Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]([CH2:14][OH:15])[CH2:4][CH2:5][N:6]1[CH:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]1=[O:13].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C>[N:16]([CH2:2][CH:3]([CH2:14][OH:15])[CH2:4][CH2:5][N:6]1[CH:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]1=[O:13])=[N+:17]=[N-:18]
Reactant: O=c1ccn(CCC(CO)CBr)c(=O)[nH]1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(CO)CCn1ccc(=O)[nH]c1=O
Temperature: 70 °C
Yield: 51.8 %

Procedure:
A solution of compound 38 (10.9 g, 0.042 mol) in dry DMF (40 mL) was treated with NaN3 (4.1 g, 0.062 mol) and heated to 70° C. for 24 h. The reaction mixture was concentrated under vacuum and crude purified by column chromatography over silica gel (30% methanol in chloroform) to give the title compound (5.2 g, 47%). TLC: Chloroform/Methanol, 1:1, Rf=0.2
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19]([OH:21])=O)=[O:5].[OH:30][CH2:31][CH2:32][NH2:33]>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:16])([CH3:17])[O:12][C:13]([CH3:14])([CH3:15])[C:9]=2[C:8]=1[C:19]([NH:33][CH2:32][CH2:31][OH:30])=[O:21])=[O:5]
Reactant: NCCO
Reactant: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)O
Product: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)NCCO

Procedure:
The title compound was prepared from the product of Example 45A and commercially available 2-hydroxyethylamine using the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 1.45 (s, 6H), 1.48 (s, 6H), 3.24 (q, J=6.2 Hz, 2H), 3.43 (q, J=5.6 Hz, 2H), 4.65 (t, J=5.6 Hz, 1H), 7.68-7.81 (m, 3H), 7.89 (t, J=5.6 Hz, 1H), 11.58 (br s, 1H). MS (ESI+) m/z 475 (M+H)+.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[F:5][C:6]1[C:11]([O:12][CH2:13]CO)=[CH:10][C:9]([O:16][CH3:17])=[CH:8][C:7]=1[C@H:18]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[NH:37])=[CH:34][CH:33]=1)[C:19]1[NH:23][C:22](=[O:24])[N:21]([C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[N:20]=1.BrC[CH2:43][CH2:44][O:45][Si](C(C)(C)C)(C)C>>[C:1]([OH:4])(=[O:3])[CH3:2].[F:5][C:6]1[C:11]([O:12][CH2:13][CH2:43][CH2:44][OH:45])=[CH:10][C:9]([O:16][CH3:17])=[CH:8][C:7]=1[C@H:18]([NH:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([NH2:38])=[NH:37])=[CH:39][CH:40]=1)[C:19]1[NH:23][C:22](=[O:24])[N:21]([C:25]2[N:26]=[CH:27][CH:28]=[CH:29][N:30]=2)[N:20]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: COc1cc(OCCO)c(F)c([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Solvent: CC(=O)O
Product: COc1cc(OCCCO)c(F)c([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1

Procedure:
The same procedure was carried out as in Examples (153a) to (153b), except that (3-bromopropoxy)-t-butyldimethylsilane was used instead of 2-(2-bromoethoxy)tetrahydro-2H-pyran in Example (153a), to give the first eluting enantiomer of the title compound.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)[CH2:2][CH3:3].[OH-].[K+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[CH2:13]([N:9]1[CH:5]([O:4][CH2:1][CH2:2][CH3:3])[CH2:6][CH2:7][C:8]1=[O:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: CCCOC1CCC(=O)N1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCOC1CCC(=O)N1Cc1ccccc1
Reaction time: 1 h
Yield: 61.4 %

Procedure:
To a mixture of 4 g of 5-(n-propyloxy)-pyrrolidin-2-one, 0.4 g of n-tetrabutylammonium bromide and 2.34 g of potassium hydroxide hydrated to 85% in 70 cm3 of tetrahydrofuran, there is added a solution of 4.78 g of benzyl bromide in 25 cm3 of tetrahydrofuran, operating at between 20° C. and 30° C. After agitating for 1 hour, filtering and then evaporating under reduced pressure, the residue is chromatographed on silica, (eluent: ethyl acetate--n-hexane, 1--1). 4 g of the expected product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]#[N:15])=[CH:5][CH:4]=1.O.N.N#N>[Ni].C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH2:15])=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(CC#N)c2c1
Agent: [Ni]
Agent: N
Agent: N#N
Solvent: O
Solvent: CCO
Product: COc1ccc2cccc(CCN)c2c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
56 g 7-methoxy-1-naphthaleneacetonitrile, 120 ml ammonia water, 332 ml 95% ethanol, 20 g Raney-Ni were added into autoclave. H2 was introduced after vacuuming it. The operation was repeated for 3 times. The reaction was stirred for 12 hours while H2 was introduced and the condition of 300 atm and 60° C. was maintained. After completion of the reaction, the reaction was kept overnight at room temperature. On the next day, it was vacuumed and N2 gas was introduced. The autoclave was opened up, and the reaction solution was filtered to remove the catalyst. The filtrate was vacuum evaporated until dry to obtain 56 g light green oil. The content is measured as 96.95% by HPLC, and the yield is 95%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([NH2:22])[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH:23]1([C:26](O)=[O:27])[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN(C=O)C>>[Cl:1][C:2]1[C:3]([CH:8]([NH:22][C:26]([CH:23]2[CH2:25][CH2:24]2)=[O:27])[C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C(O)C1CC1
Reactant: NC(c1ccc(Oc2ccccc2)cc1)c1nccnc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(c1ccc(Oc2ccccc2)cc1)c1nccnc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 120.4 %

Procedure:
In a 10 mL flask were added C-(3-chloropyrazin-2-yl)-C-(4-phenoxyphenyl)-methylamine (110 mg, 0.00035 mol), cyclopropanecarboxylic acid (0.056 mL, 0.00070 mol), DIEA (0.55 mL, 0.0032 mol), TBTU (0.17 g, 0.00053 mol) and DMF (5 mL, 0.07 mol). The reaction mixture was stirred at rt for 10 min. Reaction was left to stir over weekend. The reaction mixture was concentrated in vacuo, dissolved in DCM and washed with sat aq NaHCO3 followed by brine. The organics were collected and concentrated in vacuo to give 160 mg of the compound as a yellow solid. Purification by prep TLC in 60% EtOAc: hexanes afforded 55 mg of the title compound as a yellow solid. The compound was carried on to the next step. MS (ES+): m/z 380.08 (20)[MH+]. HPLC: tR=3.56 min (Open lynx polar—5 min).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:30])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]2[C:15]3[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=3[CH:18]=[C:19]([CH3:30])[CH:20]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(-c2cc(C)cc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)cc1
Reactant: CN
Product: CNCC1Cc2cc(C)cc(-c3ccc(OC)cc3)c2O1

Procedure:
The title compound was prepared (0.075 g, 52%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(4-methoxyphenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.19 g, 0.45 mmol) and methylamine (0.112 g, 4.5 mmol). mp 235-238° C.
Reaction SMILES: [Mg].II.[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Cl)=[CH:7][CH:6]=1.Cl[CH2:14][CH2:15][CH2:16][C:17]#[N:18]>C(OCC)C.C1(C)C=CC=CC=1>[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:17]2[CH2:16][CH2:15][CH2:14][N:18]=2)=[CH:7][CH:6]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: N#CCCCCl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Clc1ccc(CC2=NCCC2)cc1
Reaction time: 0.75 h

Procedure:
Magnesium turnings (4.04 g, 168 mmol) are introduced into diethyl ether abs. (10 ml), and the formation of the Grignard reagent is started with a crystal of iodine and 4-chlorobenzyl chloride (2.2 ml, 2.7 g, 16.8 mmol). The remaining amount of 4-chlorobenzyl chloride (19 ml, 24 g, 148.7 mmol), dissolved in diethyl ether abs. (150 ml), is added dropwise (45 min) such that the mixture boils vigorously. After addition is complete, the mixture is refluxed by heating for a further 1.5 h. A solution of 4-chlorobutyronitrile (16.6 g, 160 mmol) in diethyl ether abs. (150 ml) is added dropwise to the solution of the 4-chlorobenzyl Grignard reagent prepared in this way (45 min), the mixture is stirred for a further 45 min after the addition, toluene abs. (200 ml) is added and diethyl ether is distilled off over a bridge until a temperature of 95° C. is reached in the bottom (2.5 h). The mixture is cooled in an ice bath and dil. HCl (10%) is added at 25-30° C. until a pH of 2-3 is reached in the depositing aqueous phase. The toluene/ether phase is separated and extracted 3 times with HCl (10%, 150 ml). The collected HCl phase is washed again with toluene (100 ml) and then rendered alkaline (pH 9-10) with NaOH (32%). The depositing oily pyrroline phase is taken up in diethyl ether (300 ml), dried over K2CO3 and concentrated. The concentrated ether phase (to 50%-55% product content) is used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][C:8]([C:12]#[N:13])=[N:9]2)=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][C:8]([C:12]#[N:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(-c3ccccc3)cc(C#N)nc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(-c2ccccc2)c2ccc(CBr)cc2n1
Temperature: 25 °C

Procedure:
A solution of 7-methyl-4-phenylquinoline-2-carbonitrile (11.2 g, 41.7 mmol), N-bromo-succinimide (12.2 g, 68.6 mmol) and AIBN (2,2′-azobisisobutyronitrile) (200 mg) in carbon tetrachloride (200 mL) was heated at reflux overnight. The reaction was cooled to ambient temperature and the solid residue was filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (eluting with 5% ethyl acetate in hexane) to give the title compound. 1H NMR (400 MHz, acetone-d6): δ 8.30 (s, 1H), 8.06 (d, 1H), 7.90 (s, 1H), 7.87 (d, 1H), 7.6-7.7 (m, 5H), 4.95 (s, 2H).
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].FC1C=C(F)C=C(F)C=1CBr.[CH3:18][O:19][C:20]1C(C)=[CH:24][C:23]([N:27]2[C:32](=[O:33])[N:31]([CH2:34][C:35]3[C:40]([F:41])=[CH:39][C:38]([F:42])=[CH:37][C:36]=3[F:43])[C:30]3[CH:44]=[CH:45][CH:46]=[CH:47][C:29]=3[S:28]2(=[O:49])=[O:48])=[CH:22][C:21]=1C.C[N:52](C=O)C>>[CH3:1][O:4][C:21]1[CH:22]=[C:23]([N:27]2[C:32](=[O:33])[N:31]([CH2:34][C:35]3[C:40]([F:41])=[CH:39][C:38]([F:42])=[CH:37][C:36]=3[F:43])[C:30]3[CH:44]=[CH:45][CH:46]=[CH:47][C:29]=3[S:28]2(=[O:49])=[O:48])[CH:24]=[N:52][C:20]=1[O:19][CH3:18]
Reactant: O=C([O-])[O-]
Reactant: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Reactant: CN(C)C=O
Agent: Fc1cc(F)c(CBr)c(F)c1
Agent: [K+]
Product: COc1cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cnc1OC

Procedure:
The title compound (103 mg, 0.21 mmol) was prepared from (IntA19) (84 mg, 0.25 mmol), K2CO3 (104 mg, 0.75 mmol) and 2,4,6-trifluorobenzyl bromide (68 mg, 0.30 mmol) in DMF (2 mL) using the methods of (115).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])[CH2:4]1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>>[C:27]([NH:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])[CH2:4]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1
Agent: Cl
Product: CC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1

Procedure:
Using essentially the technique of Example 19, but starting from (5R)-3-(4-((3S)-3-aminopyrrolidin-1-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one hydrochloride (250 mg, 0.65 mM), and replacing the methyl chloroformate with acetic anhydride gave the desired product (150 mg).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C@H:11]([NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([CH2:25][C:26]#[N:27])[CH:22]=[CH:21][C:19]=2[N:20]=1)([CH2:13][CH3:14])[CH3:12].[F:28][C:29]1[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=1[C:31](OC)=[O:32].Cl>C1COCC1>[C@H:11]([NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([CH:25]([C:31]([C:30]3[CH:35]=[CH:36][CH:37]=[CH:38][C:29]=3[F:28])=[O:32])[C:26]#[N:27])[CH:22]=[CH:21][C:19]=2[N:20]=1)([CH2:13][CH3:14])[CH3:12]
Reactant: COC(=O)c1ccccc1F
Reactant: CC[C@@H](C)Nc1nc2ccc(CC#N)cc2s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@H](C)Nc1nc2ccc(C(C#N)C(=O)c3ccccc3F)cc2s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
To a solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 35.3 mL) in THF (60 mL) was added a solution of (R)-2-(2-(sec-butylamino)benzo[d]thiazol-6-yl)acetonitrile (3.74 g, 15.2 mmol) in THF (60 mL) at −78° C. over 40 min. The resulting solution was stirred at −78° C. for 10 min before a solution of methyl 2-fluorobenzoate (2.5 mL, 19.6 mmol) in THF (15 mL) was added over 5 min. The mixture was stirred at −78° C. for 1 hr and then at rt for 3 hr before it was poured into ice-cold water (100 mL). After its pH value was adjusted to 9 with 6 N HCl, the mixture was extracted with AcOEt (3×60 mL). The combined extract was washed with brine and dried over anhydrous MgSO4. The solution was concentrated under vacuum, and the residue was subjected to ISCO (2% MeOH/CH2Cl2) to give a mixture (4.09 g) of the title compound and the starting material in a ratio of 1:1.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.O.[C:12](=O)([O-])[O-].[Na+].[Na+].CI>O.C(O)C>[N+:8]([C:5]1[CH:4]=[N:3][C:2]([S:1][CH3:12])=[CH:7][CH:6]=1)([O-:10])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(S)nc1
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CCO
Product: CSc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Mercapto-5-nitro pyridine (20.0 g, 128 mmol) was suspended in water/ethanol (43 mL/13 mL). Sodium carbonate monohydrate (17.49 g, 141 mmol, dissolved in 86 mL of water) was added to the above slurry dropwise. Methyl iodide (20.0 g, 141 mmol) was added to the above mixture and the mixture was stirred at room temperature for one hour. The solid was filtered and washed with water and ethanol to provide the title compound in quantitative yield.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH2:6]([O:8][C:9]([C@@H:11]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:12][C@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14](Cl)=[O:15])=[O:10])[CH3:7]>C(Cl)Cl>[CH2:6]([O:8][C:9]([C@@H:11]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:12][C@H:13]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:14]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[O:15])=[O:10])[CH3:7]
Reactant: NCCCO
Reactant: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)NCCCO
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To the solution of 0.52 g of 3-amino-1-propanol in 10 ml of methylene chloride is added 0.5 g of 4-ethoxycarbonyl-2,4-(R*,R*)-dibenzylbutyryl chloride in 10 ml of methylene chloride. The mixture is stirred 10 minutes at room temperature. The reaction mixture is concentrated and diluted with ethyl acetate. The organic portions are washed with 1N hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride. The organic layer is dried over magnesium sulfate, filtered and concentrated to give N-[4-ethoxycarbonyl-2,4-(R*,R*)-dibenzylbutyryl]-3-amino-1-propanol as a colorless oil; NMR (CDCl3) δ 7.31 and 7.28 (s, 10H, Ar-H), 5.82 (t, 1H, J=7 Hz, NH), 4.02 (q, 2H, J=8 Hz, OCH2), 3.3-1.25 (m, 15H), 1.10 (t, 3H, J=8 Hz, CH3).
Reaction SMILES: F.[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][C:17]=3[N+:23]([O-:25])=[O:24])[CH:12]=[CH:13][CH:14]=2)=[CH:5][N:4]=1.[O:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1>>[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:28]4[CH:29]=[CH:30][O:26][CH:27]=4)=[CH:18][C:17]=3[N+:23]([O-:25])=[O:24])[CH:12]=[CH:13][CH:14]=2)=[CH:5][N:4]=1
Reactant: Nc1ncc(-c2cccc(Nc3ccc(I)cc3[N+](=O)[O-])c2)cn1
Reactant: OB(O)c1ccoc1
Agent: F
Product: Nc1ncc(-c2cccc(Nc3ccc(-c4ccoc4)cc3[N+](=O)[O-])c2)cn1

Procedure:
N-(3-(2-Aminopyrimid-5-yl)phenyl)-4-(3-furanyl)-2-nitroaniline (71) was prepared analogously from 6l (Example 10) and 3-furanylboronic acid in quantitative yield. Mp 185-186° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[C:13]([CH2:17][CH3:18])[C:14]([Cl:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:19]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.CC(C)=O>C(O)C>[ClH:16].[C:1]1([N:7]2[C:11]3[CH:12]=[C:13]([CH2:17][CH3:18])[C:14]([Cl:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:19][NH:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccncc1
Reactant: CCc1cc2c(cc1Cl)nc(CCl)n2-c1ccccc1
Solvent: CCO
Solvent: CC(C)=O
Product: CCc1cc2c(cc1Cl)nc(CNc1ccncc1)n2-c1ccccc1
Product: Cl
Yield: 29.8 %

Procedure:
A mixture of 1-phenyl-2-chloromethyl-5-chloro-6-ethylbenzimidazole (1.7 g, 5.5 mmol) prepared in the preceding step (b), 4-aminopyridine (1.8 g, 10.3 mmol) and ethanol (10.8 ml) was refluxed for 1.5 hours, then the mixture was filtered and the filtrate was concentrated in vacuo and crystallized from acetone (1.0 g, 2.35 mmol) and recrystallized from ethanol, then the objective compound (0.35 g, 0.82 mmol) was obtained.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@:9]12[CH2:14][CH:13]1[CH2:12][N:11]([C:15](=[O:34])[N:16]([C@H:18]([C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1)[CH3:19])[CH3:17])[C@H:10]2[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)C)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:28][C:26]([F:27])([F:29])[C:24]1[CH:25]=[C:20]([C@@H:18]([N:16]([CH3:17])[C:15]([N:11]2[CH2:12][CH:13]3[C@@:9]([NH:7][CH3:6])([CH2:14]3)[C@@H:10]2[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:34])[CH3:19])[CH:21]=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:23]=1
Reactant: C[C@@H](c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(C)C(=O)N1CC2C[C@@]2(N(C)C(=O)OC(C)(C)C)[C@@H]1c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@]12CC1CN(C(=O)N(C)[C@@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]2c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 103 %

Procedure:
A flask containing Intermediate 50, a mixture of four isomers, one being ((1S,2S)-3-{[(S)-1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-carbamoyl}-2-phenyl-3-aza-bicyclo[3.1.0]hex-1-yl)-methyl-carbamic acid tert-butyl ester (0.17 g, 0.30 mmol), and methylene chloride (5 mL) was immersed in a 0° C. bath. Trifluoroacetic acid (0.46 mL, 6.0 mmol) was added, and the reaction stirred for 16 hours at room temperature. The solvent was removed at reduced pressure and the residue partitioned between saturated sodium bicarbonate solution and methylene chloride, the organics were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound as an oil (0.15 g, quantitative yield).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[OH:14]>ClCCl>[F:6][C:7]1[C:8]([OH:14])=[CH:9][C:10]([CH3:13])=[C:11]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:12]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccc(F)c(O)c1
Solvent: ClCCl
Product: Cc1cc(O)c(F)cc1S(=O)(=O)Cl
Reaction time: 0.17 h
Yield: 7.5 %

Procedure:
To a solution of chlorosulfonic acid (1.5 g, 13.3 mmol) dissolved in 10 mL of dichloromethane was added 2-fluoro-5-methylphenol (1.1 g, 8.86 mmol) dropwise. After 10 minutes, the reaction was quenched by adding to ice water. The reaction was extracted with dichloromethane, washed with brine, dried over MgSO4, filtered, and concentrated to give 150 mg (7.5%) of the title compound.
Reaction SMILES: CO.O.[Cl:4][C:5]1[CH:32]=[CH:31][C:8]([O:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=O)=[CH:7][CH:6]=1>O1CCCC1>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][S:21]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)(=[O:22])=[O:23])=[CH:31][CH:32]=1
Reactant: O=C(COc1ccc(Cl)cc1)Nc1ccccc1NS(=O)(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=S(=O)(Nc1ccccc1NCCOc1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
In a 2-L three-neck flask, the product of step (2) (100.00 g) was dissolved in tetrahydrofuran (500 ml) by using a stirrer and cooled on a water bath so that the inside temperature became 2-3° C. To the resultant solution, a borane-tetrahydrofuran complex—1 M tetrahydrofuran solution (532 ml) was added by using a syringe. After stirring for one hour at 5° C., the mixture was further stirred for four hours at room temperature, to thereby obtain an almost colorless reaction mixture. The reaction mixture was cooled again on a water bath, and methanol (100 ml) was added gradually thereto by using a pipette, to dissolve the excessive borane-tetrahydrofuran complex. After completion of hydrogen gas generation, the reaction mixture was removed from the water bath and stirred for one hour during the temperature was returned to room temperature. Extremely small quantities of impurities such as fibers of filter were removed through suction-filtered and the solvent was removed under reduced pressure. To the residue was added methanol (300 ml) before drying, to thereby crystallize the residue. About one half in volume of methanol was removed under reduced pressure, to thereby yield a colorless mud-like product. The product was added to water (1 L) and the resultant solution was stirred. Crystals in the solution were suction-filtered, washed with water, and air-dried for three days, to thereby yield the target product (97.12 g). This product was submitted directly to the next reaction without further purification.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:29])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[CH2:9][C:10]=1[OH:11])(=O)[CH2:2][CH3:3].Cl.[CH2:31]([O:33][NH2:34])[CH3:32].C([O-])(=O)C.[Na+].O>C(Cl)Cl.C(O)C>[CH2:31]([O:33][N:34]=[C:1]([C:5]1[C:6](=[O:29])[CH2:7][CH:8]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]3[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=3)=[CH:16][CH:17]=2)[CH2:9][C:10]=1[OH:11])[CH2:2][CH3:3])[CH3:32]
Reactant: CCC(=O)C1=C(O)CC(c2ccc(Oc3ccc(S(C)(=O)=O)cc3)cc2)CC1=O
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CCON=C(CC)C1=C(O)CC(c2ccc(Oc3ccc(S(C)(=O)=O)cc3)cc2)CC1=O
Reaction time: 16 h

Procedure:
A solution of 1.6 g (3.9 mmol) of 2-propionyl-3-hydroxy-5-(4-(4-(methylsulfonyl)phenoxy)phenyl)-cyclohex-2-en-1-one in 10 mL of methylene chloride and 10 mL of absolute ethanol, at room temperature was treated with 0.50 g (5.2 mmol)of ethoxyamine hydrochloride and 0.40 g (4.9 mmol) of anhydrous sodium acetate. After stirring under a nitrogen atmosphere for 16 hours, the mixture was poured into 100 mL of water and extracted twice with 20 mL portions of methylene chloride. The combined extracts were dried over MgSO4, filtered and passed through a short column of silica gel. Evaporation of the solvent left the product as a solid residue which was recrystallized from a mixture of diethyl ether and methylene chloride to yield 1.5 g (84 percent of theoretical) the above named product as a white solid melting at 155°-157° C. 1H NMR (CDCl3): δ1.10-1.48 (m, 6H, both --CH2CH3 's), 2.57-3.62 (m includes s at 3.03 for CH3SO2 --, 10H), 4.12 (q, J=7 Hz, 2H, --OCH2), 6.95-7.45 (m, 6H, aromatics), 7.90 (d, J=7 Hz, 2H, aromatics), 15.0 (very broad s, enol H) (Compound 4).