Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11](=[O:18])OCC(Cl)(Cl)Cl)=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:19]1([C:25]2[N:29]=[C:28]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]([N:33]3[CH2:34][CH2:35][N:30]([C:28]4[S:27][N:26]=[C:25]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[N:29]=4)[CH2:31][CH2:32]3)=[O:18])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(Nc1ccc2[nH]cnc2c1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1ccc2[nH]cnc2c1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 4.9 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl 1H-benzimidazol-5-ylcarbamate (313 mg, 1.01 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (300 mg, 1.22 mmol) and diisopropylethylamine (0.212 ml, 1.22 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 1 day. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by high performance liquid chromatography (YMC HPLC Column eluted with 10% to 100% Liquid A; Liquid A: a 0.1% solution of trifluoroacetic acid in acetonitrile; Liquid B: an aqueous 0.1% trifluoroacetic acid solution) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 20.2 mg (5.0%) of the desired product as a solid.
Reaction SMILES: [BH4-].[Na+].[O:3]1[C@H:5]2[CH2:6][C@H:7]3[C@:20]([CH3:22])([CH2:21][C@@H:4]12)[C@@H:19]1[C@H:10]([C@H:11]2[C@@:15]([CH2:17][CH2:18]1)([CH3:16])[C:14](=[O:23])[CH2:13][CH2:12]2)[CH2:9][CH2:8]3>CO>[O:3]1[C@H:5]2[CH2:6][C@H:7]3[C@:20]([CH3:22])([CH2:21][C@@H:4]12)[C@@H:19]1[C@H:10]([C@H:11]2[C@@:15]([CH2:17][CH2:18]1)([CH3:16])[C@@H:14]([OH:23])[CH2:13][CH2:12]2)[CH2:9][CH2:8]3
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Temperature: 0 °C

Procedure:
A solution of sodium borohydride (600 mg.) in ice-cold methanol (10 ml.) is added to a solution of 2α,3α-epoxy-5α-androstan-17-one (U.S. Pat. No. 3,169,136, Example I, 1.34 g.) in methanol (60 ml.) and the mixture is stirred at 0° for 30 minutes. The mixture is washed with saline, dried over sodium sulfate and concentrated under reduced pressure to give a residue which is chromatographed on a silica gel column. Appropriate fractions (TLC) are pooled and concentrated to give 2α,3α-epoxy-17β-hydroxy-5α-androstane.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([NH2:7])[C:4]([SH:8])=[CH:3][CH:2]=1.[C:9](O)(=O)[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:11]>C1(C)C(C)=CC=CC=1>[OH:11][CH:10]([C:9]1[S:8][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=2[N:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1S
Reactant: O=C(O)C(O)c1ccccc1
Solvent: Cc1ccccc1C
Product: OC(c1ccccc1)c1nc2ccccc2s1

Procedure:
A mixture of O-aminothiophenol (23.5 g.) and dl-mandelic acid (25 g.) was refluxed in xylene with a Dean-Stark tube for two days.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[O:9]=[C:10]1[NH:19][CH:18]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[C:17]2[C:16](=[O:28])[CH2:15][CH2:14][CH2:13][C:12]=2[N:11]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1.Br.Br[CH2:41][CH2:42][CH2:43][N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1.O>CN(C)C=O>[F:37][C:35]([F:38])([F:36])[C:31]1[CH:30]=[C:29]([N:11]2[C:12]3[CH2:13][CH2:14][CH2:15][C:16](=[O:28])[C:17]=3[CH:18]([C:20]3[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=3)[N:19]([CH2:41][CH2:42][CH2:43][N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)[C:10]2=[O:9])[CH:34]=[CH:33][CH:32]=1
Reactant: BrCCCN1CCCC1
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)cc1
Agent: Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CCCN2CCCC2)cc1
Temperature: 25 °C

Procedure:
In a first flask, lithium diisopropylamide (2.0 M in tetrahydrofuran, 135 μL, 0.27 mmol) is added at 0° C. to a solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-benzonitrile (example 1, 100 mg, 0.243 mmol) in N,N-dimethyl-formamide (3 mL, solution A). In another flask, lithium diisopropylamide (2.0 M in tetrahydrofuran, 135 μL, 0.27 mmol) is added to a solution of 1-(3-bromopropyl)pyrrolidine hydrobromide (70 mg, 0.256 mmol) in N,N-dimethylformamide (2 mL, solution B). This solution is then added to solution A and the resulting mixture is stirred at room temperature over night. Water is added, and the mixture is extracted twice with dichloromethane. The combined organic layers are dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by reversed phase HPLC (Waters Xbridge-C18, gradient of methanol in water, 0.1% TFA). Yield: 15 mg; ESI mass spectrum [M+H]+=523; Retention time HPLC: 1.15 min (V001—006).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][C:5](=[O:9])[C:4]1=[O:10])[CH3:2].[CH2:11]=[O:12]>Cl>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:11][OH:12])[C:5](=[O:9])[C:4]1=[O:10])[CH3:2]
Reactant: C=O
Reactant: CCN1CCNC(=O)C1=O
Agent: Cl
Product: CCN1CCN(CO)C(=O)C1=O
Temperature: 50 °C
Reaction time: 168 h
Yield: 100 %

Procedure:
To a solution of 1-ethylpiperazine-2,3-dione (2.13 g, 15 mmol) in 30% aqueous (methanol free) formaldehyde (15 mmol) potassium hydroxide (150 mg, 2.7 mmol) was added and the mixture stirred at 50° C. for 7 days. It was neutralized with 5 N aqueous hydrochloric acid (50 μl) to pH=7. The mixture was evaporated at 15 mm and then dried in high vacuo (0.0013 mbar) (0.001 mm) to give 1-ethyl-4- (hydroxymethyl)-piperazine-2,3-dione as a colourless solid (100%). NMR-spectrum in CDCl3: 1.15 (broad signal, 1H), 1.15 (t, 3H, J=7 Hz), 3.47 (q, 2H, J=7 Hz), 3.54 (m, 2H), 3.68 (m, 2H), 4.88 (s, 2H) ppm.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][N:15]([C:17]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)=[O:18])[CH2:14][CH:13]([C:25](O)=[O:26])[CH2:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].O[N:29]=[C:30]([CH:32]1[CH2:34][CH2:33]1)[NH2:31]>>[CH:32]1([C:30]2[N:31]=[C:25]([CH:13]3[CH2:12][CH:11]([C:8]4[CH:7]=[CH:6][C:5]([C:2]([F:4])([F:1])[CH3:3])=[CH:10][CH:9]=4)[CH2:16][N:15]([C:17]([N:19]4[CH2:20][CH2:21][S:22][CH2:23][CH2:24]4)=[O:18])[CH2:14]3)[O:26][N:29]=2)[CH2:34][CH2:33]1
Reactant: CC(F)(F)c1ccc(C2CC(C(=O)O)CN(C(=O)N3CCSCC3)C2)cc1
Reactant: NC(=NO)C1CC1
Product: CC(F)(F)c1ccc(C2CC(c3nc(C4CC4)no3)CN(C(=O)N3CCSCC3)C2)cc1

Procedure:
According to General Method 6A, 150 mg (0.376 mmol) of the compound from Example 53A and 41.5 mg (0.414 mmol) of N′-hydroxycyclopropanecarboximidamide were reacted Yield: 77.9 mg (44% of theory)
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]1[NH:16][N:17]=[CH:18][C:13]=1[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]1=[N:16][N:17]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=[C:13]1[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Nc1c2c(nc3ccccc13)CCc1cn[nH]c1-2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1c2c(nc3ccccc13)CCc1cn(Cc3ccccc3)nc1-2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 11-amino-4,5-dihydro-1H-pyrazolo[3,4-a]acridine (2.36 g) in dry DMF (90 ml) was added NaH (60%)(0.50 g) slowly. The reaction was stirred at room temperature for 15 minutes and then benzyl bromide (1.88 g) was added and the reaction was stirred an additional 15 minutes. At the end of this time the product was precipitated with water, filtered off, washed well with water, and air dried to yield a product which was further purified by flash chromatography (5% Et3N-EtOAc). The product-containing fractions were combined, concentrated, and recrystallized from EtOAc to give 2.35 g, mp 206°-207°.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[CH:7][CH:6]=1.Cl>O1CCOCC1>[F:26][C:2]([F:1])([F:25])[CH2:3][O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCC(F)(F)F)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)(F)COc1ccc(OC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl 4-[4-(2,2,2-trifluoroethoxy)phenoxy]piperidine-1-carboxylate (3 g) was added 4 molar hydrogen chloride in 1,4-dioxane (50 ml), stirred at ambient temperature for 1 hour. The solvent was removed and the resultant solid triturated and washed twice with a small amount of diethyl ether to yield 4-[4-(2,2,2-trifluoroethoxy)phenoxy]piperidine as a hydrochloride salt (2.4 g). NMR Spectrum: (DMSOd6) 1.7 (m, 2H), 2.0 (m, 2H), 3.0 (m, 2H), 3.2 (m, 2H), 4.5 (m, 1H), 4.6 (m, 2H), 6.9 (m, 4H), 8.8 (broad, 2H). Mass Spectrum: M−H− 276.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[OH:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][NH2:19]>>[OH:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][NH:19][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: NCCNCCO
Product: OCCNCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The product was made from D-glucose and N-(β-hydroxyethyl)-ethylenediamine comparable as in Example A. A wax-like, colorless product was obtained.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[C:24]=1[C:25](O)=[O:26])(=[O:3])[NH2:2].[CH3:28][O:29][C:30]([CH3:34])([CH3:33])[CH2:31][NH2:32]>>[F:17][C:15]1[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:21])[CH3:22])=[CH:13][C:12]2[C:6]3[N:7]([C:24]([C:25]([NH:32][CH2:31][C:30]([O:29][CH3:28])([CH3:34])[CH3:33])=[O:26])=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3)[CH2:8][CH2:9][O:10][C:11]=2[CH:16]=1
Reactant: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)O
Reactant: COC(C)(C)CN
Product: COC(C)(C)CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(C#CC(C)(C)O)cc1-2

Procedure:
2-Carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.05 g) was reacted with (2-methoxy-2-methylpropyl)amine similar to as described in Example 2 to afford 14.8 mg of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3-(2-methoxy-2-methyl-propyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 459 (M)+. 1H NMR (400 MHz, DMSO) δ 11.24 (t, 1H), 8.60 (d, J=8.5 Hz, 1H), 8.35 (s, 1H), 7.87 (s, 1H), 7.02 (d, J=10.6 Hz, 1H), 5.48 (s, 1H), 5.10-4.90 (m, 2H), 4.63-4.45 (m, 2H), 3.34 (d, J=5.6 Hz, 2H), 3.14 (s, 3H), 1.49 (s, 7H), 1.15 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:27]=[CH:26][C:12]3[N:13]([C:16]4[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=O)=[CH:18][CH:17]=4)[CH:14]=[N:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][C:37]=2[C:43]([F:46])([F:45])[F:44])[CH2:31][CH2:30]1>C(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:27]=[CH:26][C:12]3[N:13]([C:16]4[CH:17]=[CH:18][C:19]([CH2:22][C:23]([NH:42][C:39]5[CH:40]=[CH:41][C:36]([CH2:35][N:32]6[CH2:31][CH2:30][N:29]([CH3:28])[CH2:34][CH2:33]6)=[C:37]([C:43]([F:46])([F:45])[F:44])[CH:38]=5)=[O:25])=[CH:20][CH:21]=4)[CH:14]=[N:15][C:11]=3[CH:10]=2)=[CH:7][CH:8]=1
Reactant: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: COc1ccc(-c2ccc3c(c2)ncn3-c2ccc(CC(=O)O)cc2)cc1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(-c2ccc3c(c2)ncn3-c2ccc(CC(=O)Nc3ccc(CN4CCN(C)CC4)c(C(F)(F)F)c3)cc2)cc1

Procedure:
The title compound is prepared as described in Example 1 but using {4-[5-(4-methoxy-phenyl)-benzoimidazol-1-yl]-phenyl}-acetic acid and 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (WO 03/099771). Title compound: ES-MS: 613.9 [M+H]+; single peak at tR=3.56 min (System 1); Rf=0.10 (CH2Cl2/MeOH+1% NH3aq, 9:1).
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:22]=[CH:21][C:12]([O:13][CH2:14][C@@H:15]2[O:19][C:18]([NH2:20])=[N:17][CH2:16]2)=[CH:11][CH:10]=1)([CH3:8])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5]>C(Cl)(Cl)Cl>[CH3:8][C:2]([C:9]1[CH:22]=[CH:21][C:12]([O:13][CH2:14][C@@H:15]2[O:19][C:18]3=[N:20][C:12](=[O:13])[CH:11]=[CH:10][N:17]3[CH2:16]2)=[CH:11][CH:10]=1)([CH3:1])[CH2:3][C:4]([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)CC(C)(C)c1ccc(OC[C@H]2CN=C(N)O2)cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)CC(C)(C)c1ccc(OC[C@H]2Cn3ccc(=O)nc3O2)cc1

Procedure:
The title compound was prepared from (R)-5-(4-(1,1,3,3-tetramethyl-butyl) -phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine employing the procedures as set forth in Step 3 of Example 1. [α]D25 −45.23 (c 0.489, CHCl3).
Reaction SMILES: [CH2:1]([C@:5]12[CH2:13][CH2:12][C:11]3[C:14]4[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[CH:18][C:19]=4[CH2:20][CH2:21][C:10]=3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:24])[CH2:2][CH2:3][CH3:4].N.[Na].[Cl-].[NH4+]>NC1C=CC=CC=1.O1CCCC1.CO.CCOCC>[CH2:1]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C:14]4[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[CH:18][C:19]=4[CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CC[C@@H]2O
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: Nc1ccccc1
Product: CCCC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reaction time: 12 h

Procedure:
To 13 -n-butyl-3-methoxygona-1,3,5(10),8-tetraen-17β-ol (0.8 g.) in aniline (20 cc.) and tetrahydrofuran (10 cc.) add liquid ammonia (100 cc.), followed by sodium (0.8 g.) in small pieces during 5 minutes while stirring the mixture. After a further 15 minutes stirring, discharge the blue color with solid ammonium chloride. Work up the product with ether in the usual way, and evaporate the resulting ether solution to leave as residue a gum; take this up in hot methanol (10 cc.), filter a little insoluble material and allow the solution to stand for 12 hours at 0° C. Crystals of 13-n-butyl-3-methoxygona-1,3,5(10)-trien-17β-ol are deposited and filtered off (0.6 g.), m.p. 123°-125° C after previous softening and a little melting at 60°-70° C.; ultraviolet absorption peak at 278 mμ (ε2,100); infrared absorption peaks at 2.86-2.97 (broad band), 6.21, 7.94, 9.62 μ.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[C:31]([OH:33])=[O:32])=[CH:4][CH:3]=1.C(Cl)Cl.[CH3:39][O:40][C:41]1[N:46]=[CH:45][C:44](B(O)O)=[CH:43][N:42]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH3:39][O:40][C:41]1[N:46]=[CH:45][C:44]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[C:13]([O:16][CH2:17][C:18]5[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=5)[CH:14]=[CH:15][C:10]=4[N:9]=[C:8]3[C@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]3[C:31]([OH:33])=[O:32])=[CH:34][CH:35]=2)=[CH:43][N:42]=1
Reactant: Cc1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(Br)cc4)c3c2)nc1
Reactant: COc1ncc(B(O)O)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ncc(-c2ccc(Cn3c([C@H]4CCCC[C@H]4C(=O)O)nc4ccc(OCc5ccc(C)cn5)cc43)cc2)cn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
To a 5 mL vial were added racemic cis-2-(1-(4-bromobenzyl)-6-((5-methylpyridin-2-yl)methoxy)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylic acid (77.2 mg, 0.14 mmol), Pd(dppf)Cl2.DCM (14 mg, 0.017 mmol), (2-methoxypyrimidin-5-yl)boronic acid (73 mg, 0.47 mmol), Na2CO3 (0.3 mL, 2M) and 1,4-dioxane (2 mL). The vial was flushed with N2 then capped and placed in a heating block and heated at 80° Celsius. After 6 h the mixture was cooled to RT and transferred to a round-bottomed flask and concentrated to dryness. The resulting residue was then partitioned between water (10 mL, ˜pH 3) and DCM (10 mL) with stirring for 1 h at RT. The organic layer was separated, concentrated to dryness and purified by FCC to provide 65.3 mg of the title compound. MS (ESI): mass calcd. for C33H33N5O4, 563.25; m/z found, 564.2 [M+H]+. (500 MHz; CDCl3) δ 8.70 (s, 2H), 8.37 (d, J=2.2 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.51-7.45 (m, 3H), 7.38 (d, J=8.0 Hz, 1H), 7.13 (d, J=8.1 Hz, 2H), 7.05 (dd, J=8.8, 2.3 Hz, 1H), 6.82 (d, J=2.3 Hz, 1H), 5.39-5.29 (m, 2H), 5.14 (s, 2H), 4.07 (s, 3H), 3.20 (d, J=11.3 Hz, 1H), 3.07 (s, 1H), 2.58 (d, J=10.9 Hz, 1H), 2.30 (s, 3H), 1.91-1.59 (m, 5H), 1.45 (q, J=12.4, 11.7 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8](C)[CH:7]=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].ClCCCl.Cl[O-].[Na+].[OH-].[Na+].[C:24]([O-:27])(O)=[O:25].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.[Ru](Cl)(Cl)Cl>[N+:1]([C:4]1[CH:9]=[C:8]([CH:7]=[CH:6][C:5]=1[C:11]([F:12])([F:13])[F:14])[C:24]([OH:27])=[O:25])([O-:3])=[O:2]
Reactant: O=C([O-])O
Reactant: Cc1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Agent: Cl[Ru](Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCCl
Solvent: O
Product: O=C(O)c1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 49 %

Procedure:
To a rapidly stirred mixture of 1.00 g (4.88 mmol) of 2-nitro-4-methylbenzotrifluoride (from Step A), 236 mg (0.732 mmol) of tetra-n-butylammonium bromide, 51 mg (0.244 mmol) of ruthenium trichloride hydrate, and 2 mL of 1,2-dichloroethane were added five 5.8 -mL (approximately 22 mmol) portions of 13% sodium hypochlorite solution (aqueous, approx. 3.8M) while monitoring and adjusting the pH. With each addition of sodium hypochlorite solution, 5N NaOH was added as necessary to maintain the pH between 8.5 and 10.5, and the next portion of sodium hypochlorite was added only when the pH was stable for about 5 minutes. The entire addition required approximately 2 hours, and the final pH was 10.3. After being stirred overnight at 45° C., the 2-phase mixture was cooled and separated. The aqueous phase was acidified to pH 3 by addition of 20% sulfuric acid and extracted 3× with ethyl acetate. The combined organic extracts were washed with H2O (3×), then with brine, and dried over anhydrous Na2SO4. The residue obtained upon concentration was taken up in 5% NaHCO3 (aqueous) adjusted to pH 9 with 5% NaOH. The aqueous phase was washed twice with methylene chloride and then with ether. Next, the water phase was acidified with 20% sulfuric acid and extracted with ethyl acetate as above to yield 563 mg (49%) of the title compound as an off-white solid, mp 156°-158° C.; TLC in 1:1 hexane-EtOAc (at origin); mass spectrum (EI) m/e 235 (M+). 200 MHz 1H NMR (CD3OD) δ7.87 (d, J=8 Hz, 1H), 8.31 (d, J=8 Hz, 1H), 8.45 (s, 1H).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2([CH2:30][CH:31]=O)[CH2:21][N:20]([CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:19](=[O:29])[O:18][CH2:17]2)[CH:12]=[CH:13][C:14]=1[Cl:15].Cl.Cl.[O:35]1[CH2:40][CH2:39][N:38]([CH:41]2[CH2:44][NH:43][CH2:42]2)[CH2:37][CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2([CH2:30][CH2:31][N:43]3[CH2:44][CH:41]([N:38]4[CH2:39][CH2:40][O:35][CH2:36][CH2:37]4)[CH2:42]3)[CH2:21][N:20]([CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:19](=[O:29])[O:18][CH2:17]2)[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: C1CN(C2CNC2)CCO1
Reactant: O=CCC1(c2ccc(Cl)c(Cl)c2)COC(=O)N(CC2CCCCC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: O=C1OCC(CCN2CC(N3CCOCC3)C2)(c2ccc(Cl)c(Cl)c2)CN1CC1CCCCC1
Reaction time: 1 h
Yield: 74.1 %

Procedure:
Triethylamine (0.14 ml, 1 mmol) was added to a solution of 5-(3,4-dichlorophenyl)-1-cyclohexylmethyl-5-formylmethyl-3-oxapiperidin-2-one (see Preparation 1) (177 mg, 0.46 mmol) and 3-morpholinoazetidine dihydrochloride (119 mg, 0.54 mmol) in tetrahydrofuran (10 ml). After one hour, sodium triacetoxyborohydride (136 mg, 1.4 mol equivalent) was added, followed immediately by glacial acetic acid (26 μl, 1 equivalent) and the mixture stirred for 11/2 hours. Saturated aqueous sodium bicarbonate solution (10 ml) was added and the mixture extracted with ethyl acetate (10 ml×2). The combined organic extracts were dried over magnesium sulphate and the solvent removed under reduced pressure. The residue was chromatographed using silica gel eluting with a solvent gradient of methanol:ethylacetate (1:10 to 40:60 by volume) to provide the title compound (174 mg). LRMS m/z=509 (M+). TLC Rf=0.2 (silica, ethyl acetate:methanol, 9:1 by volume). Found: C,58.24; H,7.02, N,7.48. C26H37N3O3Cl2. 0.4 CH2Cl2 requires C,58.24, H,7.00, N,7.72%. 1H-NMR (CDCl3): δ=0.75-1.35(m,5H), 1.4-1 .5(m,1H), 1.5-1.9(m,7H), 2.1-2.4(m,6H), 2.7-2.8(m,2H), 2.8-3.0(m,1H), 3.05-3.3(m,2H), 3.3-3.55(m,4H), 3.6-3.8(m,4H), 4.3-4.4(m,1H), 4.5-4.6(m,1H), 7.0-7.1 (m,1H), 7.25-7.3(m,1H), 7.35-7.45(m,1H)ppm.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH2:15]>>[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH:15][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)=[O:10]
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)c1cccc(Br)n1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 6-bromo-pyridine-2-carboxylic acid and N,N-dimethylethylenediamine.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C@@H:7]([CH3:21])[CH2:8][N:9]2[C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][N:13]=2)=[CH:4][CH:3]=1.ClCCCl.C(N(CC)C(C)C)(C)C.[C:35](Cl)(=[O:37])[CH3:36]>C(OCC)(=O)C>[O:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:12]([N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=3)[N:6]([C:35](=[O:37])[CH3:36])[C@@H:7]([CH3:21])[CH2:8]2)=[N:13]1
Reactant: CC(=O)Cl
Reactant: C[C@H]1CN(c2noc3ccccc23)c2cc(Br)ccc2N1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(=O)N1c2ccc(Br)cc2N(c2noc3ccccc23)C[C@@H]1C
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A reaction vial was charged with (S)-3-(7-bromo-3-methyl-3,4-dihydroquinoxalin-1(2H)-yl)benzo[d]isoxazole (10.33 mg, 0.03 mmol) and 1,2-dichloroethane (0.30 mL). N,N-Diisopropylethylamine (0.026 mL, 0.150 mmol) and acetyl chloride (6.4 μl, 0.090 mmol) were added, and the mixture stirred at 50° C. for 1.5 h. The reaction was diluted with ethyl acetate and washed with brine. The aqueous layer was separated and washed with ethyl acetate, and the combined organic layers were concentrated under a stream of nitrogen to afford (S)-1-(4-(benzo[d]isoxazol-3-yl)-6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.012 g, 0.03 mmol) which was used without purification. MS (ESI, pos. ion) m/z 386
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH2:20][S:21]([NH2:24])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1N=CN=C(NC2C=C(CS(N)(=O)=[O:41])C=CC=2)N=1.OC[C@@H]1CCCN1>>[OH:41][CH2:2][C@@H:3]1[CH2:4][CH2:5][CH2:6][N:1]1[C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:15]=[C:16]([CH2:20][S:21]([NH2:24])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[N:8]=1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCCCC3)n2)c1
Agent: OC[C@@H]1CCCN1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCC[C@H]3CO)n2)c1

Procedure:
B25 was prepared following the general procedure reported for B1 using A1 and (S)-2-(hydroxymethyl)pyrrolidine. MS (ES) C15H20N6O3S requires: 364. found: 365 (M+H)+.