Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:24]([NH2:26])=[O:25])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:10]=2)=[C:6]([CH3:8])[N:7]=1.[F:27][C:28]1[CH:29]=[C:30]([CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH:31]=[CH:32][C:33]=1OS(C(F)(F)F)(=O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C(O)C.O.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:24]([C:3]1[N:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([C:33]3[CH:32]=[CH:31][C:30]([CH2:42][C:43]([O:45][CH3:46])=[O:44])=[CH:29][C:28]=3[F:27])=[CH:13][CH:14]=2)[C:6]([CH3:8])=[N:7][C:2]=1[CH3:1])(=[O:25])[NH2:26]
Reactant: Cc1nc(C)c(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc1C(N)=O
Reactant: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.8 %

Procedure:
A solution of 3,5-dimethyl-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carboxamide (353 mg, 1 mmol), methyl 2-(3-fluoro-4-(trifluoromethylsulfonyloxy)phenyl)acetate (Intermediate 25-2; 411 mg, 1.30 mmol) and tripotassium phosphate (318 mg, 1.50 mmol) in DME (6 mL), ethanol (3.00 mL) and water (1.500 mL) was put under vacuum and refilled with nitrogen before addition of (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (DCM adduct) (65.8 mg, 0.08 mmol). The reaction mixture was heated to and left to stir overnight for 16 hrs. The reaction mixture was allowed to cool to room temperature and then evaporated. The residue was partitioned between water (20 mL) and EtOAc (50 mL). The aqueous was re-extracted with EtOAc (2×10 mL) and the combined organics washed with brine (20 mL), dried (MgSO4) and evaporated to give crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane on 40 g silicycle column. Pure fractions were evaporated to dryness to afford methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorobiphenyl-4-yl)acetate (180 mg, 45.8%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:18])[CH:11]=[C:12]([CH2:16][OH:17])[N:13]([OH:15])[CH:14]=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[CH:27](Br)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[C:28]1([CH:27]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:15][N:13]2[CH:14]=[C:9]([O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=3)[C:10](=[O:18])[CH:11]=[C:12]2[CH2:16][OH:17])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: COc1ccc(COc2cn(O)c(CO)cc2=O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2cn(OC(c3ccccc3)c3ccccc3)c(CO)cc2=O)cc1

Procedure:
5.54 g of 5-p-methoxybenzyloxy-1-hydroxy-2-hydroxymethyl-4-pyridone is suspended in 40 ml of N,N-dimethylformamide, and then 2.24 g of potassium t-butoxide is added with ice cooling to dissolve. 4.94 g of benzhydryl bromide is added thereto and reacted at room temperature for 2.5 hours.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@@H:15]([CH3:18])[CH2:16][OH:17])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pt].C1(C)C=CC=CC=1>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@@H:15]([CH3:18])[CH2:16][OH:17])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: C[C@@H](CO)Nc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: Cc1ccccc1
Product: C[C@@H](CO)Nc1c(N)cnc2ccccc12
Yield: 115.8 %

Procedure:
A pressure bottle was charged with platinum on carbon (5%, 0.27 g) followed by (2S)-2-[(3-nitroquinolin-4-yl)amino]propan-1-ol (1.11 g, 4.49 mmol) dissolved in 200 mL of toluene. The reaction mixture was shaken under H2 at 48 PSI (3.3×105 Pa). The next day the reaction was filtered through a pad of CELITE filter agent and rinsed with toluene. The solvent was removed under reduced pressure to give (2S)-2-[(3-aminoquinolin-4-yl)amino]propan-1-ol (1.13 g) as an orange oil.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([C:15]#N)[CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[O:17]1C2(CCC(C#N)CC2)OCC1.C1(CBr)CC1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH:1]1([CH2:4][C:5]2([CH:15]=[O:17])[CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1
Reactant: N#CC1CCC2(CC1)OCCO2
Reactant: N#CC1(CC2CC2)CCC2(CC1)OCCO2
Agent: BrCC1CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=CC1(CC2CC2)CCC2(CC1)OCCO2
Temperature: 0 °C

Procedure:
To a solution of 8-cyclopropylmethyl-1,4-dioxa-spiro[4.5]decane-8-carbonitrile, prepared from 1,4-dioxa-spiro[4.5]decane-8-carbonitrile and cyclopropylmethyl bromide in a similar fashion as described for 5, (3.00 g, 13.6 mmol) in tetrahydrofuran (40 mL) at −78° C. was added a 1M solution of diisobutylaluminium hydride in toluene (20.3 mL, 20.3 mmol, 1.5 eq.) and the reaction was allowed to warmed to 0° C. over a period of 3 h. The mixture was recooled to −78° C., neutralized by dropwise addition of a 10% aqueous citric acid solution and warmed to room temperature. The mixture was partitioned between methyl-tert.butyl ether and water, the aqueous phase extracted twice with methyl-tert.butyl ether and the combined organics were dried over magnesium sulphate, filtered and evaporated to give 8-cyclopropylmethyl-1,4-dioxa-spiro[4.5]decane-8-carbaldehyde.
Reaction SMILES: [CH:1]1([C:7]2[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][C:8]=2[C:9]#[N:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:19])=O>>[Cl:19][CH2:15][C:12]1[CH:13]=[CH:14][C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:8]([CH:11]=1)[C:9]#[N:10]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cc(CO)ccc1C1CCCCC1
Product: N#Cc1cc(CCl)ccc1C1CCCCC1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 89.4 %

Procedure:
To 2-cyclohexyl-5-(hydroxymethyl)benzonitrile (190.5 mg, 0.885 mmol) was added thionyl chloride (5.0 mL, 68.1 mmol). The mixture was heated at 50° C. for 2 h and then room temperature overnight. The mixture was poured into an ice and stirred for 5 min. The mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the title compound as a white solid (184.9 mg). LCMS m/z=234.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.23-1.31 (m, 1H), 1.40-1.52 (m, 4H), 1.76-1.82 (m, 1H), 1.83-1.92 (m, 4H), 2.93-3.03 (m, 1H), 4.55 (s, 2H), 7.37 (d, J=8.08 Hz, 1H), 7.55 (dd, J=8.02, 1.83 Hz, 1H), 7.62 (d, J=1.64 Hz, 1H).
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrCC(OCC)=O.[Cl:21]C1C=CC(S)=CC=1>CC[O-].[Na+]>[Cl:21][C:4]1[CH:5]=[CH:6][C:1]([S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:2][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CCOC(=O)CSc1ccccc1
Agent: CCOC(=O)CBr
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)CSc1ccc(Cl)cc1

Procedure:
The procedure is as in Example 2 for the preparation of ethyl (phenylthio)acetate starting with ethyl bromoacetate (16.7 g), a 2M ethanolic solution of sodium ethylate (50 cc) and 4-chlorothiophenol (14.5 g). Ethyl (4-chlorophenylthio)acetate (20.7 g) is thereby obtained, and is used in the crude state in the subsequent phases.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[NH:34]([CH2:38][CH2:39][OH:40])[CH2:35][CH2:36][OH:37].C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9]([N:34]([CH2:38][CH2:39][OH:40])[CH2:35][CH2:36][OH:37])(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: OCCNCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)N(CCO)CCO)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
Under an atmosphere of argon protective gas, 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (50 mg, 101 μmol) was dissolved in absolute THF (2.5 ml), diethanolamine (29 μl, 303 μmol; 3 eq.) and triethylamine (10.2 mg, 101 μmol; 1 eq.) were added at room temperature and the mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Gromsil C-18, 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (4.9 mg, 9% of theory).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[C:35](O)(=[O:37])[CH3:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:35](=[O:37])[CH3:36])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (50 mg, 0.136 mmol) in DMF (0.8 ml) was added N,N-diisopropylethylamine (62 mg, 0.0833 ml, 0.477 mmol), acetic acid (9.82 mg, 9.35 μl, 0.164 mmol) and TBTU (52.4 mg, 0.164 mmol). The mixture was allowed to stir at room temperature for 4 h and poured into ice/water (0.5 ml) The crude reaction mixture was concentrated in vacuo. The reaction mixture was solved with sat NaHCO3 (1×10 mL). and extracted with dichloromethane (3×20 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 20% MeOH in dichloromethane) to yield the title compound as an white solid (31 mg, 61%), MS (ISP) m/z=373.5 [(M+H)+].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)=[C:7]([CH:10]=1)[C:8]#[N:9].[Cl:23][C:24]1[N:29]=[C:28](Cl)[CH:27]=[CH:26][N:25]=1>CN(C)C=O>[Cl:23][C:24]1[N:29]=[C:28]([NH:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([O:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:20])[F:21])[CH:13]=3)=[C:7]([CH:10]=2)[C:8]#[N:9])[CH:27]=[CH:26][N:25]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: N#Cc1cc(CN)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CN(C)C=O
Product: N#Cc1cc(CNc2ccnc(Cl)n2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Yield: 71.4 %

Procedure:
A solution of 5-(aminomethyl)-2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}benzonitrile (500 mg, 1.530 mmol), 2,4-dichloropyrimidine (239 mg, 1.607 mmol) and TEA (1.280 mL, 9.18 mmol) in the N,N-dimethylformamide (5 mL) was stirred at rt overnight. Purification via Biotage-C18 system afforded the title product (480 mg) as a white solid. LC-MS (ESI): m/z 439 [M+H]+; 3.56 min (ret time).
Reaction SMILES: [ClH:1].Cl.Cl.O[N:5]([CH2:19][CH2:20][S:21][CH2:22][C:23]1[NH:27][CH:26]=[N:25][C:24]=1[CH3:28])[C:6]([NH2:18])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17].Cl.[CH3:30][O:31]N.C(=O)([O-])O.[K+]>O>[ClH:1].[ClH:1].[ClH:1].[CH3:30][O:31][NH:18][C:6]([NH:5][CH2:19][CH2:20][S:21][CH2:22][C:23]1[NH:27][CH:26]=[N:25][C:24]=1[CH3:28])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17]
Reactant: Cc1nc[nH]c1CSCCN=C(N)N(O)CCSCc1[nH]cnc1C
Reactant: CON
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: CONC(=NCCSCc1[nH]cnc1C)NCCSCc1[nH]cnc1C
Yield: 34.3 %

Procedure:
A mixture of the isothiourea trihydrochloride from Example 2 (ii) (5.1 g), methoxyamine hydrochloride (2.5 g), potassium hydrogen carbonate (5.0 g) and water (30 ml) was refluxed for 24 hours. The products were partitioned between N sodium hydroxide and n-butanol. The n-butanol solution was then extracted with N hydrochloric acid, and the extracts concentrated and dissolved in isopropanol. After filtration from inorganic material, the filtrate gave the title compound (0.6 g). When a solution in aqueous ethanol of this compound was eluted from an ion exchange column of IRA-401 in nitrate form, the corresponding trinitrate was obtained.
Reaction SMILES: C1(C(C)C[SiH](Cl)Cl)C=CC=CC=1.C(Cl)C=C.[SiH4].Cl[CH2:19][CH2:20][CH2:21][Si:22]([Cl:33])([Cl:32])[CH2:23][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:25].C1(C(C)C[Si](Cl)(Cl)Cl)C=CC=CC=1>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[Cl:32][Si:22]([Cl:33])([CH2:21][CH2:20][CH3:19])[CH2:23][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:25]
Reactant: CC(C[Si](Cl)(Cl)CCCCl)c1ccccc1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: CC(C[SiH](Cl)Cl)c1ccccc1
Agent: CC(C[Si](Cl)(Cl)Cl)c1ccccc1
Solvent: C=CCCl
Product: CCC[Si](Cl)(Cl)CC(C)c1ccccc1
Reaction time: 3 h

Procedure:
To a 500 ml, three neck, round bottomed flask equipped with a mechanical stirrer, a dropping funnel, and a reflux condenser, 6.0 g (0.03 mole) of 3-phenyl-1,1-dichloro-1-silabutane, 6.28 g (0.09 mole) of allyl chloride, and 150 μl of 1% chloroplatinic acid in isopnopanol were placed under the dry nitrogen atmosphere. The flask was then immersed in a hot water bath of 45°-50° C. The solution was stirred vigorously for three hours. Gas chromatography analysis showed that no silane was Left. Vacuum distillation of the solution gave 2.21. g (bp, 111°-2° C./0.6 mmHg) of 1,4,4-trichloro-6-phenyl-4-silaheptane and 2.63 g of 3-phenyl-1,1,1-trichloro-1-silabutane. Besides these products, a small amount of 4,4-dichloro-2-phenyl-4-silaheptane was also obtained.
Reaction SMILES: [C:1]([C:5]1[CH:36]=[CH:35][CH:34]=[CH:33][C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:32])[CH:15]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:16](OCC2C=CC=CC=2)=[O:17])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+]>>[C:1]([C:5]1[CH:36]=[CH:35][CH:34]=[CH:33][C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:32])[CH:15]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:16][OH:17])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1OC1CCN(C(=O)C(C(=O)OCc2ccccc2)c2ccccc2)CC1
Agent: [BH4-]
Agent: [Li+]
Product: CC(C)(C)c1ccccc1OC1CCN(C(=O)C(CO)c2ccccc2)CC1
Yield: 24.7 %

Procedure:
Benzyl 3-[4-(2-tert-butylphenoxy)piperidin-1-yl]-3-oxo-2-phenylpropanoate (167 mg, 0.34 mmol) obtained in Example 174 and lithium tetrahydroborate (2.0M, THF solution, 0.41 mL, 0.82 mmol) were stirred at room temperature for 3 days. The reaction mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride, and the ethyl acetate layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate 75:25-25:75) to give the title compound (32 mg, 24%) as a colorless oil.
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:9])[NH:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN(C)C=O>C1(C)C=CC=CC=1>[CH2:10]([N:8]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C1CCCCN1Cc1ccccc1
Temperature: 25 °C
Yield: 42.3 %

Procedure:
To a suspension of sodium hydride (80%, 3.3 g, 0.11 mol) in dry toluene (250 ml) under argon, was added dropwise a solution of δ-valerolactam (9.9 g, 0.10 mol) in toluene (50 ml). When the addition was complete, the mixture was heated under reflux for 1 h, then cooled to ambient temperature. A solution of benzyl bromide (13 ml, 18.8 g, 0.11 mol) in toluene (50 ml) containing dimethyl formamide (1 ml) was then added dropwise over 15 minutes. The resulting mixture was heated under reflux for 4 h. On cooling, the mixture was filtered and the filtrate was dried (Na2SO4) and evaporated in vacuo to give an oil. Bulb-to-bulb distillation gave the title compound (D26) as a yellow oil (8.0 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)[N:6]=[CH:5]2>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:19]=[CH:18][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1)[N:6]=[CH:5]2
Reactant: O=C(O)c1ccc(-n2ncc3cc(I)ccc32)cc1
Solvent: C1CCOC1
Product: OCc1ccc(-n2ncc3cc(I)ccc32)cc1
Temperature: 25 °C
Yield: 71.4 %

Procedure:
Crude 4-(5-iodo-1H-indazol-1-yl)benzoic acid (141c, 3.05 g, 8.4 mmol) was dissolved in THF (60 mL, dried over 4 Å MS) under argon atmosphere and cooled in an ice bath. Borane-THF complex (1M, 11 mL, 11 mmol) was added during 5 min. The ice bath was then removed and the mixture was allowed to reach r.t. and was finally heated at reflux for 40 min. The reaction mixture was then cooled to r.t. and sat. aqueous NH4Cl (25 mL) was added. After being diluted with EtOAc the reaction mixture was extracted trice with water and finally with brine and evaporated. The residue was subjected to chromatography (SiO2, 10-80% EtOAc in Heptane) to give (4-(5-iodo-1H-indazol-1-yl)phenyl)methanol (2.1 g, 71%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][N:8]1[C:15](=O)[CH:14]2[NH:17][CH:10]([CH2:11][CH2:12][CH2:13]2)[C:9]1=O.Cl>C1COCC1.CCOCC>[CH3:7][N:8]1[CH2:15][CH:14]2[NH:17][CH:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9]1
Reactant: CN1C(=O)C2CCCC(N2)C1=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1CC2CCCC(C1)N2

Procedure:
To a stirred cold (0-5° C.) suspension of LAH (205 mg, 5.40 mmol) in an THF (15 ml) a solution of 3-methyl-3,9-diazabicyclo[3.3.1]nonane-2,4-dione (375 mg) in THF (5 ml) was added and the mixture was heated to reflux for 1-2 h. Rxn was cooled in a ice bath and quenched by addition of water (0.2 ml), 15% NaOH (0.6 ml) and water (0.2 ml) and the suspension was vigorously stirred and filtered and dried over Na2SO4. Evaporation of solvents gave light-brown oil which was dissolved in ether and treated with 1N HCl in ether to afford 3-methyl-3,9-diazabicyclo[3.3.1]nonane and isolated as bis-HCl salt. MS: m/e 141 (MH+). 1H NMR (500 MHz, CD3OD): δ ppm 1.34-1.59 (5H, m), 2.02-2.32 (6H, m), 2.57-2.97 (4H, m).
Reaction SMILES: [CH2:1]([C:4]1([CH3:19])[C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][C:16]=3[C:8]=2[CH2:7][N:6]([CH3:18])[CH2:5]1)[CH:2]=[CH2:3].[H-].[Na+].[CH3:22][C:23]1([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:25][O:24]1>CN(C=O)C>[CH2:1]([C:4]1([CH3:19])[C:9]2[N:10]([CH2:22][C:23]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)([OH:24])[CH3:25])[C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][C:16]=3[C:8]=2[CH2:7][N:6]([CH3:18])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(C)CN(C)Cc2c1[nH]c1ccc(C)cc21
Reactant: CC1(c2ccncc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC1(C)CN(C)Cc2c1n(CC(C)(O)c1ccncc1)c1ccc(C)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.1 %

Procedure:
4-Allyl-2,4,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g, 3.9 mmol) was dissolved in DMF (10 mL) and stirred for 10 min at RT. Sodium hydride (475 mg, 11.7 mmol) was added portionwise and stirring was continued for 15 min at RT. 4-(2-Methyl-oxiranyl)-pyridine (690 mg, 5.1 mmol) diluted in DMF was added dropwise at RT and the reaction mixture was further stirred for 16 h after which it was quenched with ice water and extracted with EtOAc (3×70 mL). The combined organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was recrystallized in ether to obtain 700 mg of 1-(4-Allyl-2,4,8-trimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-4-yl-propan-2-ol.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=3)[C:13]2=[O:25])=[CH:10][CH:9]=[CH:8][C:7]=1[C:26]1[CH:31]=[C:30]([NH2:32])[C:29](=[O:33])[N:28]([CH3:34])[CH:27]=1)(=O)C.Cl[C:36]1[N:37]=[N:38][C:39]([N:42]2[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]2)=[CH:40][CH:41]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[OH-].[Li+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C(O)C.C1COCC1.O1CCOCC1>[C:21]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:25])[N:12]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([C:26]3[CH:31]=[C:30]([NH:32][C:36]4[N:37]=[N:38][C:39]([N:42]5[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]5)=[CH:40][CH:41]=4)[C:29](=[O:33])[N:28]([CH3:34])[CH:27]=3)[C:6]=1[CH2:5][OH:4])[CH2:20]2)([CH3:23])([CH3:24])[CH3:22]
Reactant: CN1CCN(c2ccc(Cl)nn2)CC1
Reactant: CC(=O)OCc1c(-c2cc(N)c(=O)n(C)c2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(c2ccc(Nc3cc(-c4cccc(N5Cc6cc(C(C)(C)C)ccc6C5=O)c4CO)cn(C)c3=O)nn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 100-mL three-neck round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet and reflux condenser was charged with 122d (550 mg, 1.19 mmol), 122e (255 mg, 1.19 mmol), cesium carbonate (860 mg, 2.64 mmol) and 1,4-dioxane (20 mL). After bubbling nitrogen through the resulting mixture for 20 minutes, Xantphos (59.0 mg, 0.102 mmol) and tris(dibenzylideneacetone)dipalladium(0) (55.0 mg, 0.06 mmol) were added, and the reaction mixture was heated at reflux for 5 h. After this time, the reaction was cooled to room temperature, filtered and concentrated under reduced pressure to afford a brown residue. Another 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with residue obtained above, THF (10 mL), ethanol (10 mL), water (10 mL) and lithium hydroxide (115 mg, 4.80 mmol). The mixture was stirred at 50° C. for 2 h. After this time, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford a 23% (165 mg) yield of 122 as a white solid: mp 171-172° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.66 (d, 1H, J=2.0 Hz), 8.57 (s, 1H), 7.72 (d, 1H, J=8.5 Hz), 7.71 (s, 1H), 7.61 (d, 1H, J=8.0, 1.5 Hz), 7.54 (d, 1H, J=9.5 Hz), 7.50 (t, 1H, J=8.0 Hz), 7.45 (dd, 1H, J=8.0, 1.5 Hz), 7.38-7.36 (m, 2H), 7.30 (d, 1H, J=9.5 Hz), 4.94 (s, 2H), 4.84 (t, 1H, J=5.0 Hz), 4.34 (d, 2H, J=5.0 Hz), 3.60 (s, 3H), 3.41 (t, 4H, J=5.0 Hz), 2.39 (t, 4H, J=5.0 Hz), 2.20 (s, 3H), 1.36 (s, 9H); MS (ESI+) m/z 594.3 (M+H).