Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[NH2:14][S:15]([C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2)(=[O:17])=[O:16].N1CCCCC1>C(O)C>[CH3:13][C:7]1[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:10][NH:9][C:8]=1[CH:11]=[C:21]1[C:20]2[C:24](=[CH:25][CH:26]=[C:18]([S:15](=[O:17])(=[O:16])[NH2:14])[CH:19]=2)[NH:23][C:22]1=[O:27]
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2ccc(S(N)(=O)=O)cc21
Yield: 70.4 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90.6 mg), 106 mg 5-aminosulfonyl-2-oxindole, and 75 μL piperidine in 2 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 132 mg (70%)of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([CH3:10])[CH3:9])=[CH:4][C:3]=1[N:12]([S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)(=[O:23])=[O:22])[CH2:13][C:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:15].CCN(CC)CC.CS(Cl)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[CH2:9])=[CH:4][C:3]=1[N:12]([S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)(=[O:22])=[O:23])[CH2:13][C:14]([N:16]([CH2:17][CH3:18])[CH2:19][CH3:20])=[O:15]
Reactant: CCN(CC)C(=O)CN(c1cc(C(C)(C)O)ccc1Cl)S(=O)(=O)c1ccc(OC)c(OC)c1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)c1ccc(Cl)c(N(CC(=O)N(CC)CC)S(=O)(=O)c2ccc(OC)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 38.7 %

Procedure:
To a solution of 2-[[2-chloro-5-(1-hydroxy-1-methyl-ethyl)-phenyl]-(3,4-dimethoxy-benzenesulfonyl)-amino]-N,N-diethyl-acetamide (0.527 g, 1 mmol) in DCM (10 mL) was added at 0° C. NEt3 (0.88 mL, 6 eq) and DMAP (7 mg). Methane sulfonylchloride (0.123 mL, 1.5 eq) was added and the mixture warmed to RT and stirred for 6 h. The mixture was partitioned between DCM and water. The aqueous phase was once more extracted with DCM and the combined organic layers dried over MgSO4 and concentrated. The residue was purified by chromatography on SiO2 (hex/EA 1:1, EA, EA/MeOH 9:1) to give the title compound as a colourless solid (0.186 g, 37%). Unreacted starting material (0.29 g, 55%) was also recovered.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C)C=O>[C:2]1([NH:1][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc2ccccc12
Reactant: CCOC(=O)C(C)Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Nc1cccc2ccccc12
Temperature: 60 °C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
To a solution of 1-aminonaphthalene (1.43 g, 10 mmol) and triethylamine (1.5 mL, 10.8 mmol) in dimethylformamide (3.0 mL) at room temperature under nitrogen was added ethyl 2-bromopropionate (1.4 mL, 10.8 mmol). After stirring at 60° C. (bath temperature) 18 hrs, the mixture was partitioned between EtOAc-water. The organic phase was washed with water, 5% KHSO4, saturated NaHCO3 and saturated NaCl solutions, dried over anhydrous Na2SO4 and evaporated to a brown oil. Purification of the crude product by flash chromatography on silica gel eluting with Et2O-hexane (5:95) to give ethyl 2-(1-naphthylamino)propionate (1.726 g, 73%) as a white crystalline solid after trituration with cold hexane. TLC(Et2O-hexane; 2:3) Rf=0.43.
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[C:7]2([CH2:12][CH2:11][N:10]([CH2:13][CH2:14]CCN3C(=O)C4C=CC=C5C=4C(=CC=C5)C3=O)[CH2:9][CH2:8]2)[N:6]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:5][NH:4]1.BrCC[CH2:41][CH2:42][CH2:43][N:44]1[C:53](=[O:54])[C:52]2[CH:55]=[CH:56][CH:57]=[C:50]3[C:51]=2[C:46](=[CH:47][CH:48]=[CH:49]3)[C:45]1=[O:58].BrCCCCN1C(=O)C2C=CC=C3C=2C(=CC=C3)C1=O>>[ClH:1].[O:2]=[C:3]1[C:7]2([CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:41][CH2:42][CH2:43][N:44]3[C:53](=[O:54])[C:52]4[CH:55]=[CH:56][CH:57]=[C:50]5[C:51]=4[C:46](=[CH:47][CH:48]=[CH:49]5)[C:45]3=[O:58])[CH2:11][CH2:12]2)[N:6]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:5][NH:4]1
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCN1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCBr
Agent: Cl
Agent: O=C1c2cccc3cccc(c23)C(=O)N1CCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCN1CCC2(CC1)C(=O)NCN2c1ccccc1

Procedure:
Following the procedure of part (b) of example 26 but substituting 2-(5-bromopentyl)-1H-benz[de]isoquinoline-1,3(2H)-dione for the 2-(4-bromobutyl)-1H-benz[de]isoquinoline-1,3(2H)-dione, one obtains the titled compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[NH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]=12.[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][OH:23])=[CH:19][CH:18]=1.O.C(#N)C.C(O)(C(F)(F)F)=O>Cl.CN1C(=O)CCC1.C(=O)(O)[O-].[Na+].ClCCl>[NH:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:6]1[N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]2=[C:2]([NH:16][C:17]2[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][OH:23])=[CH:19][CH:18]=2)[CH:7]=1
Reactant: Clc1cc(-c2ccc[nH]2)nc2c1CCC2
Reactant: Nc1ccc(CCO)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: OCCc1ccc(Nc2cc(-c3ccc[nH]3)nc3c2CCC3)cc1
Temperature: 140 °C
Yield: 34.9 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-(1H-pyrrol-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.077 g, 0.35 mmol), 4-aminophenethyl alcohol (0.072 g, 0.53 mmol) and cone. HCl (1 drop) in NMP (2.5 mL). The resulting mixture was heated at 140° C. under microwave irradiation for 1.5 h. After this time, the reaction mixture was cooled, diluted with saturated aqueous sodium bicarbonate (15 mL) affording a brown solid. The solid was isolated by filtration and chromatography on silica using dichloromethane/(90:10:0.25 dichloromethane/methanol. conc. NH4OH) (10:0 to 0:10) as eluent followed by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford 2-(4-((2-(1H-pyrrol-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanol (0.039 g, 35%) as a light brown. MW=319.40. 1H NMR (DMSO-d6, 500 MHz) δ 11.16 (br s, 1H), 7.90 (br s, 1H), 7.22-7.18 (m, 2H), 7.15-7.11 (m, 2H), 7.01 (s, 1H), 6.73 (s, 1H), 6.38 (s, 1H), 6.06-6.01 (m, 1H), 4.62 (t, J=5.0 Hz, 1H), 3.65-3.58 (m, 2H), 2.86 (t, J=7.5 Hz, 2H), 2.78 (t, J=7.5 Hz, 2H), 2.71 (t, J=7.0 Hz, 2H), 2.05 (quin, J=7.5 Hz, 2H); ESI MS m/z 320 [M+H]+. Treatment with 1.25 M HCl in methanol (0.25 mL, 0.32 mmol) afforded the title compound (0.034 g, 92%) as a light brown solid. MW=355.86. M.p. 138-140° C. 1H NMR (DMSO-d6, 500 MHz) δ 13.50 (br s, 1H), 12.08 (br s, 1H), 9.44 (br s, 1H), 7.36-7.32 (m, 2H), 7.30-7.26 (m, 2H), 7.12-7.09 (m, 1H), 7.06 (s, 2H), 6.28-6.25 (m, 1H), 4.68 (br s, 1H), 3.66 (t, J=7.0 Hz, 2H), 3.11 (t, J=7.5 Hz, 2H), 2.87 (t, J=7.5 Hz, 2H), 2.78 (t, J=7.0 Hz, 2H), 2.20 (quin, J=7.5 Hz, 2H); ESI MS: ES m/z 320 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]1[CH2:8][NH:7][CH2:6][CH2:5][NH:4]1.Cl[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19].CCN(C(C)C)C(C)C>CCO>[CH3:17][N:16]1[C:12]([N:7]2[CH2:6][CH2:5][NH:4][CH:3]([C:2]([F:10])([F:9])[F:1])[CH2:8]2)=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[N:15]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: FC(F)(F)C1CNCCN1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc([N+](=O)[O-])c1N1CCNC(C(F)(F)F)C1
Temperature: 140 °C
Yield: 104 %

Procedure:
A mixture of (±)-2-(trifluoromethyl)piperazine (1 g, 6.2 mmol), 5-chloro-1-methyl-4-nitro-1H-pyrazole (2.1 g, 13 mmol), DIPEA (2.4 g, 18.6 mmol) in EtOH (10 mL) was heated in a microwave oven at 140° C. for 5 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using DCM/MeOH (10:1) as eluting solvents to afford (±)-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)-3-(trifluoromethyl)piperazine as a yellow oil (1.8 g, 99%). MS (ESI) m/z: 280 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]2[C:6](=[O:17])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][C:8]=3[F:16].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29]CC)=[O:28].[OH-].[Na+].Cl>O.CN(C=O)C>[Cl:1][C:2]1[C:3]([O:18][CH2:26][C:27]([OH:29])=[O:28])=[CH:4][C:5]2[C:6](=[O:17])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][C:8]=3[F:16]
Reactant: CCOC(=O)CBr
Reactant: O=c1c2cc(O)c(Cl)cc2oc2cccc(F)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)COc1cc2c(=O)c3c(F)cccc3oc2cc1Cl
Reaction time: 5 h
Yield: 37.9 %

Procedure:
A mixture of 2.6 g of 3-chloro-8-fluoro-2-hydroxy-9-oxo-9H-xanthene, 3.4 g of potassium carbonate, 4.2 g of ethyl bromoacetate and 60 ml of DMF was stirred at 60°-65° C. for 5 hours. After cooling the mixture, 4 g of sodium hydroxide and 100 ml of water were added and the resulting mixture was stirred at 90°-100° C. for 30 minutes. After cooling, the mixture was rendered acidic with hydrochloric acid and the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 1.2 g of 3-chloro-8-fluoro-9-oxo-9H-xanthene-2-yloxyacetic acid. m.p. 242°-245° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 322.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[NH2:3].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.C(O)C>[CH:13](=[N:3][NH:2][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NNc1ccccc1C(=O)O
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccccc1NN=Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution of 2-hydrazino-benzoic acid mono hydrochloric acid salt (13.66 g, 72.42 mmol) dissolved in water (580 mL) and ethanol (125 mL) was added a solution of benzaldehyde (7.35 mL, 72.42 mmol) in ethanol (20 mL) dropwise at room temperature. The reaction mixture was stirred at room temperature for an additional 3 hours. The resulting solid was collected by filtration and dried in a vacuum oven to provide 12.0 g (69%) of 2-(N′-benzylidene-hydrazino)-benzoic acid as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]#[N:19])=[CH:15][CH:16]=2)[O:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:24]>CN(C=O)C>[C:1]([O:5][C:6](=[O:20])[N:7]([CH:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]#[N:19])=[CH:15][CH:16]=2)[O:11][CH2:10][CH2:9]1)[CH3:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC1CCOc2cc(C#N)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1CCOc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (7-cyano-chroman-4-yl)-carbamic acid tert-butyl ester (769 mg, 2.81 mmol, 1.0 eq), NaH (Aldrich, 449 mg (60% by weight), 11.2 mmol, 4.0 eq) in DMF (15 mL) was stirred at RT for 3 h. Iodomethane (Aldrich, 1.99 g, 14.1 mmol, 5.0 eq) was added slowly. The resulting mixture was stirred at RT for 21 h. The reaction was quenched with saturated NH4Cl (40 mL) DMF was removed with a rotary evaporator at 70° C. The crude was diluted with H2O (100 mL), extracted with EtOAc (80 mL×4). The extract phase was washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. Flash column chromatography (silica gel, 0-15% EtOAc-Hexane) afforded the title compound as an off-white solid. MS (ESI, pos. ion) m/z: 289 (M+1).
Reaction SMILES: C([O:4][C@H:5]1[CH2:9][CH2:8][C@@H:7]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)[C@:6]1([CH3:26])[CH2:22][C:23]([OH:25])=[O:24])(=O)C.[OH-].[K+]>CO.O>[CH3:21][O:20][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([C@H:7]1[C@:6]([CH3:26])([CH2:22][C:23]([OH:25])=[O:24])[C@@H:5]([OH:4])[CH2:9][CH2:8]1)[CH2:19][CH2:18]2
Reactant: COc1ccc2c(c1)CCC([C@@H]1CC[C@H](OC(C)=O)[C@@]1(C)CC(=O)O)C2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)CCC([C@@H]1CC[C@H](O)[C@@]1(C)CC(=O)O)C2

Procedure:
To a solution of 3.33 g of (1S,2S,5S)-2-acetoxy-5-(1,2,3,4-tetrahydro-6-methoxy-2-naphthyl)-1-methylcyclo-pentaneacetic acid in 50 ml of methanol is added a solution of 3.00 g of potassium hydroxide in 15 ml of water. The resultant solution is refluxed for 2 hours, then diluted with 250 ml of water. Clarification is effected by filtration. The filtrate is acidified with hydrochloric acid. A solid precipitates which, isolated by filtration and recrystallized from a mixture of ethyl acetate and hexane, affords (1S,2S,5S)-5-(1,2,3,4-tetrahydro-6-methoxy-2-naphthyl)-2-hydroxy-1-methylcyclopentaneacetic acid melting at approximately 141.5°-142.5°. The product has a specific rotation of +65°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH:21]([CH3:24])[CH2:22][NH2:23].NCCC1N=CNC=1>>[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH:21]([CH3:24])[CH2:22][NH:23][C:13]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([C:8]([F:9])([F:10])[F:11])=[C:5]([Br:12])[N:4]=1)=[O:15]
Reactant: CC(CN)c1ncc[nH]1
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)O
Agent: NCCc1c[nH]cn1
Product: CC(CNC(=O)c1nc(Br)c(C(F)(F)F)nc1N)c1ncc[nH]1

Procedure:
The title compound was prepared from 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (Intermediate C) and 2-(1H-imidazol-2-yl)propan-1-amine (prepared according to the procedure of Steffens, Robert; Schunack, Walter. Histamine analogs, XXVI. Racemic histamine H1-agonists. Archiv der Pharmazie (Weinheim, Germany) (1984), 317(9), 771-6; 1H NMR (400 MHz, DMSO-d6) δ 11.8 (1H, s), 9.0 (1H, t), 8.1 (2H, s), 7.0 (1H, s), 6.8 (1H, s), 3.55 (2H, m), 3.15 (1H, m), 1.2 (3H, d). LC-MS [M+H]+ 393.0/395.1
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[CH:6][CH:5]=1)(=O)[NH2:2].P(Cl)(Cl)(Cl)=O>>[C:1]([C:4]1[N:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: NC(=O)c1cccc(C(=O)O)n1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cccc(C(=O)O)n1

Procedure:
6-Carbamoyl-pyridine-2-carboxylic acid (compound G1) (500 mg, 3 mmol) and phosphorus oxychloride (POCl3) (15 mL) are heated to reflux temperature for 2 h. The mixture is worked up in the usual manner and the crude product is further used without any purification.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([OH:8])=[O:7].[Si:14]([O:21][C@H:22]1[CH2:31][C@H:30](O)[C@H:29]2[C:24]([CH:25]=[CH:26][C@H:27]([CH3:50])[C@@H:28]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[CH2:36]2)=[CH:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>>[Si:14]([O:21][C@H:22]1[CH2:31][C@H:30]([O:7][C:6](=[O:8])[CH:5]([O:4][C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]=2[Cl:1])[CH3:9])[C@H:29]2[C:24]([CH:25]=[CH:26][C@H:27]([CH3:50])[C@@H:28]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:44])[CH3:45])[CH2:36]2)=[CH:23]1)([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:16])[CH3:15]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CC(Oc1ccccc1Cl)C(=O)O
Product: CC(Oc1ccccc1Cl)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 96.9 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 0.72 g of (2RS)-2-(2-chlorophenoxy)propionic acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.29 g of the title compound as a colorless foam.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]([F:49])([F:48])[C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]2[O:24][CH:25]=[C:26]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][CH2:39][N:40]4[CH:44]=[CH:43][N:42]=[C:41]4[CH2:45][CH2:46]O)=[CH:32][CH:31]=3)[N:27]=2)=[CH:17][CH:16]=1.[C:50]1(=[O:60])[NH:54][C:53](=[O:55])[C:52]2=[CH:56][CH:57]=[CH:58][CH:59]=[C:51]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[F:48][C:14]([F:13])([F:49])[C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]2[O:24][CH:25]=[C:26]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][CH2:39][N:40]4[CH:44]=[CH:43][N:42]=[C:41]4[CH2:45][CH2:46][N:54]4[C:50](=[O:60])[C:51]5[C:52](=[CH:56][CH:57]=[CH:58][CH:59]=5)[C:53]4=[O:55])=[CH:32][CH:31]=3)[N:27]=2)=[CH:17][CH:16]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Reaction time: 24 h
Yield: 172.1 %

Procedure:
Diethyl azodicarboxylate (1.86 ml) was added to a solution of 2-[1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]-1-ethanol (2.00 g), phthalimide (605 mg) and triphenylphosphine (1.08 g) in THF (30 ml) at room temperature, and the mixture was stirred for 24 hr. The reaction mixture was diluted with ethyl acetate, successively washed with 1N aqueous sodium hydroxide solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crude 2-[2-[1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]ethyl]-1H-isoindole-1,3(2H)-dione (4.31 g) as pale yellow crystals. 2-Aminoethannol (4.31 ml) was added to a solution of the product (3.94 g) in ethanol (70 ml), and the mixture was refluxed for 75 min. The reaction mixture was concentrated, diluted with ethyl acetate, successively washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Chromatorex, 100-200 mesh, Fuji silicia chemical) (eluent; dichloromethane to dichloromethane:methanol=200:1 to 40:1) to give the titled compound (1.34 g) as a colorless amorphous form.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=[CH:12]2)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=[CH:12]2
Reactant: CC(C)(C)OC(=O)n1ccc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ccc2cc(O)ccc21
Reaction time: 0.17 h

Procedure:
A solution (0.18 M) of tert-butyl 5-{[tert-butyl(dimethyl)silyl]oxy}-1H-indole-1-carboxylate in THF was treated with TBAF (1.1 eq) at 0° C. The mixture was stirred at that temperature for 10 min and allowed to reach room temperature. The reaction was quenched by the addition of saturated aqueous NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with H2O, brine and dried over Na2SO4. The crude product was purified by column chromatography on silica gel (Petroleum ether:EtOAc 92/8) to afford the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=[CH:11][C:10]([S:23]([C:26]1[CH:27]=[C:28]([CH:44]=[CH:45][CH:46]=1)[C:29]([N:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38]OS(C)(=O)=O)[CH2:33][CH2:32]1)=[O:30])(=[O:25])=[O:24])=[CH:9][C:8]=2[CH3:47])(=[O:3])[NH2:2].[NH2:48][CH2:49][C@@H:50]([C:59]1[CH:68]=[CH:67][C:66]([OH:69])=[C:65]2[C:60]=1[CH:61]=[CH:62][C:63](=[O:70])[NH:64]2)[O:51][Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53].CCN(C(C)C)C(C)C.O>CS(C)=O>[Si:52]([O:51][CH:50]([C:59]1[CH:68]=[CH:67][C:66]([OH:69])=[C:65]2[C:60]=1[CH:61]=[CH:62][C:63](=[O:70])[NH:64]2)[CH2:49][NH:48][CH2:38][CH2:37][N:34]1[CH2:35][CH2:36][N:31]([C:29]([C:28]2[CH:27]=[C:26]([S:23]([C:10]3[CH:11]=[C:12]4[C:7](=[C:8]([CH3:47])[CH:9]=3)[N:6]=[CH:5][C:4]([C:1]([NH2:2])=[O:3])=[C:13]4[NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)(=[O:25])=[O:24])[CH:46]=[CH:45][CH:44]=2)=[O:30])[CH2:32][CH2:33]1)([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCN(CCOS(C)(=O)=O)CC5)c4)cc23)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCN(CCNCC(O[Si](C)(C)C(C)(C)C)c6ccc(O)c7[nH]c(=O)ccc67)CC5)c4)cc23)c1
Reaction time: 1 h

Procedure:
To a solution of Intermediate 138 (360 mg, 0.53 mmol) and Intermediate 2 (209 mg, 0.53 mmol) in 3 mL DMSO, DIEA (276 μL, 1.59 mmol) was added at 50° C. The reaction mixture was stirred for 1 h and water was added. The solid was collected by filtration and purified with prep HPLC to give the title compound. ES/MS calcd. for C48H58N7O8Ssi+ 920.4. Found m/z=920.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:25])[C:5]([N+:22]([O-:24])=[O:23])=[C:6]([C:8]([C:20]#[N:21])([CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)C(OCC)=O)[N:7]=1.Cl>[OH-].[Na+]>[NH2:1][C:2]1[NH:3][C:4](=[O:25])[C:5]([N+:22]([O-:24])=[O:23])=[C:6]([CH:8]([CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[C:20]#[N:21])[N:7]=1
Reactant: CCOC(=O)C(C#N)(Cc1cccs1)c1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#CC(Cc1cccs1)c1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2-Amino-α-cyano-1,6-dihydro-5-nitro-6-oxo-α-(2-thienylmethyl)-4-pyrimidineacetic acid, ethyl ester as prepared above (5.0 g) in 1N NaOH (200 mL) is stirred at room temperature for 90 min. The reaction mixture is acidified to pH 1 with 4N HCl and stirred for 5 min. The reaction mixture is neutralized (pH 7) with 1N NaOH and the product 2-Amino-1,6-dihydro-5-nitro-6-oxo-α-(2-thienylmethyl)-4-pyrimidineacetonitrile (4.1 g, 98%) is collected by filtration. ##STR16##
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:17]([NH:20][S:21]([C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:23])=[O:22])([CH3:19])[CH3:18]>>[CH:17]([NH:20][S:21]([C:24]1[NH:25][C:26]2[C:31]([C:32]=1[CH:6]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:5]1[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:23])=[O:22])([CH3:19])[CH3:18]
Reactant: CC(C)NS(=O)(=O)c1cc2ccccc2[nH]1
Reactant: OC(c1ccc(F)cc1)c1ccc(F)cc1
Product: CC(C)NS(=O)(=O)c1[nH]c2ccccc2c1C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 79.4 %

Procedure:
Substantially the same procedure as in Example 266 was repeated using 4,4'-difluorobenzhydrol (0.99 g, 4.50 mmol) and N-isopropylindole-2-sulfonamide (1.00 g, 4.46 mmol) to give 1.56 g (yield: 80%) of the title compound.