Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C2(C(O)=O)CCCC2)C=CC=CC=1.[CH3:15][CH:16](C)[CH:17]([C:40]1C=C[CH:43]=[CH:42][CH:41]=1)[C:18]([NH:20][C@@H:21]1[C@H:28]2[C@H:24]([CH2:25][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH2:27]2)[CH2:23][CH2:22]1)=[O:19].C(N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[F:37][C:36]([F:38])([F:39])[C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=1)[CH2:29][N:26]1[CH2:27][C@H:28]2[C@@H:21]([NH:20][C:18]([CH:17]3[CH2:16][CH2:15][CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:19])[CH2:22][CH2:23][C@H:24]2[CH2:25]1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1ccccc1
Agent: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Agent: O=C(O)C1(c2ccccc2)CCCC1
Product: O=C(N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)C1CCCCCC1

Procedure:
The title compound was prepared by substituting cycloheptanecarboxylic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4S*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 1: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.79 (d, J=6.9, 1H), 7.71 (s, 1H), 7.62 (d, J=7.7, 1H), 7.56 (s, 1H), 7.47 (t, J=7.7, 1H), 4.48-4.40 (m, 1H), 3.54 (d, J=13.2, 1H), 3.46 (d, J=13.2, 1H), 2.86 (ddd, J=3.0, 7.8, 16.6, 1H), 2.76 (dd, J=3.0, 9.5, 1H), 2.51-2.39 (m, 2H), 2.37-2.30 (m, 2H), 2.26 (dd, J=7.5, 9.4, 1H), 2.00-1.80 (m, 5H), 1.75-1.60 (m, 4H), 1.49-1.41 (m, 4H), 1.33 (ddt, J=7.2, 8.9, 12.1, 3H); MS (ESI+) m/z 409 (M+H)+.
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:15]([CH2:16][NH:17][C@H:18]([C:23]([O:25][CH3:26])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:27][CH3:28])[O:7]1)=O)C>C(#N)C>[CH3:26][O:25][C:23](=[O:24])[C@@H:18]([N:17]1[CH2:16][C:15]2=[CH:14][C:13]3[C:12]([O:27][CH3:28])=[CH:11][CH:10]=[CH:9][C:8]=3[O:7][CH:6]2[C:4]1=[O:3])[CH2:19][CH:20]([CH3:21])[CH3:22]
Reactant: CCOC(=O)C1Oc2cccc(OC)c2C=C1CN[C@@H](CC(C)C)C(=O)OC
Solvent: CC#N
Product: COC(=O)[C@H](CC(C)C)N1CC2=Cc3c(OC)cccc3OC2C1=O
Yield: 63.5 %

Procedure:
A solution of 5-methoxy-3-[((S)-1-methoxycarbonyl-3-methyl-butylamino)-methyl]-2H-chromene-2-carboxylic acid ethyl ester (0.45 g, 1.14 mmol) and N,N′-diisopropylethyl amine (0.8 mL, 4.50 mmol) in acetonitrile (2 mL) was heated in a sealed tube at 140° C. for 48 hours. The reaction mixture, after aqueous work-up, extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated in vacuo and the residue was purified over neutral alumina using hexanes-ethyl acetate as eluents to afford (S)-2-(8-methoxy-3-oxo-3,3a-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid methyl ester (0.25 g, 62.9%) as a solid.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:7]=[CH:8][CH:9]=1)=[N+]=[N-].[F:19][C:20]([F:26])([F:25])[S:21]([OH:24])(=[O:23])=[O:22].FC(F)(F)C(O)=O.N>>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[C:7]([O:24][S:21]([C:20]([F:26])([F:25])[F:19])(=[O:23])=[O:22])=[CH:8][CH:9]=1
Reactant: [N-]=[N+]=Nc1cccc(-c2nc3ccccc3s2)c1
Reactant: O=S(=O)(O)C(F)(F)F
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(OS(=O)(=O)C(F)(F)F)c(-c2nc3ccccc3s2)c1
Temperature: 20 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
2-(3-Azidophenyl)benzothiazole (1 g) was added in small portions (5×0.2 g) to a mixture of trifluoromethanesulphonic acid (4 ml), trifluoroacetic acid (5 ml) and triflucromethylacetic anhydride (1 ml) at 0° C. After evolution of nitrogen ceased, the mixture was stirred at 20° C. for 18 hours, basified with aqueous ammonia and the products extracted into ethyl acetate. The organic layer was washed with water, dried (MgSO4) and evaporated to give a gum which was separated on silica with hexane-ethyl acetate (6:4) as eluent. The product obtained was the title compound (70% yield). (Found: M+ 374. C14H9F3N2O3S2 requires MW 374). An in vitro assay of this compound against MCF-7 (wild type) cells gave an IC50 value of 50 nM which again indicates a useful level of activity.
Reaction SMILES: O=[C:2]1[C:7]2[CH:8]=[C:9]([C:11]#[N:12])[S:10][C:6]=2[CH:5]=[CH:4][NH:3]1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:2]1[C:7]2[CH:8]=[C:9]([C:11]#[N:12])[S:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1cc2c(=O)[nH]ccc2s1
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cc2c(Cl)nccc2s1

Procedure:
A solution of 4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-nitrile (500 mg, 2.84 mmol) prepared as in F. Eloy and A. Deryckere, Bull. Soc. Chim. Belg. 1970, 79, 301) and phosphoryl chloride (5 mL) was heated at reflux for 1 hour. The formed red solution was poured onto ice and extracted with methylene chloride (2×150 mL). The dichloromethane solution was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography with 1:10 EtOAc/hexanes to provide the title compound.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)C1C=CC=CC=1>C(OC(C)=O)(C)C.[Pd]>[OH:8][CH2:9][CH:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1
Reactant: O=S1(=O)CCC(COCc2ccccc2)N1
Agent: [Pd]
Solvent: CC(=O)OC(C)C
Product: O=S1(=O)CCC(CO)N1
Reaction time: 72 h
Yield: 64.8 %

Procedure:
Dioxide 7 (40 g, 0.17 mol) was placed in the glass liner within a 2 L Parr hydrogenator and dissolved in a mixture of IMS (150 ml) and iPrOAc (150 ml). A suspension of 5% palladium on carbon (Johnson Matthey type 392, 18 g) in iPrOAc (50 mL) was added and the suspension stirred under a hydrogen atmosphere of 70 psi for 3 days. After this time an NMR IPC was carried out that showed approx 15% benzylated material still present. After a further 4 days the reaction was 94% complete and it was decided to stop the hydrogenolysis. The palladium catalyst was filtered under nitrogen on a bed of celite, which was subsequently washed with IMS (250 mL) and iPrOAc (250 mL). The filtrate and washings were concentrated to give the crude product as an oil (26.26 g). The oil was purified by flash column chromatography (silica gel, DCM/methanol (9:1)) yielding 16.65 g (67%) of the hydroxyl-dioxide 8 as a white solid.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([CH:19]=O)[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[CH:21]1([NH2:24])[CH2:23][CH2:22]1.CC(O)=O.[BH3-]C#N.[Na+]>C1COCC1.CO>[CH:21]1([NH:24][CH2:19][C:17]2[CH:16]=[CH:15][C:13]3[N:14]=[C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]5[CH2:3][CH2:2]5)[CH2:5][CH2:6]4)[S:11][C:12]=3[CH:18]=2)[CH2:23][CH2:22]1
Reactant: NC1CC1
Reactant: O=Cc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: c1cc2nc(N3CCN(C4CC4)CC3)sc2cc1CNC1CC1
Yield: 79.3 %

Procedure:
To a solution of 2-(4-cyclopropylpiperazin-1-yl)benzothiazole-6-carbaldehyde (400 mg, 1.39 mmol) and cyclopropylamine (159 mg, 2.78 mmol) in a 1:3 mixture of CH3OH and THF (40 mL) was added AcOH (417 mg, 6.95 mmol), followed by NaCNBH3 (140 mg, 2.22 mmol). The mixture was heated at reflux for 12 h and then the volatiles were evaporated. Water (10 mL) was added and the mixture was extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by the preparative HPLC to give 362 mg (79%) of cyclopropyl-[2-(4-cyclopropylpiperazin-1-yl)-benzothiazol-6-ylmethyl]-amine as a trifluoroacetate salt.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C>[Si:23]([O:22][CH2:21][CH2:20][CH2:19][O:10][C:8]1[CH:9]=[C:2]([F:1])[C:3]([CH:4]=[O:5])=[C:6]([F:11])[CH:7]=1)([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:25])[CH3:24]
Reactant: O=Cc1c(F)cc(O)cc1F
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCOc1cc(F)c(C=O)c(F)c1
Yield: 95.9 %

Procedure:
As described in the previous experiment, a mixture of 2,6-difluoro-4-hydroxybenzaldehyde (515 mg, 3.25 mmol), K2CO3 (675 mg, 4.88 mmol) and (3-bromopropoxy)-tert-butyldimethylsilane (1.00 mL, 4.23 mmol) in DMF (8 mL) were reacted, processed and purified by flash chromatography (15% EtOAc/Hex) to afford 4-(3-(tert-butyldimethylsilyloxy)propoxy)-2,6-difluorobenzaldehyde as a white solid (1.03 g, 96%). MS (EI) m/z 331.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:10]([S:11][CH3:12])=[C:9](Cl)[N:8]=[C:7]([Cl:14])[N:6]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:10]([S:11][CH3:12])=[C:9]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:8]=[C:7]([Cl:14])[N:6]=1
Reactant: COC(=O)Cc1nc(Cl)nc(Cl)c1SC
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: COC(=O)Cc1nc(Cl)nc(N2CCOCC2)c1SC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (2,6-dichloro-5-methylsulfanyl-pyrimidin-4-yl)-acetic acid methyl ester (860 mg, 3.22 mmol.), morpholine (336 mg, 3.86 mmol, 1.2 eq.) and THF (10 ml) was stirred at room temperature for 2.0 hrs. The reaction mixture was dried and the solvent was evaporated. The reaction mixture was subjected to addition of 0.1 N HCl washing free morpholine, extraction with EA and evaporation to remove the EA so as to give a crude. Purification of the crude by flash chromatography on silica gel (Hexane/EtOAc 2:1) gave a gray solid of 427 mg (42.7%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].[Br:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[N:11]=[C:12](Cl)[C:13]([CH3:19])=[N:14]2.[H-].[Na+]>C1COCC1.CN(C=O)C>[Br:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[N:11]=[C:12]([O:5][CH:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])[C:13]([CH3:19])=[N:14]2
Reactant: CC(O)C(F)(F)F
Reactant: Cc1nc2cccc(Br)c2nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc2cccc(Br)c2nc1OC(C)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 88.5 %

Procedure:
To a suspension of 1,1,1,-trifluoro-2-propanol (0.85 mL, 9.38 mmol) and 5-bromo-3-chloro-2-methylquinoxaline (126e) (1.21 g, 4.69 mmol) in 5 mL of THF and 3 mL of DMF at 0° C. was added NaH (60% wt. in mineral oil) (0.31 g, 7.74 mmol). The resulting dark purple homogeneous solution was stirred at 0° C. for 5 min then RT for 1 h. It was quenched with 15 mL of sat. NH4Cl aq. solution, and extracted with 2×75 mL of EtOAc. The organic extracts were concentrated and the residue was purified on a silica gel column (1-35% EtOAc in hexanes) to give 5-bromo-2-methyl-3-((1,1,1-trifluoropropan-2-yl)oxy)quinoxaline (452a) (1.39 g, 4.15 mmol, 88% yield) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.09 (1H, m), 8.00 (1H, dd, J=8.2, 1.0 Hz), 7.60 (1H, t, J=7.9 Hz), 6.02 (1H, dt, J=13.4, 6.7 Hz), 2.62 (3H, s), 1.64 (3H, d, J=6.7 Hz). 19F NMR (376 MHz, DMSO-d6) δ ppm −77.20 (1F, s). m/z (ESI, +ve) 335.0/337.0 (M+H)+. A mixture of Pd(dppf)Cl2 (51 mg, 0.06 mmol), (BPin)2 (637 mg, 2.50 mmol), KOAc (492 mg, 5.01 mmol), 5-bromo-2-methyl-3-((1,1,1-trifluoropropan-2-yl)oxy)quinoxaline (452a) (420 mg, 1.25 mmol) in THF (5 mL) was heated in a microwave at 90° C. for 90 min. It was diluted with 50 mL of EtOAc and filtered through a pad of Celite. The filtrate was concentrated and the residue was purified on a silica gel column (25-75% EtOAc in hexanes) to give 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((1,1,1-trifluoropropan-2-yl)oxy)quinoxaline (452b) (400 mg, 84% yield) as a brown solid. m/z (ESI, +ve) 383.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[C:6]([CH3:16])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].CO[CH2:25][CH2:26]OC>O.[Pd]>[CH3:16][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH:25]=[CH2:26])[C:7]=1[CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1
Reactant: Cc1ccnc(Cl)c1COC1CCCCO1
Reactant: COCCOC
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=Cc1nccc(C)c1COC1CCCCO1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
2-Chloro-4-methyl-3-(tetrahydro-pyran-2-yloxymethyl)-pyridine (500 mg. 2.07 mmol) was dissolved in a mixture of 1,2-dimethoxyethane (16.5 mL) and water (7 mL). K2CO3 (286 mg. 2.07 mmol) and 2,4,6-trivinyl-cyclotriboroxane pyridine complex (498 mg. 2.07 mmol) were added and the reaction mixture was degassed two times before the addition of Pd((PPh3)4 (120 mg. 0.10 mmol). The reaction mixture was stirred at 100° C. for 18 h. The solvents were removed in vacuo and the residue was purified by flash chromatography on silica gel (elution with hexane/EtOAc 6:1) to give the title compound. MS (m/z): 234.1 [M+H+]
Reaction SMILES: [CH3:1][N:2]([CH3:25])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[C:10](=[O:23])[C:9]2=[O:24])(=[O:5])=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]([CH3:25])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([OH:18])=[O:17])[C:10](=[O:23])[C:9]2=[O:24])(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2CC(=O)O

Procedure:
A solution of tert-butyl 2-(5-(N,N-dimethylsulfamoyl)-2,3-dioxoindolin-1-yl)acetate (0.926 g, 2.51 mmol) and TFA (3 ml, 38.9 mmol) in DCM (10 ml) was stirred at room temperature for 4 hours. The volatiles were removed under vacuum affording 2-(5-(N,N-dimethylsulfamoyl)-2,3-dioxoindolin-1-yl)acetic acid which was used as such in the next step (1.29 g, 4.13 mmol).MS/ESI+ 312.9 [MH]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][S:17][C:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])=[CH:24][CH:25]=2)[N:20]([C:35]2[N:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][N:36]=2)[CH:19]=1>CN(C=O)C.C(OCC)(=O)C.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]>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:38]2[CH:39]=[N:40][C:35]([N:20]3[C:21]4[C:26](=[CH:25][CH:24]=[C:23]([C:27]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[O:28])[CH:22]=4)[C:18]([S:17][CH3:16])=[CH:19]3)=[N:36][CH:37]=2)[CH:7]=1
Reactant: CSc1cn(-c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reactant: COc1ccnc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccnc(-c2cnc(-n3cc(SC)c4ccc(C(=O)N5CCOCC5)cc43)nc2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
2-Bromo-4-methoxypyridine (215 mg, 1.145 mmol, 1.1 eq), potassium carbonate (431 mg, 3.124 mmol, 3.0 eq) and PdCl2(dppf) (85 mg, 0.104 mmol, 0.1 eq) were added at room temperature and under an inert atmosphere to a solution of the raw product from 141a) (500 mg, 1.041 mmol, 1.0 eq) in DMF (10 mL). The reaction mixture was stirred at 100° C. for 3 h and then cooled to room temperature. For the work up, the mixture was diluted with ethyl acetate (20 mL), washed with water (2×20 mL) and brine, and dried over anhydrous sodium sulfate. The solvents were removed under reduced pressure and the remnant was purified by column chromatography [100-200 mesh silica gel; 5% methanol in dichloromethane]. White solid. Yield: 200 mg (41% of theory over two steps)
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]2)OCC1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>CN(C=O)C>[CH2:15]([O:12][CH2:11][CH:8]1[CH2:7][CH2:6][C:5](=[O:1])[CH2:10][CH2:9]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: OCC1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C1CCC(COCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
1,4-dioxaspiro[4.5]decan-8-ylmethanol (1.33 g, 7.72 mmol) was dissolved in DMF (14 mL) and then cooled to 0° C. To the solution was added NaH (0.402 g, 10.04 mmol) in portions and the mixture agitated at 10° C. for 1 h and then benzyl bromide (1.194 mL, 10.04 mmol) was added and the mixture agitated over 72 h. The reaction mixture was quenched with water and extracted with ether and the combined organic extracts dried (MgSO4), filtered and concentrated in vacuo and the crude product 8-((benzyloxy)methyl)-1,4-dioxaspiro[4.5]decane dissolved in acetonitrile (35 mL) and water (25 mL) and treated with 3N HCl (13 mL) and agitated at room temperature for 20 min upon which LCMS indicated desired product. The reaction mixture was quenched with 40 mmol aqueous NaOH and then extracted with EtOAc (200 mL) and the organic layer was washed with water and dried (MgSO4), filtered and concentrated in vacuo and the residue purified by flash chromatography (0-50% EtOAc/heptane) to afford 1.23 g of the desired product as a colorless syrup (73%). LCMS (m/z): 329.2 (MH+), 1.33 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:14](I)[CH3:15].[BH4-].[Na+]>CN(C=O)C.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH:12]=[CH:11][CH2:10][N:9]2[CH2:14][CH3:15])=[CH:6][CH:7]=1
Reactant: Brc1ccc(-c2ccccn2)cc1
Reactant: CCI
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCN1CC=CCC1c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
To a solution of 2-(4-bromophenyl)pyridine (2.7 g, 11.5 mmol) in DMF (50 mL) was added ethyl iodide (1.9 mL, 23.1 mmol) and the reaction mixture was heated to 80° C. for 16 h. The mixture was cooled then evaporated and the resultant residue dissolved in methanol (100 mL) before addition of sodium borohydride (1.5 g, 39.2 mmol) portionwise. The reaction mixture was stirred at ambient temperature for 1 h then evaporated and saturated aqueous sodium carbonate solution was added. The mixture was extracted with ethyl acetate (2×100 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated then the residue was purified by flash chromatography (silica, Biotage 100 g column, 50% ethyl acetate in cyclohexane) to afford the title compound (0.9 g, 29%), which was used without further purification. 1H NMR (CDCl3, 300 MHz): 7.47-7.42 (m, 2H), 7.24-7.19 (m, 2H), 5.86-5.74 (m, 2H), 3.47-3.35 (m, 2H), 2.98-2.87 (m, 1H), 2.64-2.46 (m, 1H), 2.33-2.26 (m, 2H), 2.13-2.00 (m, 1H), 0.99 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([CH:20]=C)=[CH:18][N:17]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[C:14]2=[CH:15][N:16]=1)[CH3:2].C1C[O:34]CC1.O>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([CH:20]=[O:34])=[CH:18][N:17]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[C:14]2=[CH:15][N:16]=1)[CH3:2]
Reactant: C1CCOC1
Reactant: C=Cc1cn(-c2ccc(C(C)C)cc2)c2cnc(-c3c(CC)cccc3CC)cc12
Solvent: O
Product: CCc1cccc(CC)c1-c1cc2c(C=O)cn(-c3ccc(C(C)C)cc3)c2cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-3-vinyl-1H-pyrrolo[2,3-c]pyridine (400 mg, 1.0 mmol) in a THF/water mixture (3:1, 10 mL), NaIO4 (0.65 g, 3.0 mmol) and OSO4 (4% in water, 3 drops) are added and the mixture is stirred for 18 hours at room temperature. The solvent is removed under reduced pressure, and the residue is extracted with EtOAc. The combined organic extracts are washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue is purified by chromatography on silica gel (Hexane/EtOAc, 6:1) to afford 5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde as a colorless oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]3[O:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:30][C:25]=2[N:24]=[CH:23]1>>[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][N:22]3[C:26]4[CH:27]=[CH:28][C:29]([C:31]5[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=5)=[CH:30][C:25]=4[N:24]=[CH:23]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Reactant: NCCn1cnc2cc(C3=NNC(=O)CC3)ccc21
Product: O=C1CCC(c2ccc3c(c2)ncn3CCNCC(O)COc2ccc(CCOCC3CC3)cc2)=NN1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxy-ethyl)phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][C@H:21]([CH3:23])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].C=O.[BH3-][C:27]#N.[Na+]>CC(O)=O>[CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[N:22]([CH3:27])[C@H:21]([CH3:23])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N[C@H](C)CO3
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N(C)[C@H](C)CO3
Yield: 66.1 %

Procedure:
Compound 102 was prepared according to General Method 5 (EXAMPLE 2) from (3R)-3,4-dihydro-8-isopropoxy-3-methyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (12 mg, 0.04 mmol), 37% formaldehyde solution (0.010 mL, 0.2 mmol, 5 equiv) and NaCNBH3 (10 mg, 0.2 mmol, 5 equiv) in 1 mL AcOH (0.04 M) to afford 9 mg (ca. 70%) of (R)-3,4-dihydro-8-isopropoxy-3,4-dimethyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline. This material (9 mg, 0.03 mmol) was taken on directly according to General Method 4 (EXAMPLE 1) by treatment with 3 mL acetic acid and 3 mL concentrated HCl and heated at 90° C. for 4 h to afford 7 mg (89%) of Compound 102 after flash chromatography (3:1 hexanes:EtOAc to 1:1 hexanes:EtOAc, gradient elution). 1H NMR (500 MHz, CDCl3) δ 11.90 (bs, 1H), 7.12 (s, 1H), 7.01 (d, J=9.3, 1H), 6.96 (d, J=9.3, 1H), 4.19 (dd, J=10.7, 2.9, 1H), 4.11 (dd, J=10.7, 3.7, 1H), 3.43 (m, 1H), 2.93 (s, 3H), 1.21 (d, J=6.8, 3H)
Reaction SMILES: [CH2:1]([OH:21])[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4].C(N(CC)CC)C.[S:29](Cl)([CH3:32])(=[O:31])=[O:30]>C(Cl)Cl>[S:29]([O:21][CH2:1][CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4])(=[O:31])(=[O:30])[CH3:32]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOS(C)(=O)=O
Temperature: -15 °C
Reaction time: 1.5 h

Procedure:
Phytanol (20.0 g, 66.7 mmol), triethylamine (18.6 mL, 133 mmol) and a stir bar were added to a 1000 mL round bottom flask. The flask was sealed and flushed with nitrogen Anhydrous DCM (250 mL) was added, and the mixture cooled to −15° C. (Ice and NaCl). Mesyl Chloride (10.4 mL, 133 mmol) was added slowly via syringe over a 30 minute period, and the reaction stirred at −15° C. for a further 1.5 hours. At this point TLC showed that the starting material had been used up. The solution was diluted with DCM (250 mL) and washed with saturated NaHCO3 (2×200 mL). The organic phase was then dried (MgSO4), filtered and concentrated (rotovap). The crude product was purified by column chromatography. Yield 21.5 g, 85.7%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[CH3:16]O>>[OH:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:16])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CO
Reactant: O=C(O)c1cc(O)nc2ccccc12
Agent: Cl
Product: COC(=O)c1cc(O)nc2ccccc12

Procedure:
To a solution of 2-hydroxyquinoline-4-carboxylic acid (1 eq.) in methanol (0.11 M) was added HCl (4 M dioxane solution, 1 eq.) and the resulting suspension was heated at reflux for 24 h. The reaction was quenched with sat. aq. NaHCO3 and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound.