Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@:2]1([C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C:20](=[CH:21][CH2:22]2)[C@:18]2([CH3:19])[C@H:13]([CH2:14][C:15](=[O:25])[CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][C@@H:7]1[CH3:26])[C:3](=[O:6])[CH2:4][OH:5].[OH:27][C@:28]1([C@:49]2([CH3:50])[C@H:35]([C@H:36]3[C:46](=[CH:47][CH2:48]2)[C@:44]2([CH3:45])[C@H:39]([CH2:40][C:41](=[O:51])[CH2:42][CH2:43]2)[CH2:38][CH2:37]3)[CH2:34][C@H:33]1C)[C:29](=[O:32])[CH2:30][OH:31].[OH:53][C@:54]1([C@:75]2([CH3:76])[C@H:61]([C@H:62]3[C:72](=[CH:73][CH2:74]2)[C@:70]2([CH3:71])[C@H:65]([CH2:66][C:67](=[O:77])[CH2:68][CH2:69]2)[CH2:64][CH2:63]3)[CH2:60][CH2:59]1)[C:55](=[O:58])[CH2:56][OH:57]>>[OH:1][C@:2]1([C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C:20](=[CH:21][CH2:22]2)[C@:18]2([CH3:19])[C@H:13]([CH2:14][C:15](=[O:25])[CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][C@@H:7]1[CH3:26])[C:3](=[O:6])[CH2:4][OH:5].[OH:27][C@:28]1([C@:49]2([CH3:50])[C@H:35]([C@H:36]3[C:46](=[CH:47][CH2:48]2)[C@:44]2([CH3:45])[C@H:39]([CH2:40][C:41](=[O:51])[CH2:42][CH2:43]2)[C@@H:38]([CH3:54])[CH2:37]3)[CH2:34][CH2:33]1)[C:29](=[O:32])[CH2:30][OH:31].[OH:53][C@:54]1([C@:75]2([CH3:76])[C@H:61]([C@H:62]3[C:72](=[CH:73][CH2:74]2)[C@:70]2([CH3:71])[C@H:65]([CH2:66][C:67](=[O:77])[CH2:68][CH2:69]2)[CH2:64][CH2:63]3)[CH2:60][CH2:59]1)[C:55](=[O:58])[CH2:56][OH:57]
Reactant: C[C@@H]1C[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)C3=CC[C@]2(C)[C@@]1(O)C(=O)CO
Agent: C[C@H]1C[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)C3=CC[C@]2(C)[C@@]1(O)C(=O)CO
Agent: C[C@]12CC=C3[C@@H](CC[C@H]4CC(=O)CC[C@]34C)[C@@H]1CC[C@]2(O)C(=O)CO
Product: C[C@H]1C[C@@H]2C(=CC[C@@]3(C)[C@H]2CC[C@]3(O)C(=O)CO)[C@@]2(C)CCC(=O)C[C@H]12

Procedure:
Following the general procedure of Example 282 and making non-critical variations but starting with the 17-butyrate esters of 17α,21-dihydroxy-16β-methyl-5α-pregn-9(11)-ene-3,20-dione, 17α,21-dihydroxy-16α-methyl-5α-pregn-9(11)-ene-3,20-dione or 17α,21-dihydroxy-5α-pregn-9(11)-ene-3,20-dione (Examples 192, 197 and 202) the corresponding 17,21-diesters, namely the 17-butyrate 21-acetate diesters of 17α,21-dihydroxy-16β-methyl-5α-pregn-9(11)-ene-3,20-dione, 17α,21-dihydroxy-6α-methyl-5α-pregn-9(11)-ene-3,20-dione, or 17α,21-dihydroxy-5α-pregn-9(11)-ene-3,20-dione are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:13])[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12].Br[CH2:15][CH2:16][Si:17]([CH2:20][CH2:21]Br)([CH3:19])[CH3:18].CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH3:18][Si:17]1([CH3:19])[CH2:20][CH2:21][N:1]([CH2:2][CH2:3][NH:4][C:5](=[O:13])[CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH2:15][CH2:16]1
Reactant: C[Si](C)(CCBr)CCBr
Reactant: NCCNC(=O)CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: C[Si]1(C)CCN(CCNC(=O)CN2CCCC2=O)CC1
Yield: 15 %

Procedure:
A mixture of 1.90 g (10.3 mmol) of N-(2-aminoethyl)-2-oxo-1-pyrrolidineacetamide, 2.76 g (10.1 mmol) of bis(2-bromoethyl)dimethylsilane, 5.20 g of Huenig base, and 20 ml of chloroform was stirred and then the solvent was removed in vacuo. The resulting mixture was heated at 100°-105° C. for 8 hours. Aqueous NaHCO3 was added to the cooled reaction mixture, and the aqueous solution was extracted with chloroform. The dried chloroform solution was concentrated in vacuo and chromatographed on silica gel column to afford 450 mg (Yield: 15.0%) of the desired compound.
Reaction SMILES: [CH3:1][CH:2]([N:4]([CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[C:5]([NH2:7])=[O:6])[CH3:3].[C:18](Cl)(=[O:20])[CH3:19]>C(N(CC)CC)C>[CH3:5][N:4]([CH3:8])[CH2:2][CH2:1][NH:7][C:5](=[O:6])[N:4]([CH:2]([CH3:1])[CH3:3])[CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:20])[CH3:19])=[CH:15][CH:16]=1
Reactant: CC(=O)Cl
Reactant: CC(C)N(CCOc1ccc(N)cc1)C(N)=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(OCCN(C(=O)NCCN(C)C)C(C)C)cc1

Procedure:
The title compound is prepared by reacting the compound of Example 64: N'-[2-dimethylamino)ethyl]-N-(1-methylethyl)-N-[2-(4-aminophenoxy)ethyl]urea with acetyl chloride in triethylamine.
Reaction SMILES: C[Li].[C:3]([O:11][CH3:12])(=[O:10])[C:4]#[C:5][CH2:6][CH2:7][CH:8]=[CH2:9].[CH2:13](O)C>C1COCC1.CCOCC.[Cu]I>[CH3:13]/[C:5](/[CH2:6][CH2:7][CH:8]=[CH2:9])=[CH:4]/[C:3]([O:11][CH3:12])=[O:10]
Reactant: CCO
Reactant: C=CCCC#CC(=O)OC
Agent: [Cu]I
Agent: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC/C(C)=C\C(=O)OC
Temperature: -20 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A suspension of copper(I) iodide (12.38 g, 65 mmol) in 150 mL of dry THF under a nitrogen atmosphere was cooled to −20° C., and methyllithium (1.6 M in ether, 81.5 mL, 130 mmol) was added dropwise over 15 min. The solution was cooled to −78° C., and 4.49 g (32.5 mmol) of the compound from Example 19 in 15 mL of dry THF was added gradually, keeping the temperature below −70° C. After 1 h, 40 mL of ethanol was added cautiously, and the mixture was allowed to warm to room temperature. The mixture was diluted with ether, and washed with satd aq NH4Cl (200 mL), 5N NH3 (4×250 mL), water (200 mL), and brine (200 mL), dried, and the bulk of the solvent was evaporated to give the title compound (6.8 g, 100%) as an oil. The material had only minor solvent contamination and was adequate for use in the next reaction.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.C[Si]([N:13]=[C:14]=[O:15])(C)C>>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:14]([NH2:13])=[O:15])[CH2:4][CH2:3]1
Reactant: CN1CCC(N)CC1
Reactant: C[Si](C)(C)N=C=O
Product: CN1CCC(NC(N)=O)CC1

Procedure:
(1-methyl-piperidin-4-yl)-urea was prepared from 1-methyl-piperidin-4-ylamine and trimethylsilylisocyanate, in analogy to Example 5.0; 1H-NMR (300 MHz, d6-DMSO) 5.86 (1H, d), 5.32 (2H, s), 3.21-3.38 (1H, m), 2.58-2.67 (2H, m), 2.11 (3H, s), 1.88-1.98 (2H, m), 1.65-1.72 (2H, m), 1.22-1.35 (2H, m).
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]2[N:15]=[C:14]3[S:18][C:19]([C:22](=[O:24])[NH2:23])=[C:20]([NH2:21])[C:13]3=[C:12]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)(=O)C.N>CO>[NH2:21][C:20]1[C:13]2[C:14](=[N:15][C:16]3[CH2:17][NH:8][CH2:9][CH2:10][C:11]=3[C:12]=2[C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[S:18][C:19]=1[C:22]([NH2:23])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCc2c(nc3sc(C(N)=O)c(N)c3c2-c2cccs2)C1
Agent: N
Solvent: CC(=O)Cl
Solvent: CO
Product: NC(=O)c1sc2nc3c(c(-c4cccs4)c2c1N)CCNC3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 3-amino-2-carbamoyl-4-thiophen-2-yl-5,8-dihydro-6H-1-thia-7,9-diaza-cyclopenta[b]naphthalene-7-carboxylic acid tert-butyl ester (100 mg) in 10 ml of anhydrous methanol under argon 0.5 ml of acetyl chloride was added dropwise, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was neutralized with 7N ammonia in methanol and evaporated to dryness under vacuum. The residue was purified by silica gel column (chloroform/methanol, 30:1) to give a yellow solid. 1H-NMR (300 MHz, DMSO-d6): δ 7.88 (d, J=5.1 Hz, 1H), 7.28 (dd, J=3.6, 5.1 Hz, 1H), 7.16 (d, J=3.6 Hz, 1H), 7.01 (brs, 2H), 5.64 (brs, 2H), 4.84 (brs, 1H), 3.16 (s, 2H), 2.94 (m, 2H), 1.86 (m, 2H). ES MS m/z 331 (M+H)+, 329 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:44])[CH2:10][C@@H:11]([N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:26]1)[C:12]([NH:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:52]C(=O)C(N)[C@@H](C(OCCCC)=O)C(N[C@@H](CC1C=CC=CC=1)CO)=O)C1C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(=O)C[C@@H](N)C(N[C@@H](CC1C=CC=CC=1)CO)=O)C1C=CC=CC=1>ClCCCl>[CH2:1]([O:8][C:9](=[O:44])[CH2:10][CH:11]([N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][C:33]([C:36]3[CH:37]=[CH:38][C:39]([C:42](=[O:52])[NH2:43])=[CH:40][CH:41]=3)=[CH:34][CH:35]=2)=[CH:26]1)[C:12]([NH:14][CH:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(-c2ccc(-c3ccn([C@H](CC(=O)OCc4ccccc4)C(=O)N[C@H](CO)Cc4ccccc4)c3)cc2)cc1
Reactant: CCCCOC(=O)[C@@H](C(=O)N[C@H](CO)Cc1ccccc1)C(N)C(=O)OCc1ccccc1
Agent: N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](CO)Cc1ccccc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc(-c2ccc(-c3ccn(C(CC(=O)OCc4ccccc4)C(=O)NC(CO)Cc4ccccc4)c3)cc2)cc1
Yield: 31 %

Procedure:
As described in Example 4(a) for the preparation of N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-[3-(4′-cyano-biphenyl-4-yl)-1H-pyrrol-1-yl]succinamic acid benzyl ester, N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-butoxycarbonyl-amino-succinamic acid benzyl ester (0.320 mmol) was deprotected. A solution of the resultant crude N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-amino-succinamic acid benzyl ester trifluoroacetate salt and crude 3-(4′-carboxamidobiphenyl-4-yl)-2,5-dimethoxytetrahydrofuran (110 mg, 0.330 mmol) in 1,2-dichloroethane condensed in 18 hours to give a brown solid, which was purified via flash column chromatography with 5% MeOH/CH2Cl2as eluant to provide 60 mg(31%) of N-(1-benzyl-2-hydroxyethyl)-3-[3-(4′-carbamoylbiphenyl-4-yl)-1H-pyrrol-1-yl]succinamic acid benzyl ester as a pale yellow solid, mp 1924° C. 1H NMR (DMSO-d6): δ 8.18 (d, 1H, J=8.5 Hz), 8.00 (s, 1H), 7.94 (d, 2H, J=8.1 Hz), 7.76 (d, 2H, J=8.5 Hz), 7.68 (d, 2H, J=8.5 Hz), 7.58 (d, 2H, J=8.5 Hz), 7.36-7.14 (bm, 7H), 6.84 (t, 1H, J=2.2 Hz), 6.47 (s, 1H), 5.10-4.95 (m, 3H), 4.81 (t, 1H, J=5.1 Hz), 3.88-3.75 (m, 1H), 3.00 (d, 2H, J=7.4 Hz), 2.80 (dd, 1H, J=5.5, 13.2 Hz), 2.67-2.60 (m, 1H). IR (KBr): 3330, 2962, 1729, 1655, 1606, 1560, 1498, 1261, 1092 cm−1. FABMS: 602 (M+H+). Anal. Calculated for C37H35N3O5.0.4CH2Cl2: C, 70.67; H, 5.68; N, 6.61. Found: C, 70.78; H, 5.86; N, 6.98.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([NH2:23])(=[O:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:12][C:11]1[C:2]([NH:23][S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[F:13])(=[O:22])=[O:21])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: NS(=O)(=O)c1ccccc1F
Reactant: Clc1nc2ccccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1ccccc1F
Yield: 74.8 %

Procedure:
According to Reference Example 6-1, by use of 2,3-dichloroquinoxaline (80 mg, 0.40 mmol), dimethyl sulfoxide (2 mL), 2-fluorobenzenesulfonamide (70 mg, 0.40 mmol) and potassium carbonate (56 mg, 0.40 mmol), the mixture was stirred and reacted at 150° C. for 1.5 hours. Thus, N-(3-chloroquinoxalin-2-yl)-2-fluorobenzenesulfonamide (Compound AE) (101 mg, yield: 75%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][NH:12][C:11](=[O:23])[C:10]=2[C:24]#[N:25])=[CH:5][CH:4]=1.[CH:26]1([CH2:31]Cl)[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:31][CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[C:11](=[O:23])[C:10]=2[C:24]#[N:25])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2n[nH]c(=O)c(C#N)c2-c2ccc(OC)cc2)cc1
Reactant: ClCC1CCCC1
Product: COc1ccc(-c2nn(CC3CCCC3)c(=O)c(C#N)c2-c2ccc(OC)cc2)cc1
Yield: 42.4 %

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-cyano-2H-pyridazin-3-one and cyclopentylmethyl chloride as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 42.4%.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[N:10][C:9]([NH2:12])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]2[O:23][CH2:24][O:25][C:19]=2[CH:18]=1)=O.C(=O)([O-])O.[Na+]>C(O)C>[CH2:24]1[O:23][C:20]2[CH:21]=[CH:22][C:17]([C:15]3[N:12]=[C:9]4[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH:1]5[CH2:2][CH2:3]5)=[N:11][N:10]4[CH:14]=3)=[CH:18][C:19]=2[O:25]1
Reactant: O=C(CBr)c1ccc2c(c1)OCO2
Reactant: Nc1ccc(OCC2CC2)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: c1cc2c(cc1-c1cn3nc(OCC4CC4)ccc3n1)OCO2

Procedure:
A stirred mixture of 6-cyclopropylmethoxypyridazin-3-amine (110 mg), 2-bromo-1-(3,4-methylenedioxyphenyl]ethanone (162 mg), sodium hydrogen carbonate (84 mg, 1 mmol) and ethanol (5 mL) was heated under reflux for 3 hours. Sodium hydrogen carbonate (56 mg) was added and the mixture was refluxed for a further 0.5 hour. The mixture was evaporated. The residue was extracted with chloroform (50 mL) and the extract washed with saturated, aqueous, sodium chloride solution (50 mL), dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel. Elution with 1-3% methanol in dichloromethane afforded Compound 43 (162 mg). 1H n.m.r. (CDCl3) δ 0.33-0.43, m, 2H; 0.62-0.72, m, 2H; 1.22-1.44, m, 1H; 4.13, d, 2H; 6.0, s, 2H; 6.72, d, 1H; 6.86, d, 1H; 7.38, s, 1H; 7.40, d, 1H; 7.78, d, 1H; 7.90, s, 1H.
Reaction SMILES: C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:30][CH2:31][CH2:32][N:33]1[C:37]2[N:38]=[C:39]([C:68]#[N:69])[N:40]=[C:41]([C:42]3[CH:63]=[CH:62][C:45]([O:46][CH2:47][CH2:48][CH:49]4[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]4)=[C:44]([C:64]([F:67])([F:66])[F:65])[CH:43]=3)[C:36]=2[CH:35]=[CH:34]1)(C(C)(C)C)(C)C.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[C:68]([C:39]1[N:40]=[C:41]([C:42]2[CH:63]=[CH:62][C:45]([O:46][CH2:47][CH2:48][CH:49]3[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:59])([CH3:60])[CH3:61])=[O:56])[CH2:51][CH2:50]3)=[C:44]([C:64]([F:65])([F:67])[F:66])[CH:43]=2)[C:36]2[CH:35]=[CH:34][N:33]([CH2:32][CH2:31][OH:30])[C:37]=2[N:38]=1)#[N:69]
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(-c3nc(C#N)nc4c3ccn4CCO[Si](C)(C)C(C)(C)C)cc2C(F)(F)F)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(-c3nc(C#N)nc4c3ccn4CCO)cc2C(F)(F)F)CC1
Reaction time: 7 h
Yield: 99.7 %

Procedure:
Acetic acid (0.1 mL) and a 1.0 M solution of tetrabutylammonium fluoride in THF (1 mL) were added to a solution of tert-butyl 4-(2-{4-[7-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-cyano-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-(trifluoromethyl)phenoxy}ethyl)piperidine-1-carboxylate (390 mg) in THF (5 mL) at room temperature, and the mixture was stirred at the same temperature for 7 hours. After a saturated aqueous NaHCO3 solution was added to the reaction mixture, extraction thereof was performed using EtOAc, and the extract was washed with water and saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=70:30 to 40:60), whereby tert-butyl 4-(2-{4-[2-cyano-7-(2-hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-(trifluoromethyl)phenoxy}ethyl)piperidine-1-carboxylate (323 mg) was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH2:23][C:24]2[N:29]=[C:28]([N+:30]([O-])=O)[C:27]([O:33][CH2:34][CH2:35][OH:36])=[CH:26][CH:25]=2)[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=2)=[CH:11][CH:12]=1>C(O)C.C(O)(=O)C.C([O-])(O)=O.[Na+].[Fe]>[NH2:30][C:28]1[C:27]([O:33][CH2:34][CH2:35][OH:36])=[CH:26][CH:25]=[C:24]([CH2:23][N:9]2[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=3)=[CH:11][CH:12]=[C:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:29]=1
Reactant: CCCOc1ccc(-c2ccc(-c3ccccc3Cl)n2Cc2ccc(OCCO)c([N+](=O)[O-])n2)cc1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCOc1ccc(-c2ccc(-c3ccccc3Cl)n2Cc2ccc(OCCO)c(N)n2)cc1
Temperature: 96 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
To a solution of 0.1 gm (0.2 mmol) of 2-{6-[2-(2-Chlorophenyl)-5-(4-propoxyphenyl)-pyrrol-1ylmethyl]-2-nitro-pyridin-3-yloxy}-ethanol in 4 mL of 1:1 ethanol-acetic acid was added 0.55 gm of Fe powder. The reaction mixture was allowed to stir at 96° C. for 2 h. The mixture was cooled and poured in 100 mL of saturated NaHCO3 and extracted twice with CH2Cl2. The combined organic layers were dried (Na2SO4) and the solvents removed under reduced pressure. The residue was purified by column chromatography using 1%-2% methanol-chloroform-0.5% Et3N as an eluent to yield 0.037 gm (39% yield) of a solid mp 89-92° C. 1H NMR (500 MHz, CDCl3) δ: 1.00 (t, 3H, J=7.4 Hz), 1.23 (br s, 3H), 1.77 (m, 2H), 3.88 (m, 4H), 3.98 (t, 2H, J=4.3 Hz), 4.99 (s, 2H), 5.65 (d, 1H, J=8.05 Hz), 6.29 (s, 2H), 6.72 (d, 1H, J=8.05 Hz), 6.84 (d, 1H, J=8.78 Hz), 7.21 (m, 2H), 7.25 (m, 3H), 7.36 (m, 1H); MS (ES) m/z 478.2 ([M+H]+).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[C:11]([O:12][CH2:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[F:22])=[CH:10][C:9]([N:23]2[C:31](=[O:32])[NH:30][C:29]3[C:24]2=[N:25][C:26]([CH2:35][OH:36])=[N:27][C:28]=3[O:33][CH3:34])=[C:8]([Cl:37])[CH:7]=1)([OH:3])=O.CN.Cl.[CH2:41]([N:43]=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[Cl:37][C:8]1[C:9]([N:23]2[C:31](=[O:32])[NH:30][C:29]3[C:24]2=[N:25][C:26]([CH2:35][OH:36])=[N:27][C:28]=3[O:33][CH3:34])=[CH:10][C:11]([O:12][CH2:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[F:22])=[C:6]([CH:7]=1)[O:5][CH2:4][C:1]([NH:43][CH3:41])=[O:3]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cccc(F)c1COc1cc(-n2c(=O)[nH]c3c(OC)nc(CO)nc32)c(Cl)cc1OCC(=O)O
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(CO)nc32)cc1OCc1c(F)cccc1OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
To a mixture of 9-[4-carboxymethoxy-2-chloro-5-(2-fluoro-6-methoxybenzyloxy)-phenyl]-2-hydroxymethyl-6-methoxy-7,9-dihydro-8H-purin-8-one (0.1 g), 40% aqueous methylamine solution (0.06 mL), 1-hydroxybenzo[r]azole monohydrate (34 mg) and triethylamine (0.1 mL) in N,N-dimethylformamide (2 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (72 mg), and the mixture was stirred at 60° C. overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate−ethyl acetate/methanol=9/1) to give the title compound (54 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[CH2:15][O:14][C:13]2[CH:16]=[C:17]3[C:21](=[CH:22][C:12]1=2)[CH2:20][CH2:19][O:18]3.CC1C2C=[C:30]3[C:35]4(C5C(=CC=CC=5)NC4=O)[CH2:34][O:33][C:31]3=[CH:32]C=2ON=1.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:32][C@H:31]1[CH2:30][CH2:35][CH2:34][O:33]1)[C:6](=[O:11])[C:5]12[CH2:15][O:14][C:13]2[CH:16]=[C:17]3[C:21](=[CH:22][C:12]1=2)[CH2:20][CH2:19][O:18]3
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Reactant: O=C1Nc2ccc(F)cc2C12COc1cc3c(cc12)CCO3
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(C[C@H]2CCCO2)c2ccc(F)cc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 5′-fluoro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (60%) as a colorless solid: mp 167-169° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) 7.06-6.85 (m, 3H), 6.47 (s, 1H), 6.39 (s, 1H), 4.76 (ABq, 2H), 4.52 (t, J=9.0 Hz, 2H), 4.28-4.20 (m, 1H), 3.89-3.69 (m, 4H), 2.98-2.95 (m, 2H), 2.10-1.63 (m, 4H); 13C NMR (75 MHz, CDCl3) 178.0, 161.9, 161.2, 157.9, 138.7, 134.3, 120.0, 118.8, 115.1, 114.8, 111.7, 111.4, 110.5, 93.3, 80.5, 72.4, 68.2, 58.0, 44.8, 29.0, 28.9, 25.7; MS (ES+) m/z 382.1 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:22]=[N:23][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][CH:26]=3)[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH3:33].[OH-].[Na+]>C(O)C>[CH3:33][C:7]1[CH:8]=[C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:22]=[N:23][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][CH:26]=3)[O:18][C:19]=2[CH3:20])[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]([OH:34])=[O:2]
Reactant: COC(=O)CCc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)nc3)oc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OCCc2nc(-c3ccc(-c4ccccc4)nc3)oc2C)ccc1CCC(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
To a solution of 3-(2-Methyl-4-{2-[5-methyl-2-(6-phenyl-pyridin-3-yl)-oxazol-4-yl]-ethoxy}-phenyl)-propionic acid methyl ester (40 mg) in ethanol (1 mL) is added NaOH (5 N, 1.0 mL), stirred for 2 hr at 50° C., cooled to room temperature, concentrated. The residue is treated with ether and acidified by 5 N HCl, extracted with ether, concentrated. Reversed phase HPLC (water/acetonitrile) gave the title compound (22 mg). MS (ES): 443.3 (M++1).
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.S(Cl)([Cl:27])=O>C(Cl)Cl>[Cl:27][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: N#Cc1ccccc1-c1ccc2c(c1)CCC2O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccccc1-c1ccc2c(c1)CCC2Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(1-hydroxy-indan-5-yl)-benzonitrile (3.3 grams, 14 mmol) and pyridine (2.4 mL, 30 mmol)in CH2Cl2 (30 mL) at 0° C. was added thionyl chloride (3.3 grams, 2.04 mL, 28 mmol). The reaction mixture was allowed to warm slowly to room temperature. After 1 hour, the reaction mixture was cooled to 0° C., quenched with saturated aqueous NaHCO3 (10 mL) and diluted with methylene chloride (CH2Cl2) (100 mL). The organic layer was separated and washed with saturated aqueous NaHCO3 (1×25 mL) and saturated aqueous NaCl (1×25 mL), dried (MgSO4) and concentrated in vacuo to give a yellow oil. 1H NMR (250 MHz, CDCl3): d 7.78 (1H, d), 7.65 (1H, t), 7.48 (m, 5 H), 5.48 (dd, 1 H), 3.25 (m, 1 H), 2.98 (m, 1 H), 2.67 (m, 1 H), 2.45 (m, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35]>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:22][CH2:23][CH2:24][N:25]2[C:29](=[O:30])[C:28]3[C:27](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:26]2=[O:35])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CC(C)(C)OC(=O)NCC1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC1CCN(CCCN2C(=O)c3ccccc3C2=O)C1
Yield: 65.3 %

Procedure:
Dimethylformamide (200 ml) was added to 3-(tert-butoxycarbonylaminomethyl)pyrrolidine (14 g), and potassium carbonate (30 g) and N-(3-bromopropyl)phthalimide (18 g) were added at room temperature with stirring, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure, and aqueous potassium carbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The mixture was dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 17 g of 2-(3-(3-tert-butoxycarbonylaminomethylpyrrolidin-1-yl)propyl)-2,3-dihydro-1 H-isoindole-1,3-dione.