:23]([NH:24][S:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:5]=2)(=[O:11])=[O:10])=[CH:22][C:21]([Cl:25])=[CH:20][N:19]=1
Reactant: Nc1cc(Cl)cnc1Br
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1C(F)(F)F
Solvent: c1ccncc1
Product: CCc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2Br)cc1C(F)(F)F

Procedure:
Prepared from 1.04 g (3.82 mmol) of 4-ethyl-3-trifluoromethyl-benzenesulfonyl chloride and 0.87 g (4.20 mmol) of 2-bromo-5-chloro-pyridin-3-ylamine in 3 mL pyridine using procedure x. Yield: 0.45 g of a white solid. LC-MSD, m/z for C14H11BrClF3N2O2S [M+H]+=442.9, 444.9, 446.9
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([I:29])=[N:23][C:24]=2Cl)(=[O:3])[CH3:2].Cl.[CH3:31][O:32][NH2:33].C(N(CC)CC)C>O1CCCC1>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([I:29])=[N:23][C:24]=2[NH:33][O:32][CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CON
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CONc1nc(I)nc2c1ncn2[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
(2R,3R,4R,5R)-4-acetyloxy-5-(acetyloxymethyl)-2-(6-chloro-2-iodopurin-9-yl)oxolan-3-yl acetate (3.71 mmol) in dry tetrahydrofuran (60ml) was mixed with O-methyl hydroxylamine hydrochloride (37.1 mmol) and triethylamine (6.2 mL). The mixture was stirred at room temperature for 96 hours under an atmosphere of nitrogen. The solvent was removed in vacuo and the residue chromatographed on a flash silica gel column eluting with CHCl3—CH3OH (99:1), to give (2R,3R,4R,5R)-4-acetyloxy-5-(acetyloxymethyl)-2-[2-iodo-6-(methoxyamino)purin-9-yl]oxolan-3-yl acetate, a compound of formula (4), which was crystallized from a mixture of chloroform/hexanes (1:1).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6](O)[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:46])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38]S(C)(=O)=O)[C:24]=1[CH2:43][CH2:44][CH3:45])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:15]([O:17][C:18](=[O:46])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:24]=1[CH2:43][CH2:44][CH3:45])[CH3:16]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCOCCOc2c(C(C)=O)ccc(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 17.7 %

Procedure:
A mixture of 1 g (0.0052 mol) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.45 g (0.0052 mol) of 4-[4-acetyl-3-[2-[2-[(methylsulfonyl)oxy]ethoxy]-ethoxy]-2-propylphenoxy]butanoic acid ethyl ester and 2.6 g (0.019 mol) of anhydrous potassium carbonate in 100 ml of anhydrous acetone and 50 ml of anhydrous dimethylformamide was stirred at reflux for 19 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil which was treated with ethyl acetate and sodium chloride solution. The organic phase was washed with 1N sodium hydroxide solution and sodium chloride solution. The yellow oil obtained on concentration of the ethyl acetate was purified by column chromatography, eluting with 5% ethyl acetate-toluene to yield 0.526 g (18% yield) of 4-[4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester as a pale yellow oil.
Reaction SMILES: [CH2:1]([NH:9][C:10]([C@@H:12]1[CH2:14][C@H:13]1[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:22]1(=[O:28])[O:27][C:25](=[O:26])[CH:24]=[CH:23]1>C1C=CC=CC=1>[CH2:1]([NH:9][C:10]([C@@H:12]1[CH2:14][C@H:13]1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:28])/[CH:23]=[CH:24]\[C:25]([OH:27])=[O:26])=[CH:17][CH:16]=1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCCCCCCNC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1
Solvent: c1ccccc1
Product: CCCCCCCCNC(=O)[C@@H]1C[C@H]1c1ccc(NC(=O)/C=C\C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a refluxing solution of 1.6 g. of trans-N-octyl-2-(4-aminophenyl)cyclopropanecarboxamide in 30 ml. of benzene was added 598 mg. of maleic anhydride all at once. Refluxing was continued for 10 minutes, and then the reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was recrystallized twice from ethanol to give 930 mg. of the title compound as a white solid, m.p. 178.5°-179.5° C. The IR spectrum (KBr disc) showed absorptions at 3280, 2925, 1725, 1640 and 1550 cm-1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[C:15]2[O:14][CH2:13][CH2:12][C:11]=2[C:10]([OH:16])=[CH:9][CH:8]=1)[CH3:2].Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH:36]([CH3:38])[CH3:37])=[CH:31][CH:30]=2)[O:26][C:27]=1[CH3:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[C:15]2[O:14][CH2:13][CH2:12][C:11]=2[C:10]([O:16][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH:36]([CH3:38])[CH3:37])=[CH:31][CH:30]=3)[O:26][C:27]=2[CH3:28])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c2c1OCC2)OCC
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(OC(C)C)cc3)oc2C)c2c1OCC2)OCC

Procedure:
In analogy to the procedure described in example 120 f], [rac]-2-ethoxy-3-(4-hydroxy-2,3-dihydro-benzofuran-7-yl)-propionic acid ethyl ester (example 125 a]) was reacted with 4-chloromethyl-2-(4-isopropoxy-phenyl)-5-methyl-oxazole (example 124 a]) in the presence of potassium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,3-dihydro-benzofuran-7-yl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,3-dihydro-benzofuran-7-yl}-propionic acid as white solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
Sodium hydride, 80% dispersion in oil (0.14 g, 4.8 mmoI) was added to a solution of 1-(tert-butoxycarbonyl)-4-hydroxypiperidine (1.0 g, 4.8 mmol) [prepared from 4-hydroxypiperidine and di-tert-butyl dicarbonate] in dimethylformamide (30 ml) and the mixture stirred for 30 minutes. Benzyl bromide (0.68 ml, 5.7 mmol) was added and the reaction mixture stirred overnight. The mixture was poured into water and extracted with dichloromethane. The extracts were washed with water and brine, dried (MgSO4) and the residue after evaporation purified by flash chromatography eluting with 0-20% ethyl acetate in hexane to give 1-(tert-butoxycarbonyl)-4-benzyloxypiperidine (1.1 g, 94% ); δH (CDCl3) 1.39 (9H, s, C(CH3)3), 1.82 (2H, m, piperidinyl. H), 3.04 (2H, m, piperidinyl H), 3.59 (3H, m, piperidinyl H), 4.51 (2H, s, OCH2Ph), 7.24-7.39 (5H, m, PhH).