Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]C(CC)C.CON(C)[C:44]([C:46]1[O:47][CH:48]=[CH:49][CH:50]=1)=[O:45]>C1COCC1>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:44]([C:46]2[O:47][CH:48]=[CH:49][CH:50]=2)=[O:45])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Reactant: CON(C)C(=O)c1ccco1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3ccco3)c(F)c2F)C[C@H](C)O1
Temperature: -70 °C
Yield: 75.5 %

Procedure:
To a stirred solution of (2R,6S)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (Intermediate 3, 1 g, 2.02 mmol) in THF (8 mL) was added sBuLi (1.3 M in cyclohexane/hexanes, 3.1 ml, 4.03 mmol) at −70° C. under nitrogen atmosphere. After stirring for 1 h at this temperature, N-methoxy-N-methylfuran-2-carboxamide (0.939 g, 6.05 mmol) was added in 3 ml of THF. After stirring for 1½ h at −70° C., the reaction quenched with sat. ammonium chloride solution and the aqueous layer extracted by ethyl acetate (2×100 mL). The organic phases were combined, dried (Na2SO4), and concentrated. The residue purified over a silica gel flash column using a gradient of ethyl acetate in hexanes to give the title compound (0.90 g, 76%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.[C:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)#[N:20].CCOCC>CCOC(C)=O>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:22]2[C:21]([C:19]#[N:20])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:4][CH2:5]1)=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N#Cc1cccnc1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: N#Cc1cccnc1NCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 100 °C

Procedure:
A mixture of benzyl 4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, Step 1) (1 g, 4.03 mmol) and 3-cyanopyridine (0.25 g) was heated to 100° C. for 30 min. The reaction mixture was partitioned between EtOAc and pH5.2 citrate buffer. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent evaporated to give a solid which was stirred with 5 mL ether and 0.5 mL EtOAc for 1 h and filtered to give the title compound as a solid. M.S (M+1): 351
Reaction SMILES: [Ti:1](Cl)(Cl)(Cl)Cl.[CH2:6]([N-:9][CH2:10][CH2:11][CH3:12])[CH2:7][CH3:8].[Li+]>C1(C)C=CC=CC=1>[CH2:6]([N-:9][CH2:10][CH2:11][CH3:12])[CH2:7][CH3:8].[CH2:6]([N-:9][CH2:10][CH2:11][CH3:12])[CH2:7][CH3:8].[CH2:6]([N-:9][CH2:10][CH2:11][CH3:12])[CH2:7][CH3:8].[CH2:6]([N-:9][CH2:10][CH2:11][CH3:12])[CH2:7][CH3:8].[Ti+4:1]
Reactant: Cl[Ti](Cl)(Cl)Cl
Agent: CCC[N-]CCC
Agent: [Li+]
Solvent: Cc1ccccc1
Product: [Ti+4]
Reaction time: 0.5 h

Procedure:
The same apparatus described in Step (1) of Example 1-F is used in this procedure. The 250 ml dropping funnel is charged with toluene, 100 ml, and titanium tetrachloride, 10.7 g (0.0562 mole). This is added dropwise to the flask containing lithium dipropylamide while stirring magnetically. Total addition times are typically 30 minutes. The mixture is then refluxed for 1.5 hours. All volatiles are removed by distillation and under vacuum to give a deeply colored brown, oily residue. The residue is extracted with hexane, 2×150 ml, and the extracts are combined and solvent removed under vacuum. The remaining oil is transferred to a small scale distillation apparatus. Vacuum distillation at 157° C. and 0.05 mm Hg gave the product as an orange-brown liquid, titanium tetrakis(dipropylamide).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[N:3]=1.[NH:22]1[CH:26]=[N:25][C:24]([NH2:27])=[N:23]1>C(O)C>[NH:22]1[CH:26]=[N:25][C:24]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]([F:21])([F:20])[F:19])[N:3]=2)=[N:23]1
Reactant: FC(F)(F)c1ccccc1-c1cc2ccccc2c(Cl)n1
Reactant: Nc1nc[nH]n1
Solvent: CCO
Product: FC(F)(F)c1ccccc1-c1cc2ccccc2c(Nc2nc[nH]n2)n1
Temperature: 160 °C
Yield: 4 %

Procedure:
A solution of 1-chloro-3-(2-trifluoromethyl-phenyl)-isoquinoline (0.326 mmol) and 1H-[1,2,4]triazol-3-ylamine (0.651 mmol) in ethanol (3 mL) was heated at 160° C. and the solvent evaporated with a stream of nitrogen. The remaining oil was then heated at 160° C. for 18 hours under nitrogen. The resulting melt was dissolved in 5% methanol/dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (1×25 mL) then dried over magnesium sulfate. Purification by silica gel chromatography afforded IX-175 as a colorless oil (4% yield). 1H NMR (500 MHz, CDCl3) δ9.18 (d, 1H), 8.82 (s, 1H), 7.90 (d, 1H), 7.85-7.75 (m, 3H), 7.71-7.62 (m, 3H), 7.60-7.55 (m, 2H), 4.42-4.35 (m, 1H). LC−MS (ES+) 356.16 (M+H); HPLC-Method D, Rt 3.55 min.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH2:17][O:18][CH3:19])[CH:12]([C:20]1[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.C([S-])C.[Na+].CN(C=O)C>C(OCC)(=O)C>[OH:26][C:23]1[CH:24]=[CH:25][C:20]([CH:12]2[CH:13]([CH2:17][O:18][CH3:19])[C:14]3[CH:15]=[CH:16][C:3]([OH:2])=[CH:4][C:5]=3[CH:6]3[CH:11]2[CH2:10][CH2:9][CH2:8][CH2:7]3)=[CH:21][CH:22]=1
Reactant: COCC1c2ccc(OC)cc2C2CCCCC2C1c1ccc(OC)cc1
Agent: CC[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCC1c2ccc(O)cc2C2CCCCC2C1c1ccc(O)cc1
Reaction time: 18 h
Yield: 31.7 %

Procedure:
Combine 6-methoxy-9-methoxymethyl-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthrene (0.050 g, 0.14 mmol), sodium ethanethiolate (0.037 g, 0.44 mmol), and DMF (4 mL), and reflux under nitrogen atmosphere. After 18 hours, cool the reaction to room temperature and add ethyl acetate, wash with sat ammonium chloride solution (aq), then brine several times. Concentrate, and purify using reverse phase chromatography (5% to 95% 0.001% TFA buffer in acetonitrile/water) to yield the titled compound (0.015 g, 33%) as a white solid. TLC Rf=0.27 in 3:1 hexanes:ethyl acetate. 1H NMR (d-methanol): 7.42 (d, 1H, J=8.4 Hz), 7.13 (d, 2H, J=8.4 Hz), 6.84 (s, 1H), 6.79 (d, 2H, J=8.4 Hz), 6.65 (dd, 1H, J=7.9, 1.8 Hz), 3.70 (d, 1H, J=7.0 Hz), 3.35 (m, 3H), 3.17 (s, 3H), 3.07 (m, 1H), 2.48 (d, 1H, J=14.1 Hz), 1.87 (m, 1H), 1.64 (m, 2H), 1.41 (m, 2H), 1.16 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[N:9][NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[N:9][N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]ncc2ccc([N+](=O)[O-])cc12
Reactant: ClCc1ccccn1
Agent: Cl
Product: O=c1c2cc([N+](=O)[O-])ccc2cnn1Cc1ccccn1

Procedure:
Step (b) of Example 125 was repeated, except that the compound prepared in step (b) of Example 137 and 2-(chloromethyl)pyridine hydrochloride were used as the starting compounds. Thus, 7-nitro-2-(pyridin-2-yl)methyl-2H-phthalazin-1-one was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([OH:16])=[C:14]([CH:17]=O)[C:13]([CH3:19])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([NH:30][NH2:31])=[O:29])=[CH:26][CH:25]=1)=[O:23]>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14](=[CH:17][NH:31][NH:30][C:28](=[O:29])[C:27]3[CH:26]=[CH:25][C:24]([C:22]([O:21][CH3:20])=[O:23])=[CH:33][CH:32]=3)[C:13]([CH3:19])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nn(-c2ccc(C(C)(C)C)cc2)c(O)c1C=O
Reactant: COC(=O)c1ccc(C(=O)NN)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NNC=C2C(=O)N(c3ccc(C(C)(C)C)cc3)N=C2C)cc1
Yield: 41.9 %

Procedure:
1.0712 g (4.21 mmol) of the 1-(4-tert-butylphenyl)-5-hydroxy-3-methyl-1H-pyrazole-4-carbaldehyde synthesized in 1) and 819.6 mg (4.22 mmol) of 4-methoxycarbonylbenzhydrazide were stirred in 10 ml of dimethylformamide at room temperature for 3 hours. After the solvent was removed by evaporation, the precipitated solid was washed with a small amount of methanol and dried to obtain 765.9 mg of the above-identified desired product as a yellow solid (yield 42%).
Reaction SMILES: [OH:1][CH:2]([CH2:7][NH:8][C:9]([C:11]1[NH:12][C:13]([C:16]2[CH:21]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:19]=[C:18]([O:33][C@@H:34]([CH3:38])[CH2:35][O:36][CH3:37])[CH:17]=2)=[CH:14][CH:15]=1)=O)[C:3]([O:5][CH3:6])=[O:4].CS(OS(C)(=O)=O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:37][O:36][CH2:35][C@H:34]([CH3:38])[O:33][C:18]1[CH:17]=[C:16]([C:13]2[NH:12][C:11]([C:9]3[O:1][CH:2]([C:3]([O:5][CH3:6])=[O:4])[CH2:7][N:8]=3)=[CH:15][CH:14]=2)[CH:21]=[C:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[CH:19]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NCC(O)C(=O)OC)[nH]2)c1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCC(C(=O)OC)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 88 %

Procedure:
Methyl 2-hydroxy-3-{[(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)carbonyl]amino}propanoate (686 mg, 1.26 mmol) synthesized in Example (27a) was dissolved in tetrahydrofuran (15 mL), and methanesulfonic anhydride (330 mg, 1.89 mmol) and triethylamine (0.53 mL, 3.80 mmol) were added, followed by stirring at room temperature for 19 hours under nitrogen atmosphere. A saturated aqueous sodium hydrogencarbonate solution (10 mL) was added, and the solution was separated with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-70%) to afford the desired product (586 mg, yield 88%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[S:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[OH:9])#[N:2].[Cl:19]N1C(=O)CCC1=O>C(#N)C>[Cl:19][C:11]1[CH:12]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[S:14][C:10]=1[C:5]1[CH:6]=[CH:7][C:8]([OH:9])=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: COC(=O)c1ccc(-c2ccc(O)c(C#N)c2)s1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: COC(=O)c1cc(Cl)c(-c2ccc(O)c(C#N)c2)s1

Procedure:
Methyl 5-(3-cyano-4-hydroxyphenyl)thiophene-2-carboxylate and N-chlorosuccinimide were stirred at room temperature in acetonitrile to obtain methyl 4-chloro-5-(3-cyano-4-hydroxyphenyl)thiophene-2-carboxylate. ESN: 292.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[C:14]([OH:16])[C:13]([CH:17]2[CH:22]3[CH2:23][CH:20]([C:21]3([CH3:25])[CH3:24])[C:19](=[O:26])[CH2:18]2)=[C:12]([OH:27])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[OH:16][C:14]1[C:13]2[C@H:17]3[CH2:18][C:19](=[O:26])[CH2:20][CH2:23][C@H:22]3[C:21]([CH3:25])([CH3:24])[O:27][C:12]=2[CH:11]=[C:10]([C:2]([CH3:1])([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:15]=1
Reactant: CCCCCCC(C)(C)c1cc(O)c(C2CC(=O)C3CC2C3(C)C)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(=O)C[C@H]21

Procedure:
The process according to claim 5 wherein optically active 4-[4-(1,1-dimethylheptyl)-2,6-dihydroxyphenyl]-6,6-dimethyl-2-norpinanone is reacted with para-toluenesulfonic acid to provide optically active cis-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[N:26]=2)[N:4]=1)[CH3:2].[BH-](OC(C)=O)(OC(C)=O)O[C:42](C)=O.[Na+].C=O>CO>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][N:34]3[CH2:35][CH2:36][N:37]([CH3:42])[CH2:38][CH2:39]3)[N:26]=2)[N:4]=1)[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCc1nn(Cc2cccc(OCCN3CCNCC3)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CCc1nn(Cc2cccc(OCCN3CCN(C)CC3)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To N-(3-ethyl-1-((6-(2-(piperazin-1-yl)ethoxy)pyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (5 mg, 0.0095 mmol; prepared as in Example 43) in MeOH (2 mL) was added NaBH(OAc)3 (6.1 mg, 0.029 mmol) and HCHO (as a 35% aqueous solution) (19 mg, 0.19 mmol). The reaction mixture was stirred for 30 minutes, concentrated under reduced pressure and the residue was purified by silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1) to provide the final product (4 mg). MS (ES+APCI) m/z=539 (M+H).
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(C[Br:25])=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1.O[CH:29]([C:31]1[CH:36]=[CH:35][C:34]([C:37](=[O:56])[CH2:38][N:39]2[C:44](=[O:45])[CH:43]=[C:42]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][N:49]=3)[CH:41]=[N:40]2)=[C:33]([CH3:57])[CH:32]=1)[CH3:30].C(OC1C=CN(CC(C2C=CC(CO)=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1>>[Br:25][CH:29]([C:31]1[CH:36]=[CH:35][C:34]([C:37](=[O:56])[CH2:38][N:39]2[C:44](=[O:45])[CH:43]=[C:42]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][N:49]=3)[CH:41]=[N:40]2)=[C:33]([CH3:57])[CH:32]=1)[CH3:30]
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Reactant: COc1ccc(COc2cnn(CC(=O)c3ccc(C(C)O)cc3C)c(=O)c2)nc1
Agent: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Product: COc1ccc(COc2cnn(CC(=O)c3ccc(C(C)Br)cc3C)c(=O)c2)nc1
Yield: 93 %

Procedure:
2-{2-[4-(1-Bromo-ethyl)-2-methyl-phenyl]-2-oxo-ethyl}-5-(5-methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one is prepared following preparation 1d employing 2-{2-[4-(1-Hydroxy-ethyl)-2-methyl-phenyl]-2-oxo-ethyl}-5-(5-methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one instead of preparation 1c.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]([C:8]1[N:9]=[CH:10][NH:11][CH:12]=1)([CH3:7])[CH3:6])[CH3:2].[H-].[Na+].CI.[C:18](=O)([O-])O.[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:13])[C:5]([CH3:7])([C:8]1[N:9]=[CH:10][N:11]([CH3:18])[CH:12]=1)[CH3:6])[CH3:2]
Reactant: O=C([O-])O
Reactant: CCOC(=O)C(C)(C)c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)c1cn(C)cn1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.82 g of 2-(1H-imidazol-4-yl)-2-methyl-propionic acid ethyl ester [CAS 21149-99-5] in 20 ml of dry N,N-dimethylformamide is treated with 0.480 g sodium hydride (60% dispersion). The mixture is stirred for 30 minutes at 60° C. 0.81 ml of methyl iodide are added and the mixture stirred for 4 hours at 60° C. The reaction mixture is poured onto saturated aqueous sodium hydrogencarbonate solution and extracted with tert-butyl methyl ether (3×). The combined extracts are washed with brine, dried over sodium sulphate and concentrated by evaporation. Flash chromatography (SiO2 60F) of the residue provides the title compound which is identified on the basis of its Rf-value.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=1)=O>C(#N)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=3)[N:1]=2)[CH:4]=1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Reactant: Nc1ccc(Br)cn1
Solvent: CC#N
Product: O=[N+]([O-])c1cc(-c2cn3cc(Br)ccc3n2)ccc1C(F)(F)F
Temperature: 100 °C
Yield: 106.7 %

Procedure:
A stirred mixture of 2-amino-5-bromopyridine (0.259 g, 1.5 mmol) and 2-bromo-1-[3-nitro-4-(trifluoromethyl)phenyl]ethanone (0.468 g, 1.5 mmol) in acetonitrile (3 mL) is heated at 100° C. for 18 hr. The mixture is concentrated to give the title compound (618 mg), which is used without further purification. LCMS m/z=388.3 [M+H]+, tR=2.94 min.
Reaction SMILES: [N:1]1([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5][CH2:4][CH:3]([C:6]([O:8][CH3:9])=[O:7])[CH2:2]1.[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI.[Cl-].[NH4+]>C1COCC1>[CH3:20][C:3]1([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:5][N:1]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:2]1
Reactant: COC(=O)C1CCN(C(=O)OCc2ccccc2)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.9 %

Procedure:
To 1-benzyl 3-methyl pyrrolidine-1,3-dicarboxylate (3.45 g, 13.1 mmol) in THF (20 mL) was added lithium bis(trimethylsilyl)amide (16.4 mL, 16.4 mmol) in THF at −78° C., and the reaction was stirred at this temperature for 20 minutes. MeI (1.10 mL, 17.7 mmol) was added, and the reaction was warmed to room temperature. After 2 hours at room temperature, the mixture was poured onto saturated ammonium chloride (20 mL) and extracted with ether, washed with brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by chromatography (hexane:ethyl acetate 4:1) to give 1-benzyl 3-methyl 3-methylpyrrolidine-1,3-dicarboxylate (2.72 g, 75% yield) as an oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[N:10]([C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=O)[CH2:9][CH2:8]2.C(Cl)(Cl)Cl.CO.C(Cl)(Cl)Cl>C1COCC1>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:16][N:10]1[CH:11]2[CH2:12][CH2:13][N:7]([CH2:15][CH2:14]2)[CH2:8][CH2:9]1
Reactant: O=C(c1ccccn1)N1CCN2CCC1CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: c1ccc(CN2CCN3CCC2CC3)nc1
Reaction time: 12 h

Procedure:
To a stirred solution of lithium aluminum hydride (0.33 mL of 1M THF solution) at ambient temperature was added dropwise a solution of (1,4-diazabicyclo[3.2.2]non-4-yl)(pyridin-2-yl)methanone (120 mg, 0.52 mmol) in dry THF (2 mL). The resulting yellowish solution was stirred for 12 hours, quenched with water and aqueous NaOH, and filtered through diatomaceous earth. The filtrate was concentrated to give the product which was subjected to chromatography on silica gel eluting with an ammoniated-chloroform to 15% MeOH/chloroform gradient to give the title compound as a free base syrup (28.0 mg). MS (ES+) 218 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][C:4]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[ClH:22]>O1CCOCC1>[C:16]1([C:4]2[CH2:5][NH:6][CH2:7][CH2:8][C:3]=2[CH2:2][OH:1])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1.[ClH:22]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)=C(c2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: OCC1=C(c2ccccc2)CNCC1
Reaction time: 1 h

Procedure:
To a solid of tert-butyl 4-(hydroxymethyl)-3-phenyl-5,6-dihydropyridine-1(2H)-carboxylate (300 mg, 1.04 mmol) in round bottom flask was added 4N HCl in dioxane (6 mL) at room temperature, after stirring for 1 h, the mixture was concentrated and dried under high vacuum to give (5-phenyl-1,2,3,6-tetrahydropyridin-4-yl)methanol as HCl salt.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[NH:12][C:11]=2[C:19]([NH2:21])=[O:20])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[NH:12][C:11]=2[C:19]([NH2:21])=[O:20])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: NC(=O)c1[nH]c2cccnc2c1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1[nH]c2cccnc2c1-c1ccc(N)cc1
Yield: 74.6 %

Procedure:
0.113 g of Pd/C (10%) is added to a solution of 0.15 g of 3-(4-nitrophenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide in 10 ml of methanol. After stirring at 22° C. for 3.5 hours under 2 bar of hydrogen, the reaction medium is filtered over silica gel and then concentrated under reduced pressure, to give 0.1 g of 3-(4-aminophenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide, the characteristics of which are as follows:
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[OH:1][C:2]1([C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH:5]([N:16]2[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=3)=[O:22])[CH2:17]2)[CH2:4][CH2:3]1
Reactant: Cc1cccc(C2(O)CCC(=O)CC2)c1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: Cc1cccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-hydroxy-4-m-tolyl-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:18])[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:11]2[N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(O)(C)(C)C.CCCCCCC.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[CH3:22][S:19]([C:12]1[C:13]([CH3:18])=[N:14][C:15]2[C:10]([C:11]=1[N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[CH:9][C:8]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[CH:17][CH:16]=2)(=[O:21])=[O:20]
Reactant: Cc1nc2ccc(Br)cc2c(N2CCOCC2)c1S(C)(=O)=O
Reactant: C1CCNCC1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CC(C)(C)O
Product: Cc1nc2ccc(N3CCCCC3)cc2c(N2CCOCC2)c1S(C)(=O)=O
Temperature: 110 °C
Yield: 79 %

Procedure:
A tube placed under argon was charged with tris(dibenzylideneacetone)dipalladium chloroform complex (11 mg, 0.010 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (10 mg, 0.021 mmol) and cesium carbonate (1.3 g, 3.99 mmol). 6-Bromo-3-methanesulfonyl-2-methyl-4-morpholin-4-yl-quinoline (compound of example 6) (200 mg, 0.52 mmol) in tert.-butanol (10 ml) was added, followed by piperidine (0.053 g, 0.62 mmol). The tube was sealed and heated at 110° C. for 2 h. The reaction mixture was cooled to 20° C., diluted with heptane, filtered through dicalite and purified directly by flash chromatography on silica gel in heptane/ethyl acetate 80:20 to give a yellow solid (160 mg, 79%). MS: m/z=390 (M+H).