Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]2[CH:19]=[C:20](OS(C(F)(F)F)(=O)=O)[CH:21]=[CH:22][CH:23]=2)[CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=[NH:97])(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])(=O)C.[Na+].Cl.NO>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]2[CH:19]=[C:20]([NH2:97])[CH:21]=[CH:22][CH:23]=2)[CH2:13]1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Oc1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Product: Nc1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 20.5 %

Procedure:
A mixture of trifluoro-methanesulfonic acid 3-{(R*)-1-[(S)-1-(2,3-dihydro-benzo[1,4]dioxin-2-yl)methyl]-piperidin-3-yl}-phenyl ester (1.039 g, 2.27 mmol), cesium carbonate (1.036 g, 3.18 mmol), palladium acetate (0.015, 0.068 mmol), (R)-(+)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (0.064 g, 0.102 mmol) and benzophenone imine (0.457 ml, 2.73 mmol) in dry tetrahydrofuran (6 ml) was heated in a microwave reactor at 80° C. for 10 hours. The mixture was filtered and evaporated to dryness. The crude product was purified by flash chromatography using a gradient of heptane and EtOAc as eluent. The residue on evaporation was dissolved in dry methanol, sodium acetate (0.54 g, 6.55 mmol) and hydroxylamine hydrochloride (0.36 g, 5.24 mmol) was added and the mixture was stirred at room temperature for 1.5 h. The mixture was evaporated to dryness, dissolved in EtOAc and washed with 1M Na2CO3. The organic layer was dried (Na2SO4), filtered and evaporated to dryness. The crude product was purified by flash chromatography using gradient of heptane and EtOAc as eluent to give 151 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.Br[CH2:18][CH2:19][CH3:20].CC(C)([O-])C.[K+].O>CN(C)C=O>[Br:1][C:2]1[C:3]([O:16][CH2:18][CH2:19][CH3:20])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2
Reactant: CCCBr
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1c(Br)ccc2c1CC[C@H](C)N2C(C)=O
Temperature: 80 °C
Reaction time: 24 h
Yield: 58.1 %

Procedure:
A mixture of (S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1 (2H)-yl)ethanone (0.150 g, 0.528 mmol), 1-bromopropane (0.24 mL, 2.64 mmol), and potassium tert-butoxide (0.296 g, 2.64 mmol) in N,N-dimethylformamide (3.0 mL) was heated at 80° C. After 24 h, a second portion of 1-bromopropane (0.24 mL, 2.64 mmol) and potassium tert-butoxide (0.296 g, 2.64 mmol) was added and the mixture was heated at 100° C. for 24 h. The reaction mixture was cooled to rt and water was added. The mixture was extracted with dichloromethane and the combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a yellow oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 50-100% ethyl acetate-hexane) to afford (S)-1-(6-bromo-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.100 g, 58%) as a colorless oil. MS (ESI, pos. ion) m/z 326, 328 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([C:17]2[N:22]=[C:21]([CH3:23])[C:20]([C:24]([OH:26])=O)=[CH:19][N:18]=2)[CH:14]=[CH:15][CH:16]=1.[N+:27]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([NH2:39])[CH:34]=[CH:33]2)([O-:29])=[O:28].CN(C(SC1[N+]([O-])=CC=CC=1)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N+:27]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([NH:39][C:24]([C:20]1[C:21]([CH3:23])=[N:22][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[CH:12]=3)=[N:18][CH:19]=1)=[O:26])[CH:34]=[CH:33]2)([O-:29])=[O:28]
Reactant: Nn1ccc2cc([N+](=O)[O-])ccc21
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Agent: CN(C)C(Sc1cccc[n+]1[O-])=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2cc([N+](=O)[O-])ccc21
Temperature: 85 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
DIPEA (12.65 mmol) is added a solution of 2-(3-fluoro-phenyl) -4-methyl-pyrimidine-5-carboxylic acid (4.22 mmol), 5-nitro-indole-1-ylamine (4.22 mmol) and HOTT (S-(1-oxido-2-pyridyl)-thio-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (7.6 mmol) in anhydrous DMF (15 mL) and the mixture is heated at 80-90° C. overnight. After evaporation of solvent, the residue is dissolved in EtOAc (150 mL), washed with water (20 mL), 5% sodium sulfate (20 mL), water (mL) and brine (20 mL). The organic layer is dried (Na2SO4), filtered and concentrated. The residue is kept at rt overnight to yield 4-methyl-2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (5-nitro-indol-1-yl)-amide (730 mg, 44%) as a solid. MS: 392 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.78(s, 3H), 6.88(d, H), 7.38-7.53(m, H), 7.57-7.76(m, 2H), 7.81(d, H), 8.06-8.32(m, 2H), 8.34(d, H), 8.65(d, H), 9.27(s, 2H).
Reaction SMILES: O1CC1CO[C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)=[O:9].C1(CN)CCCCC1>C(O)C>[NH:15]1[C:16]2[C:12](=[C:11]([NH:10][C:8](=[O:9])[C:7]3[CH:6]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCC1CO1
Agent: NCC1CCCCC1
Solvent: CCO
Product: O=C(Nc1cccc2[nH]ccc12)c1ccccc1

Procedure:
A solution of 2.5 g of 2-[(2-oxiranyl)methoxy]-N-(1H-indol -4-yl)-benzamide in 50 ml of ethanol in the presence of 1.147 g of cyclohexane methylamine was refluxed for 2 hours and 15 minutes and the solvent was evaporated under reduced pressure. The residue was chromatographed over silica (eluent: methylene chloride - methanol, 9-1) to obtain 1.97 g of 2-[3-(cyclohexylmethyl)amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)-benzamide.
Reaction SMILES: Cl.[OH:2][NH2:3].C(N(CC)CC)C.[C:11]([C:13]1[CH:37]=[CH:36][C:16]([O:17][CH:18]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[C:25]([O:33][CH2:34][CH3:35])[CH:24]=2)[C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1)#[N:12]>CS(C)=O.C(OCC)(=O)C>[OH:2][NH:3][C:11]([C:13]1[CH:14]=[CH:15][C:16]([O:17][CH:18]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[C:25]([O:33][CH2:34][CH3:35])[CH:24]=2)[C:19]([O:21][CH3:22])=[O:20])=[CH:36][CH:37]=1)=[NH:12]
Reactant: CCOc1cc(C(Oc2ccc(C#N)cc2)C(=O)OC)ccc1OC(C)C
Reactant: NO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(Oc2ccc(C(=N)NO)cc2)C(=O)OC)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To hydroxyamine HCl salt (363 mg, 5.2 mmol) in DMSO (5.0 mL) was added triethyl amine (0.725 mL, 5.2 mmol). After stirring at rt for 10 min, the cloudy solution was filtered directly into a round-bottom flask containing 9A (482 mg, 1.3 mmol). The mixture was stirred at 60° C. for 18 h before it was diluted with ethyl acetate and washed with 5% NaHCO3/brine. The organic extract was dried over Na2SO4 and concentrated to give 9B as a white solid. LC-MS 403 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Cl.Cl[CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[Cs+].[Cs+]>Cl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: ClCCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC1(C)C(=O)N(CCCN2CCOCC2)c2cc([N+](=O)[O-])c(N)cc21
Reaction time: 96 h
Yield: 101.3 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (0.5 g) is alkylated using 4-(3-chloro-propyl)-morpholine hydrocloride (0.57 g; 2.85 mmol), Cs2CO3 (1.55 g; 4.75 mmol) and a catalytic amount of nBU4NI at 70° C. for 4 days. After aqueous work-up the crude material is de-acetylated in hydrochloric acid (6 N, 20 ml) at 80° C. in 4 h. After aqueous work-up 5-amino-3,3-dimethyl-1-(3-morpholin-4-yl-propyl)-6-nitro-1,3-dihydro-indol-2-one (0.67 g) is obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:50]([O:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([NH2:65])[CH:60]=2)=[CH:55][C:54]=1[CH3:66])[CH3:51]>CN(C=O)C>[CH2:50]([O:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([NH:65][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:60]=2)=[CH:55][C:54]=1[CH3:66])[CH3:51]
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: CCOc1ccc(-c2cccc(N)c2)cc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)cc1C
Temperature: 25 °C
Yield: 62.6 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.016 g, 0.067 mmol) and HATU (0.028 g, 0.072 mmol) in 0.37 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-ethoxy-3′-methyl-biphenyl-3-ylamine (0.015 g, 0.067 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.018 g of product in 65% yield: LCMS (ESI) m/z 430 (MH+).
Reaction SMILES: B(Br)(Br)Br.[CH3:5][NH:6][C:7](=[O:38])[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]([CH3:22])([CH2:19][O:20]C)[C:17](=[O:23])[N:16]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=3)[C:15]2=[S:36])=[CH:10][C:9]=1[F:37].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH3:5][NH:6][C:7](=[O:38])[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]([CH2:19][OH:20])([CH3:22])[C:17](=[O:23])[N:16]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=3)[C:15]2=[S:36])=[CH:10][C:9]=1[F:37]
Reactant: CNC(=O)c1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)COC)cc1F
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CNC(=O)c1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)CO)cc1F
Temperature: -78 °C
Reaction time: 3 h

Procedure:
BBr3 (53 mkl, 0.55 mmol) was added dropwise to solution of N-methyl-4-[5-methyl-5-(methoxymethyl)-4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]imidazolidin-1-yl]-2-fluorobenzamide (55 mg, 0.11 mmol) in CH2Cl2 (1.5 ml) in argon atmosphere at −78° C. The reaction mixture was stirred at −78° C. for 3 h and then for another 3 h at room temperature. After the reaction was completed the excess of BBr3 was neutralized by addition of 5% Na2CO3 solution (10 ml), the product was extracted with AcOEt, dried over Na2SO4, evaporated in vacuo, and by HPLC method N-methyl-4-[5-(hydroxymethyl)-5-methyl-4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]imidazolidin-1-yl]-2-fluorobenzamide 1.2.2(3) was isolated, Ki1.2.2(3)=46.3 nM, 1H NMR (DMSO-d6, 400 MHz): 8.43 (br. m, 1H), 8.39 (d, J=8.4 Hz, 1H), 8.13 (s, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.78 (t, J=8.0 Hz, 1H), 7.42 (d, J=10.8 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 5.93 (t, J=4.4 Hz, 1H), 3.81 (dd, J1=11.6 Hz, J2=4.4 Hz, 1H), 3.45 (dd, J1=11.6 Hz, J2=5.0 Hz, 1H), 2.79 (d, J=4.0 Hz, 3H), 1.38 (s, 3H).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:28]([OH:30])=O)[C:9]2[NH:13][C:12]([NH:14][C:15]([C:17]3[N:18]=[CH:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:16])=[N:11][C:10]=2[CH:27]=1)(=[O:5])=[O:4])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.S(O)(O)(=O)=O.[NH2:69][C:70]1[NH:71][CH:72]=[CH:73][N:74]=1>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:28](=[O:30])[NH:69][C:70]2[NH:71][CH:72]=[CH:73][N:74]=2)[C:9]2[NH:13][C:12]([NH:14][C:15]([C:17]3[N:18]=[CH:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:16])=[N:11][C:10]=2[CH:27]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: Nc1ncc[nH]1
Reactant: CCS(=O)(=O)c1cc(C(=O)O)c2[nH]c(NC(=O)c3cc4ccccc4cn3)nc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1cc(C(=O)Nc2ncc[nH]2)c2[nH]c(NC(=O)c3cc4ccccc4cn3)nc2c1
Yield: 49 %

Procedure:
62 mg (0.15 mmol) of 6-ethylsulfonyl-2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid and 200 mg (0.53 mmol) of HBTU were dissolved in 1.0 mL of DMF and 0.5 mL of DIEA and treated with 132 mg (1.0 mmol) of 2-aminoimidazole sulfate as described in general procedure A. After the reaction was complete, diluted with brine 10 (mL). The resulting solid was filtered, washed with water, EtOAc and dried under vacuum to produce 36 mg (57%) of isoquinoline-3-carboxylic acid [5-ethanesulfonyl-7-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 490 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:11])[CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([O-])(=O)C.[NH4+].[Br:17]N1C(=O)CCC1=O.CCOC(C)=O>C(#N)C>[Br:17][C:7]1[C:6]([CH3:8])=[CH:5][C:4]([N:9]([CH3:10])[CH3:11])=[CH:3][C:2]=1[F:1]
Reactant: Cc1cc(F)cc(N(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc(N(C)C)cc(F)c1Br
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of (3-Fluoro-5-methyl-phenyl)-dimethyl-amine (2.82 g, 18.4 mmol) in acetonitrile (28 mL) were sequentially added ammonium acetate (0.142 g, 1.84 mmol) and a solution of N-bromosuccinimide (3.27 g, 18.4 mmol) in acetonitrile (23 mL) drop-wise at 0° C. After 1 h., at r.t., the solvent was switched to EtOAc, and the solution was washed with saturated NaHCO3 (aq), dried (MgSO4), filtered, and concentrated in vacuo to give an orange, oily residue. Purification of this oil by flash chromatography (SiO2, 5% EtOAc/Hexanes) gave (4-Bromo-3-fluoro-5-methyl-phenyl)-dimethyl-amine as an ivory solid (3.96 g, 93%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:11][CH:12]=[O:13])=[CH:2]1.[CH2:14]([CH:16]1[O:18][CH2:17]1)Br.[OH-].[K+].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[OH:18][CH2:17][CH2:16][CH2:14][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:11][CH:12]=[O:13])=[CH:2]1
Reactant: O=CC=Cc1c[nH]c2ccccc12
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=CC=Cc1cn(CCCO)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 10 mL Pyrex-glass vessel is mixed 3-(1H-indol-3-yl)acrylaldehyde (171 mg, 1 mmol), epibromohydrin (137 mg, 1 mmol), KOH (224 mg, 4 mmol) and anhydrous K2CO3 (553 mg, 4 mmol) in 1 mL DMF. This mixture is subjected to microwave irradiation at 350 W in successive 30 s periods, with 30 s periods at room temperature between each irradiation to avoid overheating the reaction. After the reaction has reached completion as monitored by TLC (5:1-hexanes:EtOAc) the reaction mixture is allowed to cool to room temperature and then is quenched by the addition of 10 mL 1M NaOH under vigorous stirring. The mixture is stirred for an additional 2 hrs, whereupon it is poured into 50 mL of ice-cold water. The precipitated solids are removed by filtration and washed 3×25 mL with water. The resulting solids are dried under vacuum and then recrystallized from ethanol to afford colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][CH2:15][NH2:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:19]1([C:25](O)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][CH2:15][NH:16][C:25]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:26])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CCN)CCN(C)C1
Reactant: O=C(O)C1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CCNC(=O)C2CCCCC2)CCN(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.9 %

Procedure:
A mixture of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethanamine (100 mg, 0.41 mmol), cyclohexane carboxylic acid (52 mg, 0.41 mmol), N,N′-dicyclohexylcarbodiimide (93 mg, 0.45 mmol) and 4-dimethylaminopyridine (55 mg, 0.45 mmol) in dry dichloromethane (2.5 ml) were stirred at room temperature for 3 h. The reaction mixture was filtered through Celite and concentrated using rotary evaporator to afford 10 mg of N-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethyl)cyclohexanecarboxamide as TFA salt after purification by reversed-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 ml). 1H NMR (DMSO) 9.94 (bs, 1H), 7.86 (t, 1H), 7.38 (d, 1H), 7.11 (s, 1H), 7.0 (d, 1H), 4.56-4.63 (m, 1H), 4.22-4.29 (m, 1H), 4.08-4.13 (m, 3H), 3.72-3.81 (m, 3H), 3.08-3.14 (m, 3H), 2.97 (s, 3H), 2.38 (s, 3H), 1.95-2.0 (m, 1H), 1.50-1.84 (m, 5H), 1.02-1.2 (m, 4H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.[CH3:19][C@@H:20]([C:36](=[O:43])[C@@H:37]([CH3:42])[C@H:38]([OH:41])[CH2:39][CH3:40])[C:21]([N:23]1[C@@H:27]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:26][O:25][C:24]1=[O:35])=[O:22].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>C(O)(=O)C.C(#N)C>[CH3:19][C@@H:20]([C@@H:36]([OH:43])[C@@H:37]([CH3:42])[C@H:38]([OH:41])[CH2:39][CH3:40])[C:21]([N:23]1[C@@H:27]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:26][O:25][C:24]1=[O:35])=[O:22]
Reactant: CC[C@@H](O)[C@H](C)C(=O)[C@H](C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC[C@@H](O)[C@H](C)[C@H](O)[C@H](C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
Tetramethylammonium triacetoxyborohydride (2.89 g) was dissolved in a mixture of acetic acid (11 ml) and acetonitrile (11 ml), stirred for 30 minutes at ambient temperature, then cooled to −15° C. before addition of (4S)-N-[(2S,4S,5R)-2,4-dimethyl-5-hydroxy-3-oxoheptanoyl]-4-benzyl-2-oxazolidinone (0.764 g). After stirring for 4 hours, 34 ml of 0.5 M sodium tartrate was added and stirring was continued for an additional 3 hours. After extraction with 3 portions of CH2Cl2, the organic phases were combined and dried over MgSO4. The solvent was removed under vacuum, and the crude product was evaporated 3 times from 50 ml of methanol to yield 0.644 g of product (84%).
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=2[Br:22])=[C:6]([CH2:25][CH2:26][CH3:27])[C:5]=1[OH:28])(=[O:3])[CH3:2].[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[C:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([O:19][CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34][O:29]3)=[O:18])=[CH:15][C:14]=2[Br:22])=[C:6]([CH2:25][CH2:26][CH3:27])[C:5]=1[OH:28])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)O)cc2Br)ccc(C(C)=O)c1O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCCc1c(OCCCOc2ccc(C(=O)OC3CCCCO3)cc2Br)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In methylene chloride (30 ml) was dissolved 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3-bromobenzoic acid (1.35 g). To the solution were added dihydropyran (0.9 ml) and p-toluene sulfonic acid.monohydrate (5 mg). The mixture was stirred at room temperature for 30 minutes, to which was further added methylene chloride (30 ml). The resulting solution was washed with an aqueous solution of sodium hydrogen carbonate and then with water, followed by drying with sodium sulfate. The solvent was evaporated off, and the residue was purified by means of a silica-gel column chromatography (Developing solvent: chloroform) to give 1.4 g of tetrahydropyranyl 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3-bromobenzoate as colorless oily substance.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]2=[N:5][N:4]=1.[OH:14]O>C(O)(=O)C>[F:13][C:2]([F:12])([F:1])[C:3]1[N:7]2[CH:8]=[CH:9][N+:10]([O-:14])=[CH:11][C:6]2=[N:5][N:4]=1
Reactant: FC(F)(F)c1nnc2cnccn12
Reactant: OO
Solvent: CC(=O)O
Product: [O-][n+]1ccn2c(C(F)(F)F)nnc2c1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A mixture of 250 mg (1.33 mmol) of 3-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyrazine (Intermediate 6, Step A), 0.479 mL (4.66 mmol) of 30% hydrogen peroxide aqueous solution, and 2 mL of glacial acetic acid was stirred at 95° C. After 8 h, the solution was cooled and concentrated. The residue was partitioned between dichloromethane and saturated sodium bicarbonate aqueous solution. Thin-layer chromatography on silica gel (90:10:1 dichloromethane:methanol:concentrated ammonium hydroxide solution) revealed that the product was in the aqueous phase. Therefore, the aqueous solution was concentrated to dryness, and the residue was purified by preparative HPLC (C18 reverse phase column, 0-50% acetonitrile in water containing 0.05% trifluoroacetic acid) to provide the title compound as a white solid. LC-MS 205 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=1)[CH:4]=[CH2:5].[CH:16]1([CH2:19]Br)[CH2:18][CH2:17]1>CS(C)=O>[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][CH2:19][CH:16]2[CH2:18][CH2:17]2)=[CH:9][CH:8]=1)[CH:4]=[CH2:5]
Reactant: BrCC1CC1
Reactant: C=CCOc1ccc(CCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C=CCOc1ccc(CCOCC2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
To a flask charged with redistilled dimethylsulphoxide (50 ml) and sodium hydride (50% dispersion, 4.8 g) was slowly added 2-(4-allyloxyphenyl)ethanol (17.8 g) at ice-bath temperature. Cyclopropylmethyl bromide (13.5 g) in dry dimethyl sulphoxide (20 ml) was added with cooling under nitrogen. The reaction mixture was stirred at room temperature overnight, poured on to ice-water and extracted into diethyl ether. The organic layer was thoroughly washed with saturated brine, evaporated under reduced pressure and chromatographed on silica using petroleum ether (40°-60°) as an eluant to afford 1-allyloxy-4-[2-(cyclopropylmethoxy)ethyl]benzene (9 g).