Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=O)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([CH:16]=[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([CH3:29])([CH3:28])[NH2:27])=[CH:21][CH:20]=1)[CH3:18])([O:14][CH3:15])=[O:13]>>[C:12]([CH:16]=[C:17]([C:19]1[CH:20]=[CH:21][C:22]([CH2:25][C:26]([NH:27][CH2:10][CH:8]([OH:9])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([CH3:29])[CH3:28])=[CH:23][CH:24]=1)[CH3:18])([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C=C(C)c1ccc(CC(C)(C)N)cc1
Reactant: O=CC(=O)c1ccccc1
Solvent: O
Product: COC(=O)C=C(C)c1ccc(CC(C)(C)NCC(O)c2ccccc2)cc1
Yield: 55.8 %

Procedure:
This was prepared in an identical manner to the compound described in Example 13 using phenylglyoxal monohydrate (1.5 g) and 2{4-(2-carbomethoxy-1-methylethenyl)phenyl}-1, 1-dimethylethanamine (2.47 g). The title compound (2.02 g) m.p. 98°-103° C. (benzene/hexane) was obtained after chromatography on Kieselgel 60 eluting with 1% methanolchloroform. τ(CDCl3) 8.9 (6H, s), 7.55 (3H, d, J=1.5 Hz), 7.35 (2H, s), 6.8-7.6 (4H, m) 6.3 (3H, s), 5.4 (1H, dd) 3.85 (1H, q, J=1.5 Hz), 3.0-2.2 (9H, m).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16](I)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1.[NH:31]1[CH2:36][CH2:35][S:34](=[O:38])(=[O:37])[CH2:33][CH2:32]1>CN1CCCC1=O>[O:37]=[S:34]1(=[O:38])[CH2:35][CH2:36][N:31]([C:16]2[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=[C:14]([C:7]3[C:8]4[C:9](=[N:10][CH:11]=[CH:12][CH:13]=4)[N:5]([CH2:4][C:3]4[CH:27]=[CH:28][CH:29]=[CH:30][C:2]=4[F:1])[N:6]=3)[N:15]=2)[CH2:32][CH2:33]1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Reactant: O=S1(=O)CCNCC1
Solvent: CN1CCCC1=O
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N3CCS(=O)(=O)CC3)c21
Temperature: 200 °C

Procedure:
Under argon atmosphere, 200 mg (purity 62%, 0.24 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was suspended in 4 ml of absolute 1-methyl-2-pyrrolidone and 652 mg (4.82 mmol) of thiomorpholine-1,1-dioxide was added. The mixture was heated in the microwave for 3 h at 150° C. and 1 h at 200° C. After cooling, the reaction mixture was purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→100:0). 72 mg (57% of theor.) of the target compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH:11]1/[CH:17]=[CH:18]/[CH:19]([OH:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH:11]1[CH2:17][CH2:18][CH:19]([OH:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [H][H]
Reactant: COC(=O)CCCCCCN1C(=O)CCCC1/C=C/C(O)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCCCN1C(=O)CCCC1CCC(O)Cc1ccccc1
Reaction time: 22 h
Yield: 64.2 %

Procedure:
Palladium on carbon (10 wt. %, 5 mg) was added to a solution of 7-[2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acid methyl ester (20 mg, 0.052 mmol) in MeOH (2.0 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 22 h. The reaction mixture was filtered through celite, washing with MeOH, and the filtrate was concentrated in vacuo to afford 13 mg (65%) of the title compound.
Reaction SMILES: C([NH:4][C:5]1[C:6]([Cl:15])=[C:7]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:8]([OH:10])=[O:9])(=O)C.C(O)(=O)C>Cl>[NH2:4][C:5]1[C:6]([Cl:15])=[C:7]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:8]([OH:10])=[O:9]
Reactant: CC(=O)Nc1c(Cl)ccc(C(=O)O)c1Cl
Agent: Cl
Solvent: CC(=O)O
Product: Nc1c(Cl)ccc(C(=O)O)c1Cl

Procedure:
3-Acetylamino-2,4-dichloro-benzoic acid (21.0 g, 84.6 mmol) is stirred in 6 M aq. HCl-solution (120 mL) and acetic acid (250 mL) at reflux for 24 h. The reaction mixture is cooled, concentrated, diluted with water and concentrated again. The residue is diluted with water, stirred under cooling and filtered. The filtercake is washed and dried to give the sub-title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].N1C=CC=CC=1.[SH:15][CH2:16][C:17]#[N:18]>CCOCC>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([S:15][CH2:16][C:17]#[N:18])=[O:7]
Reactant: O=C(Cl)c1ccco1
Reactant: N#CCS
Solvent: CCOCC
Solvent: c1ccncc1
Product: N#CCSC(=O)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
To an ice cold solution of furoyl chloride (4.0 ml; 0.04 mol) in ether (100 ml) is added dropwise a freshly prepared solution of pyridine (3.24 ml; 0.04 mol) in 1 N mercaptoacetonitrile (40 ml; 0.04 mol). After the addition is completed, the mixture is allowed to stir at room temperature overnight. The reaction mixture is then washed with water, saturated sodium bicarbonate solution, saturated brine, dried over sodium sulfate, and is concentrated in vacuo. The residue (6.0 g) is filtered through a 25 g column of silica gel and eluted with methylene chloride. The methylene chloride eluent is diluted with hexane, cooled and filtered to yield 4.3 g (64%) of title product, an orange solid, melting point 76°-78° C. Recrystallization from methylene chloride-hexane affords 3.7 g product, as a pale orange solid, melting point 77°-78° C.
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>CO>[CH3:15][N:16]1[CH2:21][CH2:20][CH:19]([C:10]2[C:9]3[C:13](=[CH:14][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=3)[NH:12][CH:11]=2)[CH2:18][CH2:17]1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CN1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CCC(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Temperature: 90 °C
Reaction time: 6 h
Yield: 37.5 %

Procedure:
KOH (3.96 g, 70.71 mmol) was added to a solution of 6-nitro-1H-indole (5 g, 30.86 mmol) in methanol (50 mL). 1-methylpiperidin-4-one (4.53 g, 40.09 mmol) was then added, and the resulting solution was stirred for 6 hours at 90° C. After cooling, the mixture was concentrated and the residue was recrystallized from ethanol (20 mL) to afford 3.0 g (36%) of 3-(1-methylpiperidin-4-yl)-6-nitro-1H-indole as a yellow powder.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[CH:13][CH:14]=2)[C:9]1=[O:19])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[CH:13][CH:14]=2)[C:9]1=[O:19]
Reactant: O=[O+][O-]
Reactant: CC=CCC1Cc2ccc(OC)cc2C1=O
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2c(c1)C(=O)C(CC=O)C2
Reaction time: 8 h
Yield: 50.9 %

Procedure:
Ozone (3 g ozone/hour) was conducted for 60 minutes while stirring through a solution, cooled to -70°, of 13.6 g of (RS)-2-(2-buten-1-yl)-6-methoxy-1-indanone in 200 ml of anhydrous dichloromethane and 400 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen and then 6.4 ml of dimethyl sulfide were added to the cold solution. The solution came to room temperature overnight and was evaporated in a vacuum. The residue was dissolved in 1600 ml of dichloromethane. The solution was treated with 600 g of silica gel and 100 ml of 10% oxalic acid solution and stirred overnight. Then, the mixture was filtered and the filtrate was concentrated in a vacuum. 6.5 g (51%) of (RS)-2-(2-oxoethyl)-6-methoxy-1-indanone were obtained as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][NH:7][CH2:6][C@@H:5]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH2:4]1.[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]2[N:31]=[CH:30][C:29](=[O:32])[N:28]([CH2:33][CH:34]=O)[C:27]=2[N:36]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH3:1][O:2][CH:3]1[CH2:8][N:7]([CH2:34][CH2:33][N:28]2[C:29](=[O:32])[CH:30]=[N:31][C:26]3[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[N:36][C:27]2=3)[CH2:6][CH:5]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH2:4]1
Reactant: COc1ccc2ncc(=O)n(CC=O)c2n1
Reactant: CO[C@H]1CNC[C@@H](CN2C(=O)c3ccccc3C2=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2ncc(=O)n(CCN3CC(CN4C(=O)c5ccccc5C4=O)CC(OC)C3)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
To cis-2-{[(3RS,5SR)-5-(methyloxy)-3-piperidinyl]methyl}-1H-isoindole-1,3(2H)-dione (125 mg, 0.43 mmol) in MeOH (1 ml) and CHCl3 (5 ml) was added [6-(methyloxy)-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl]acetaldehyde (for a preparation see Example 126(e)) (100 mg; 0.50 mmol) and the reaction was allowed to stir at room temperature under N2 for 4 hours. Na(OAc)3BH (210 mg; 1.0 mmol) was added and the reaction was allowed to stir at room temperature under nitrogen for an additional 14 hours. The reaction was partitioned between saturated aqueous NaHCO3 (5 mL) and CH2Cl2 (20 mL), the aqueous layer was further extracted with CH2Cl2 (20 mL), and the combined organic layers were dried over Na2SO4. The solvents were removed and the crude residue was purified by chromatography on silica gel using a 0-10% MeOH/DCM gradient to provide the desired compound (10 mg; 55%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].C(N(CC)CC)C.[CH:17]1([O:22][C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=2[O:32][CH3:33])[C:26](Cl)=[O:27])[CH2:21][CH2:20][CH2:19][CH2:18]1>ClCCl>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH:4][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:23]([O:22][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)[CH:24]=1
Reactant: Nc1c(F)cccc1F
Reactant: COc1ccc(C(=O)Cl)cc1OC1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2c(F)cccc2F)cc1OC1CCCC1
Yield: 46.5 %

Procedure:
A stirred solution of 2,6-difluoroaniline (1.52 g) and triethylamine (1.19 g) in dichloromethane (50 mL) at room temperature is treated dropwise with a solution of 3-cyclopentyloxy-4-methoxybenzoyl chloride (3.0 g), that is prepared as described hereinafter in Reference Example 3) in dichloro-methane (50 mL). The solution is stirred and heated at reflux for 4 hours, then it is cooled, washed with water and dried over magnesium sulfate. The solution is concentrated and the resulting residue is recrystallized from ethyl acetate, to give N-(2,6-difluorophenyl)-3-cyclopentyloxy-4-methoxybenzamide (1.9 g), m.p. 158-160° C. [NMR(CDCl3): 1.55-1.7(m,3H),1.8-2.05(m,5H), 3.93(s,3H),4.85(m,1H),6.9(d,1H), 6.95-7.03(m,2H),7.2-7.3(m,1H),7.35(bs,1H), 7.45(q,1H),7.53(d,1H); Elemental analysis: C,65.1; H,5.6; F,10.4; N,4.2%; Calculated: C,65.7; H,5.5; F,10.9; N,40%].
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[C:5]([CH3:11])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13].[OH-].[NH4+]>S(=O)(=O)(O)O>[CH3:11][C:5]1[C:6]2[NH:7][CH:8]=[N:9][C:10]=2[C:2]([CH3:1])=[CH:3][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C)c2[nH]cnc12
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc([N+](=O)[O-])c(C)c2[nH]cnc12
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a cold (ice bath) solution of 1 g of 4,7-dimethylbenzimidazole in 8 mL of concentrated sulfuric acid is added dropwise concentrated nitric acid (0.37 mL), over 50 minutes. The mixture is stirred an additional 30 minutes in the ice bath, then poured into a mixture of crushed ice (30 mL) and ammonium hydroxide (30 mL). The resulting mixture is extracted with ethyl acetate. The extract is dried over magnesium sulfate and rotary evaporated to afford 4,7-dimethyl-5-nitrobenzimidazole as a dark tan solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(OCC)(=O)C>[CH2:26]([O:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: N#CCOc1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCOc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 22 h
Yield: 80.4 %

Procedure:
A heterogeneous mixture of 6.0 g of (4-hydroxy-3-nitro-phenoxy)-acetonitrile, 50 ml N,N-dimethylformamide, 12.8 g of potassium carbonate, and 5.8 g of benzyl bromide was heated with stirring at 70° C. for 22 hours. The mixture was cooled to room temperature, poured into ethyl acetate, washed with water, washed with 1N sodium hydroxide, again with water, dried (MgSO4), evaporated, and obtained 7.06 g of (4-benzyloxy-3-nitro-phenoxy)-acetonitrile as a tan solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[NH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C>CCO>[N+:8]([C:7]1[C:2]([NH:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1ncccc1[N+](=O)[O-]
Yield: 74.9 %

Procedure:
To a solution of 2-chloro-3-nitropyridine (25.3 g) in EtOH (300 mL) were added ethyl 2-aminoacetate hydrochloride (28.7 g) and triethylamine (28.9 mL) at room temperature, and the mixture was refluxed for 1 day. The mixture was concentrated under reduced pressure. The residual crystals were removed by filtration and washed with AcOEt. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 20%-70% AcOEt in hexane). The residual crystals were removed by filtration and washed with IPE. The filtrate was concentrated under reduced pressure to give the title compound (26.9 g).
Reaction SMILES: Cl[C@@H](C(C)CC)C(O)=[O:4].[CH:10]1([N:16]=[C:17]=[N:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CN(C)C1C=CN=CC=1.CCOCC>[CH:19]1([NH:18][C:17]([NH:16][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)=[O:4])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CCC(C)[C@H](Cl)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 60 h
Yield: 40 %

Procedure:
While stirring, 1.5 g (0.01 moles) of (S)-2-chloro-3-methylpentanoic acid, 2.06 g (0.01 moles) of DCC, 0.12 g (0.001 moles) of 4-dimethylaminopyridine (DMAP) and an amount of 1-(4-n-alkoxy-benzoyloxy)-4-hydroxy-benzene corresponding to 0.01 moles are added to 50 mL of ether. The mixture is allowed to stand 2-3 days at room temperature. The N,N'-dicyclohexylurea formed is then filtered off with suction. The mother liquor is washed several times with water and dried over sodium sulfate. The solvent is then distilled off in a rotary evaporator and the residue is recrystallized several times from methanol.
Reaction SMILES: [CH:1]([S:4]([CH2:7][C@H:8]1[C@@H:17]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][C:10]2(OCC[O:11]2)[CH2:9]1)(=[O:6])=[O:5])([CH3:3])[CH3:2].Cl>CC(C)=O>[CH:1]([S:4]([CH2:7][C@@H:8]1[CH2:9][C:10](=[O:11])[CH2:15][CH2:16][C@@H:17]1[NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)C[C@@H]1CC2(CC[C@@H]1NC(=O)OCc1ccccc1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: CC(C)S(=O)(=O)C[C@@H]1CC(=O)CC[C@@H]1NC(=O)OCc1ccccc1
Yield: 97.2 %

Procedure:
A solution of benzyl ((7R,8S)-7-(isopropylsulfonylmethyl)-1,4-dioxa-spiro[4.5]dec-8-yl)-carbamate (2.3 g, 5.6 mmol) in acetone (30 ml) is treated with 5 N HCl (30 ml) and heated to reflux for 2 hrs. The The mixture is concentrated on a rotary evaporator and the residue neutralized with 1 N NaOH and extracted into CH2Cl2. The organic extracts were washed with water, brine, and the solvent remove under vacuum to give 2.0 g of benzyl (1S,2R)-2-(isopropylsulfonylmethyl)-4-oxocyclohexylcarbamate. This is used without further purification.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:28][C:29]([O:31][CH3:32])=[O:30])=[CH:8][C:9]([N+:25]([O-])=O)=[C:10]([C:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=3)[CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[NH2:25][C:9]1[CH:8]=[C:7]([O:28][C:29]([O:31][CH3:32])=[O:30])[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:11][C:10]=1[CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1C1CCCC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)Oc1cc(N)c(C2CCN(C(=O)OC(C)(C)C)CC2)cc1C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
Tert-butyl 4-(5-cyclopentyl-4-methoxycarbonyloxy-2-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (680 mg, 1.52 mmol) in methanol (30 mL) was treated with 10% Pd/C (162 mg) and stirred under H2 for 1 h at room temperature. The reaction was filtered and concentrated in vacuo to provide tert-butyl 4-(2-amino-5-cyclopentyl-4-(methoxycarbonyloxy)phenyl)piperidine-1-carboxylate (520 mg, 82% yield). LC/MS m/z 419.7 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=O)(C)(C)C.[H-].[Na+].[CH3:19]I.[ClH:21]>ClCCl.O1CCOCC1>[ClH:21].[CH3:19][O:13][C@H:11]1[CH2:12][NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CO[C@H]1CN[C@H](C(=O)O)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
A stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (25.6 g, 111 mmol), is treated under nitrogen with sodium hydride (9.3 g, 388 mmol) and methyl iodide (31.5 g, 222 mmol), using a procedure similar to that published for the CBZ analog in J. Med. Chem. 1988, 31, 875, except that reflux is carried out for 16 h. The crude extracted product of this alkylation reaction, (2S,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid, is then dissolved in dichloromethane (200 mL), cooled to 0° C., treated with 4 N HCl in dioxane (100 mL), and then stirred at room temperature overnight. After further cooling at −20° C. for 3 h, the precipitate is collected by filtration, washed with ethyl ether, and dried in vacuo to give 18.5 g (92%) of the pure mono HCl salt of (2S,4R)-4-methoxypyrrolidine-2-carboxylic acid: MS: 146 (M+H)+; 1H NMR (d6-DMSO) δ 14.02 (brs, 1H), 10.30 (brs, 1H), 8.98 (brs, 1H), 4.33-4.22 (m, 1H), 4.10 (brs, 1H), 3.43-3.34 (m, 1H), 3.24 (s, 3H), 3.26-3.19 (m, 1H), 2.45-2.36 (m, 1H), 2.10-2.00 (m, 1H); [α]22D-29.7 (CH3OH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[C:15]([Cl:17])[N:14]=[C:13](Cl)[CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:19][NH2:20].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[Cl:17][C:15]1[N:14]=[C:13]([NH:20][CH3:19])[CH:12]=[C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]3=[N:10][CH:9]=2)[CH:16]=1
Reactant: Clc1ccn2c(-c3cc(Cl)nc(Cl)c3)cnc2c1
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNc1cc(-c2cnc3cc(Cl)ccn23)cc(Cl)n1

Procedure:
7-Chloro-3-(2,6-dichloro-pyridin-4-yl)-imidazo[1,2-a]pyridine (1.0 eq, 0.64 mmol, 190 mg), methyl amine (8M in EtOH, 3.5 eq, 2.2 mmol, 0.28 ml) and Cs2CO3 (2.5 eq, 1.59 mmol, 518 mg) are dissolved in DMF (2 ml) and the reaction mixture is heated using microwave radiation at 160° C. for 30 min, it is diluted with CH2Cl2. The reaction mixture is washed with NaHCO3 and brine, dried over MgSO4, filtered and evaporated. The product is purified by flash column chromatography eluting with 8:2 DCM/MeOH to afford [6-chloro-4-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-pyridin-2-yl]-methyl-amine as a brown solid; [M+H]+=294
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.[C:23]1([Si:29]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1>C1C=CC=CC=1>[C:37]1([Si:29]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:1][CH2:2][C@@:3]23[C@@H:20]4[C@H:11]([C@H:12]5[C@@:16]([CH2:18][CH2:19]4)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]5)[CH2:10][CH2:9][C:8]2=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]3)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO[Si](c3ccccc3)(c3ccccc3)c3ccccc3)[C@@H]1CCC2=O

Procedure:
A solution of 19-hydroxy-4-androstene-3,17-dione, triphenylchlorosilane and pyridine contained in 100 ml of benzene is refluxed for a period of 18 hours. The resulting suspension is filtered and concentrated in vacuo to a yellow oil. The oil is placed on a silica gel chromatographic column packed in chloroform which is further eluted with chloroform. The chloroform eluant is evaporated to dryness in vacuo and the residue is recrystallized from methanol to yield 19-triphenylsiloxy-4-androstene-3,17-dione.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1)(OC(C)(C)C)=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](C=O)[CH:34]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:8][N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]2)[CH:34]=1
Reactant: O=Cc1cccnc1
Reactant: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)N(CC1CCCN(Cc2cccnc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 (21 mg, 0.061 mmol) in 0.5 mL of dry CH2Cl2 at 0° C. (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude compound was dissolved in DMF (0.5 mL) and 3-pyridine carboxaldehyde (8.6 μL, 1.5 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 20.3 mg, 1.5 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3×10 mL). The extracts were combined and washed with aqueous NaHCO3 (sat., 2×5 μL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford N-[1-(Pyridin-3-ylmethyl)-piperidin-3-ylmethyl]-N-phenyl-propionamide 12 as a colorless oil (15.6 mg, 76%). LRMS 338.