Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:26][CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:38].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:38])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:28][CH:29]=1)[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccc(CCc3ccccc3)cc2)C(=O)O1
Reactant: [OH-]
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(CCc2ccccc2)cc1)C(=O)O
Reaction time: 3 h

Procedure:
5.15 g (10.31 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-{[p-(2-phenylethyl)-phenyl]methyl}dihydrofuran-2-(3H)-one in 166 ml of dimethoxyethane and 85 ml of water are hydrolysed, under protective gas, with 41 ml of a 1 M lithium hydroxide solution. After 3 h, the dimethoxyethane is evaporated off on an RE, and the residue is treated with an ice-cold mixture of 506 ml of sat. NH4Cl solution, 42 ml of 10% citric acid solution and 207 ml of methylene chloride. Methanol is added to dissolve the product completely. The aqueous phase is separated off and extracted 2× with methylene chloride/methanol, 10:1. The organic phases are washed with saline, dried with Na2SO4 and evaporated: tRet (II)=17.8 min.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]([CH2:23][C:24]1[N:28]([CH3:29])[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[N:25]=1)[C:6](=[O:22])[O:7][CH2:8][CH:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2.Cl>O1CCCC1>[CH3:29][N:28]1[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[N:25]=[C:24]1[CH2:23][N:5]([CH2:4][CH:3]=[O:2])[C:6](=[O:22])[O:7][CH2:8][CH:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: COC(CN(Cc1nc2ccccc2n1C)C(=O)OCC1c2ccccc2-c2ccccc21)OC
Agent: Cl
Solvent: C1CCOC1
Product: Cn1c(CN(CC=O)C(=O)OCC2c3ccccc3-c3ccccc32)nc2ccccc21
Temperature: 75 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
A solution of the product of Example 64B (0.2 g) in tetrahydrofuran (0.2 mL) was treated with 30% HCl (0.2 mL), stirred at 75° C. for 6 hours, cooled to 25° C. and concentrated. The residue was partitioned between 10% NaHCO3 and ethyl acetate, the organic layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated to give the title compound (175 mg).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[S:24][C:23]([CH3:25])=[N:22][C:21]=1[CH3:26]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[S:24][C:23]([CH3:25])=[N:22][C:21]=2[CH3:26])[CH:11]=1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1nc(C)c(Br)s1
Product: Cc1nc(C)c(C#Cc2cc(Cl)ccc2OCC(=O)O)s1

Procedure:
Following the general method as outlined in Example 8, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and 5-bromo-2,4-dimethyl-1,3-thiazole (Acros), the title compound was obtained as a white solid after purification by preparative HPLC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[NH2:26][C:27]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][C:30]([CH:36]2[CH2:40][CH2:39][CH2:38][N:37]2[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[C:29](F)[CH:28]=1>C(OCC)(=O)C>[NH2:26][C:27]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][C:30]([CH:36]2[CH2:40][CH2:39][CH2:38][N:37]2[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[C:29]([O:14][C:11]2[CH:10]=[CH:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:13][CH:12]=2)[CH:28]=1
Reactant: Oc1ccc(-c2ccccc2F)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cc([N+](=O)[O-])c(N)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1c1cc([N+](=O)[O-])c(N)cc1Oc1ccc(-c2ccccc2F)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
200 mg of 2′-fluorobiphenyl-4-ol and 184 mg of potassium carbonate were added to an N,N-dimethylformamide (3 ml) solution of 288 mg of t-butyl 2-(4-amino-2-fluoro-5-nitrophenyl)pyrrolidine-1-carboxylate, and the reaction liquid was stirred overnight at 80° C. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=5/1) to obtain the entitled compound as a yellow solid.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[CH2:4][CH2:3][NH:2]1.C1C[O:17][CH2:16][CH2:15]1>>[C:16]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][CH:6]=2)[CH2:1]1)(=[O:17])[CH3:15]
Reactant: O=C(O)c1ccc2c(c1)CNCC2
Reactant: C1CCOC1
Product: CC(=O)N1CCc2ccc(C(=O)O)cc2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
30.6 g 1,2,3,4-tetrahydro-7-isoquinolinecarboxylic acid are dissolved in 383 ml THF 109 ml acetic acid anhydride are added and the mixture is stirred for 5 h at ambient temperature. The resulting solid is collected and dried. 12.1 g of a colorless solid are obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:15]=2)[N:12]=[C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])[CH2:10]1.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:21][CH2:22][N:23]([S:39]([CH:36]4[CH2:38][CH2:37]4)(=[O:41])=[O:40])[CH2:24][CH2:25]3)[CH:15]=2)[N:12]=[C:11]([C:26]([C:28]([F:31])([F:30])[F:29])([C:32]([F:33])([F:35])[F:34])[OH:27])[CH2:10]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: OC(C1=NN(c2cccc(N3CCNCC3)c2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(C1CC1)N1CCN(c2cccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.6 %

Procedure:
The 5-(2-chloro-phenyl)-1-[3-(piperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.055 mmol) in the form of a yellow liquid, cyclopropanesulfonyl chloride (9.3 mg, 0.066 mmol), and triethylamine (31.0 uL, 0.221 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours, washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].[C:17](O)(=[O:19])C>C=O>[CH2:1]([N:5]1[C:9]([CH2:17][OH:19])=[C:8]([CH3:10])[N:7]=[C:6]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCn1cc(C)nc1-c1ccccc1
Agent: C=O
Product: CCCCn1c(-c2ccccc2)nc(C)c1CO

Procedure:
A solution of 112 (1 g) in acetic acid (10 mL) and 40% aqueous formaldehyde (2 mL) is refluxed for 14 h. The reaction is then concentrated and dried by repeated reconcentration with toluene. The residue is purified by column chromatography (10% MeOH/CHCl3). The fractions are assayed by GC and those fractions uncontaminated by the isomeric hydroxymethylimidazole combined. Concentration of the combined. fractions provides compound 113 (320 mg) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.4-7.6 (m, 6H), 4.61 (s, 2H, CH2OH), 4.02 (t, J=7 Hz, 2H, NCH2), 2.22 (s, 3H, Me), 1.63 (m, 2H, 1.25 (m, 2H), 0.81 (t, J=7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20]OS(C)(=O)=O)[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:26][C:27]([F:42])([F:41])[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][N:38]4[CH2:39][CH2:40][N:35]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=5[O:28][C:27]([F:26])([F:41])[F:42])[CH2:36][CH2:37]4)[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)Oc1ccccc1N1CCNCC1
Reactant: CS(=O)(=O)OCC1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(N1CCCC(CN2CCN(c3ccccc3OC(F)(F)F)CC2)C1)C1(c2ccc(Cl)cc2)CCC1
Yield: 32.3 %

Procedure:
Compound 9 was prepared using the method described in Example 3, starting with compound 2 (1.0 g, 2.60 mmol), 1-(2-trifluoromethoxyphenyl)piperazine (0.70 g, 2.86 mmol), and cesium carbonate (1.27 g, 3.90 mmol) to give 9 (0.45 g, 32%); C28H33ClF3N3O2, LRMS (m/z)=537 (MH+).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[N:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[O:9][N:10]=[C:11]([CH2:13][CH3:14])[CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[C:22]1([NH:28][C:29]([N:15]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[C:8](=[N:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[O:9][N:10]=[C:11]([CH2:13][CH3:14])[CH3:12])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCC(C)=NOC(=NC1CCCCC1)NC1CCCCC1
Solvent: ClCCl
Product: CCC(C)=NOC(=NC1CCCCC1)N(C(=O)Nc1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 1,3-dicyclohexyl-O—(N-2-butylideneamino)-isourea (Cmpd. 2) (2.93 g, 10 mmol) in dichloromethane (15 ml) is phenylisocyanate (1.19 g, 10 mmol). The mixture is stirred 1 h at room temperature and evaporated to afford 4.12 g of the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[CH2:18][CH:17]3[CH:13]([CH2:14][NH:15][CH2:16]3)[CH2:12]2)[N:4]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[CH2:18][CH:17]3[CH:13]([CH2:14][N:15]([C:27]([C:26]4[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=4[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=4)=[O:28])[CH2:16]3)[CH2:12]2)[N:4]=1
Reactant: O=C(O)c1ccccc1-c1ccccn1
Reactant: COc1cc(OC)nc(N2CC3CNCC3C2)n1
Product: COc1cc(OC)nc(N2CC3CN(C(=O)c4ccccc4-c4ccccn4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 39 and 2-pyridin-2-yl-benzoic acid. MS (ESI) mass calcd. for C24H25N5O3, 431.49; m/z found, 432.2 [M+H]+. 1H NMR (CDCl3): 8.49 (d, J=3.9 Hz, 1H), 7.69-7.49 (m, 3H), 7.48-7.29 (m, 3H), 7.15-7.04 (m, 1H), 5.32 (s, 1H), 3.92-3.61 (m, 8H), 3.60-3.40 (m, 2H), 3.35-3.15 (m, 3H), 2.98-2.65 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:12])=[O:11].Br[CH2:21][C:22]([O:24]C)=[O:23]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:21][C:22]([OH:24])=[O:23])[S:10]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:12]
Reactant: COC(=O)CBr
Reactant: COc1ccccc1NS(=O)(=O)c1ncccc1C
Product: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ncccc1C

Procedure:
prepared by reaction of 3-methyl-pyridine-2-sulfonic acid (2-methoxy-phenyl)-amide with methyl bromoacetate
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH:9]=O)=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[Si:12]([O:19][CH2:20][C:21]([CH3:24])([NH2:23])[CH3:22])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>>[Si:12]([O:19][CH2:20][C:21]([N:23]1[C:2]2[N:3]=[CH:4][N:5]=[C:6]([Cl:11])[C:7]=2[CH:8]=[CH:9]1)([CH3:24])[CH3:22])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: O=CCc1c(Cl)ncnc1Cl
Reactant: CC(C)(N)CO[Si](C)(C)C(C)(C)C
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1ccc2c(Cl)ncnc21

Procedure:
The title compound was prepared according to the method described for Preparation 1 using (4,6-dichloropyrimidin-5-yl)acetaldehyde and 1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropan-2-amine to afford the title compound as a yellow oil in 38% yield, 377 mg.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8].[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8]
Reactant: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(Cl)c([N+](=O)[O-])c4)s3)cc2)CC1
Reactant: C1COCCN1
Product: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(N5CCOCC5)c([N+](=O)[O-])c4)s3)cc2)CC1

Procedure:
This compound was prepared from the compound of Example 15 and morpholine by the procedure used in Example 57. Mass spectrum (ES) MH+=524.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:15][CH3:16])(=[O:14])[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH2:9].N1C=CC=CC=1>>[CH3:1][S:2]([NH:9][C:8]1[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=1[C:6]([O:15][CH3:16])=[O:14])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccccc1N
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
Methanesulfonyl chloride (3.4 mL, 44 mmol) was added to a solution of methyl anthranilate (5.0 mL, 39 mmol) in pyridine (10 mL, 124 mmol). Mixture stirred at room temperature for 16 hours. Reaction was quenched with 1N hydrochloric acid (150 mL). Mixture was extracted with ethyl acetate (2×200 mL). Organic layers were washed successively with 1N hydrochloric acid (2×100 mL) and brine (50 mL). Organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. Residue was crystallized from 50 mL isopropyl alcohol. Solids were filtered, washed with isopropyl alcohol and dried in vacuo. Title compound was obtained as pink crystals in 75% yield. MS m/e (M−H)−=228.0.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[C:10](=[CH:11][C:12]([F:19])=[C:13]([F:18])[C:14]=3[O:16][CH3:17])[C:9](=[O:20])[C:8]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:26]([O-])([O-:28])=[O:27].[K+]>OS(O)(=O)=O>[CH:1]1([N:6]2[C:15]3[C:10](=[C:11]([N+:26]([O-:28])=[O:27])[C:12]([F:19])=[C:13]([F:18])[C:14]=3[O:16][CH3:17])[C:9](=[O:20])[C:8]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)c1cn(C2CCCC2)c2c(OC)c(F)c(F)cc2c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cn(C2CCCC2)c2c(OC)c(F)c(F)c([N+](=O)[O-])c2c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A solution of 15 (6.1 g, 17.4 mmol) in concentrated H2SO4 (60 mL) was treated portionwise at 0° C. with solid KNO3 (2.64 g, 26 mmol). After stirring at 0° C. for 1 h, the reaction mixture was poured into 500 mL of ice-water and the resulting precipitate was removed by filtration, washed with water and dissolved in CH2Cl2. The resulting solution washed with 5% NaHCO3, dried and evaporated to yield 16 as a yellow solid (6.0 g, 87%).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)C1C=CC=CC=1.[H-].[Na+].[CH:20]([Si:23](Cl)([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21]>O1CCCC1>[CH:20]([Si:23]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[N:13]1[C:14]2[CH:15]=[CH:16][CH:17]=[C:9]([OH:8])[C:10]=2[CH:11]=[CH:12]1)([CH3:22])[CH3:21]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: c1ccc(COc2cccc3[nH]ccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(O)cccc21

Procedure:
4-Benzyloxy-indole (1.0 g) was treated with NaH (135 mg) and triisopropylsilyl chloride (1.0 g) in tetrahydrofuran for 1 hour, purified by flash chromatography (98/2 ethyl acetate/hexanes), then debenzylated in ethanol (35 mL) using Pearlman's catalyst (0.19 g) and a hydrogen balloon.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1C=CC=CC=1>[CH2:32]([O:31][C:29]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:14]2)[CH2:10][CH2:9]1)=[O:30])[CH3:33]
Reactant: c1ccc(CN2CCC3(CC2)OC(c2ccccc2)c2ccccc23)cc1
Reactant: CCOC(=O)Cl
Solvent: c1ccccc1
Product: CCOC(=O)N1CCC2(CC1)OC(c1ccccc1)c1ccccc12

Procedure:
A solution of 7.7 g. of 1'-benzyl-1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine] (Example 4), 40 ml. of benzene and 2.5 ml. of ethyl chloroformate is heated under reflux for 18 hours and concentrated to a solid. Recrystallization from cyclohexane provides colorless crystals, m.p. 115°-119°.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]3[N:20]=[C:21]([NH:31][CH:32]4[CH2:36][O:35][C@@H:34]5[C@H:37]([O:40][Si](C(C)(C)C)(C)C)[CH2:38][O:39][C@H:33]45)[N:22](COCC[Si](C)(C)C)[C:17]3=[CH:16][C:15]=2[Cl:48])=[CH:10][CH:9]=1>C(Cl)Cl>[C:8]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]3[N:20]=[C:21]([NH:31][CH:32]4[C@H:33]5[O:39][CH2:38][C@@H:37]([OH:40])[C@H:34]5[O:35][CH2:36]4)[NH:22][C:17]3=[CH:16][C:15]=2[Cl:48])=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@@H]2C(Nc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4n3COCC[Si](C)(C)C)CO[C@@H]21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O[C@@H]1CO[C@@H]2C(Nc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4[nH]3)CO[C@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TFA (0.1 mL) was added to a stirred mixture of 5-([1,1′-biphenyl]-4-yl)-N-((3aR,6R,6aS)-6-((tert-butyldimethylsilyl)-oxy)hexahydrofuro[3,2-b]furan-3-yl)-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-amine (minor isomer) (3.2 mg, 4.61 μmol) in DCM (0.5 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.1% TFA, to give title compound. LC-MS: calculated for C24H21ClN4O3 448.13 observed m/e: 449.16 (M+H)+ (Rt 1.10/2 min); 1H NMR δ (ppm) (CD3OD): 7.72 (m, 5H), 7.61 (m, 1H), 7.49 (m, 3H), 7.54 (m, 1H), 4.61 (m, 3H), 4.31 (m, 1H), 4.14 (m, 1H), 4.03 (d, 1H), 3.91 (dd, 1H), 3.62 (dd, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:22]([NH2:26])[CH2:23][CH2:24][CH3:25]>C1COCC1.CN(C=O)C>[CH2:22]([NH:26][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:14]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCN
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCNC(=O)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Oxalyl chloride (132 μL, 1.5 mmol) was added over a 10 minute period to a mixture of 3-phenylbenzoic acid (200 mg, 1 mmol) dissolved in a mixture THF/DMF (3.5 mL/58 μL). After the addition, the reaction was stirred at room temperature for 2.5 hours. n-Butylamine (247 μL, 2.5 mmol) was then added into half of the acid chloride solution at 0° C. The reaction was then stirred at room temperature for 18 hours. The reaction was concentrated and water was added to the residue. The aqueous phase was extracted 3 times with CH2Cl2. The combined organic layers were washed with 2N HCl, saturated NaHCO3, brine, dried over Na2SO4 and concentrated. Diethyl ether was added to the residue and a white solid precipitated. It was collected by filtration and rinsed with a small amount of diethyl ether. The white solid was then dried under vacuum (88 mg, 70%). NMR 1H (ppm, CDCl3): 7.96 (s, 1H), 7.69 (d, J3=8.01 Hz, 2H), 7.59 (d, J3=7.16 Hz, 2H), 7.51-7.34 (m, 4H), 6.11 (br. s., 1H), 3.51-3.44 (m, 2H), 1.64 (sext., J3=7.59 Hz, 2H), 1.43 (quint., J3=7.98 Hz, 2H), 0.96 (t, J3=7.32 Hz, 3H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][C:25]1[N:29]([C:30]2[S:31][C:32]([CH2:44][CH3:45])=[CH:33][C:34]=2[C:35](=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:28]([CH3:46])=[N:27][N:26]=1.[Cl:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[N:54]=[C:55]=[O:56].C(N(CC)CC)C>ClC(Cl)C>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:35]([C:34]1[CH:33]=[C:32]([CH2:44][CH3:45])[S:31][C:30]=1[N:29]1[C:28]([CH3:46])=[N:27][N:26]=[C:25]1[CH2:24][NH:23][C:55]([NH:54][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[Cl:47])=[O:56])=[O:43]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Reactant: O=C=Nc1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)Nc2ccccc2Cl)s1
Reaction time: 4 h

Procedure:
3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (7.40 g) was dissolved in dichloroethane (100 ml). 2-Chlorophenyl isocyanate (1.2 ml) and triethylamine (4.2 ml) were added under ice-cooling, and the mixture was stirred for 4 hours. Then, the reaction mixture was washed with water and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (developing solvent:chloroform -methanol) to give 4.50 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-N'-(2-chlorophenyl)urea as an oil.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:15]=3[CH:16]=2)[CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[N+:31]([C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=2)=[CH:36][C:35]=1[C:48]([F:51])([F:50])[F:49])([O-:33])=[O:32]>C(#N)C>[N+:31]([C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41]2[CH:42]=[CH:43][C:44]([O:47][CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([CH2:11][C:12]4[O:13][C:14]5[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:15]=5[CH:16]=4)[CH2:7][CH2:6]3)=[O:4])=[CH:45][CH:46]=2)=[CH:36][C:35]=1[C:48]([F:49])([F:50])[F:51])([O-:33])=[O:32]
Reactant: O=C(CCl)N1CCN(Cc2cc3cc(C(F)(F)F)ccc3o2)CC1
Reactant: O=[N+]([O-])c1ccc(Nc2ccc(O)cc2)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(COc1ccc(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)cc1)N1CCN(Cc2cc3cc(C(F)(F)F)ccc3o2)CC1
Temperature: 80 °C
Yield: 72.2 %

Procedure:
To a solution of 2-chloro-1-(4-[[5-(trifluoromethyl)-1-benzofuran-2-yl]methyl]piperazin-1-yl)ethan-1-one (100 mg, 0.28 mmol) in acetonitrile (10 ml) was added potassium carbonate (57.5 mg, 0.42 mmol) and 4-[4-nitro-3-(trifluoromethyl)phenyl]aminophenol (83 mg, 0.28 mmol). The mixture was stirred and heated at 80° C. (oil bath) for 3 hours. The solids were filtered off and the filtrate was concentrated under vacuum to give a residue, which was purified by Prep-TLC with 60% ethyl acetate in petroleum ether to afford 2-(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]phenoxy)-1-(4-[[5-(trifluoromethyl)-1-benzofuran-2-yl]methyl]piperazin-1-yl)ethan-1-one as a yellow solid (125.8 mg, 73%); (ES, m/z): [M+H]+ 623.20; 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J=8.8 Hz, 1H), 7.86 (s, 1H), 7.60 (m, 2H), 7.14 (overlapping s & d, 3H), 7.00 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.8 Hz, 1H), 6.72 (s, 1H), 6.29 (s, 1H), 4.74 (s, 2H), 3.91-3.53 (m, 6H), 2.60 (br s, 4H).