Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=1>CN(C=O)C.[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13][CH2:12]2)=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cc1cc(N)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 4-(2-methyl-4-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (A38) (211 mg, 0.663 mmol) in DMF (7.5 mL) was added a slurry of 10% Pd/C (100 mg) in DMF (0.5 mL) and the resulting mixture was stirred for 16 hours under a hydrogen atmosphere at room temperature. The resulting mixture was filtered through Celite then the volatiles were removed under reduced pressure. The residue was purified by silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 0-60% EtOAc in petroleum benzine 40-60° C.) to give the title compound A39 as a pale orange solid (185 mg, 96%); 1H NMR (400 MHz, CDCl3) δ 6.95 (d, J=8.0 Hz, 1H), 6.56-6.48 (m, 2H), 3.51 (s, 2H), 2.88-2.65 (m, 3H), 2.26 (s, 3H), 1.74-1.66 (m, 2H), 1.63-1.51 (m, obscured by solvent), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[Br:9]Br>C(Cl)Cl>[Br:9][C:5]1[S:4][C:3]([CH:7]=[O:8])=[C:2]([CH3:1])[CH:6]=1
Reactant: Cc1ccsc1C=O
Reactant: BrBr
Solvent: ClCCl
Product: Cc1cc(Br)sc1C=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 67.6 %

Procedure:
To 0° C. cooled solution of 3-methylthiophene-2-carbaldehyde (10.0 g, 79.3 mmol, 1.0 eq) in DCM (100 mL) was added drop wise a solution of bromine (12.6 g, 79.3 mmol, 1.0 eq) and the resulting mixture was stirred 70° C. for 4 h. The reaction was cooled to room temperature and diluted with DCM (100 mL). The resulting organic layer was washed with water (100 mL), saturated sodium bicarbonate solution (100 mL), brine (100 mL), dried (Na2SO4) and filtered. The filtrate was rotary evaporated to afford 11 g of the desired product as a brown solid. 1HNMR (400 MHz, CDCl3) δ 9.87 (s, 1H), 6.93 (s, 1H), 2.51 (s, 3H); ESI-MS (m/z) 205, 207 [(MH)+, Br79,81].
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(N[C:14]1[CH:19]=CC(O)=C(CC=C)[CH:15]=1)(=O)C>>[CH2:19]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[OH:1])[CH:6]=[O:7])[CH:14]=[CH2:15]
Reactant: C=CCc1cc(NC(C)=O)ccc1O
Reactant: O=Cc1ccc(O)cc1
Product: C=CCc1cc(C=O)ccc1O

Procedure:
The starting 3-allyl 4-hydroxybenzaldehyde was prepared from 4-hydroxybenzaldehyde using the method described in Example 1 for the preparation of 4-acetamido-2-allylphenol.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1)#[N:2].O.[OH-].[Na+]>C(OCC)C>[NH2:2][CH2:1][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(CO)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: NCc1ccc(CO)cc1
Temperature: 25 °C
Yield: 29.5 %

Procedure:
To a stirred suspension of LiAH4 (285 mg, 7.52 mmol) in diethylether (10 mL) at 0° C. was added a solution of 4-cyanobenzyl alcohol (0.5 g, 3.76 mmol) in diethylether (5 mL) over 15 min. The grey reaction mixture was heated to reflux for 3 h. After cooling to r.t., the mixture was treated successively with water (1 mL), 2M NaOH (2 mL) and water (2 mL) under vigorous stirring. The resulting white slurry was filtered and washed with CH2Cl2 (20 mL). Extraction with additional CH2Cl2 (20 mL) and n-butanol (20 mL) and evaporation yielded an oil, which upon flash chromatography (0-15% MeOH in CH2Cl2) gave 152 mg (29%) of 4-(aminomethyl)benzylalcohol (57 MBT52B) as a white solid. Rf=0.51 (30% MeOH in CH2Cl2+3.5% NH4OH).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][CH2:8][N:9]([CH2:16][CH3:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:20](=O)[CH2:21][CH2:22][CH2:23][CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:16]([N:9]([CH2:8][CH2:7][O:6][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:17]
Reactant: O=CCCCC=O
Reactant: CCN(CCOc1ccc(N)cc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCN(CCOc1ccc(N2CCCCC2)cc1)c1ccccc1
Reaction time: 8 h
Yield: 73.9 %

Procedure:
Compound 20 (120 mg, 0.47 mmol) and glutaraldehyde (46 mg, 0.23 mmol) was dissolved in 10 mL 1,2-dichloroethane and sodium triacetoxyborohydride (400 mg, 1.89 mmol) was added portionwise over 6 hrs and reaction was stirred overnight. The reaction was quenched with sat. sodium carbonate, extracted with EtOAc (2×25 mL), washed with water and then brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography provide the compound 22 (55 mg, 0.17 mmol, 36% yield). 1H NMR (CDCl3, 400 MHz) δ 7.23-7.28 (m, 2H), 6.68-6.94 (m, 7H), 4.10 (t, J=6.4 Hz, 2H), 3.72 (t, J=6.4 Hz, 2H), 3.50 (q, J=7.2 Hz, 2H), 3.05 (t, J=5.6 Hz, 4H), 1.72-1.78 (m, 4H), 1.54-1.60 (m, 2H), 1.22 (t, J=6.8 Hz, 3H); HRMS (ESI, positive) m/z calcd. for C21H29N2O [M+H]+: 325.2280, found: 325.2227.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16](=[O:35])[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[CH3:14].Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>C1COCC1>[C:41]([O:40][C:38](=[O:39])[CH2:37][CH:17]([C:16]([O:15][CH2:13][CH3:14])=[O:35])[CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[N:34])=[CH:31][CH:32]=2)=[CH:23][CH:22]=1)([CH3:44])([CH3:43])[CH3:42]
Reactant: CCOC(=O)CCCOc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(CCOc1ccc(-c2ccc(C#N)cc2)cc1)CC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 33.1 %

Procedure:
To a -78° C. solution in THF (100 mL) of diisopropylamine (0.94 mL, 7.15 mmol) was added n-butyllithium (25M in hexanes, 2.86 mL, 7. 15 mmol) and the mixture was stirred for 15 minutes. A solution in THF (25 mL) of 4-[4-(4-cyanophenyl)phenoxy]butanoic acid ethyl ester (2.01 g, 6.5 mmol), prepared as in step 1, was added dropwise and the reaction mixture was stirred for 15 minutes. Neat t-butyl bromoacetate (1.03 mL, 6.8 mmol) was added rapidly and the reaction mixture was stirred at -78° C. for 2 hours, then for 0.5 hours at ambient temperature. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted twice with ethyl ether. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Successive chromatographies on silica gel (dichloromethane, then 1:3 ethyl acetate-hexanes) gave 3-carboethoxy-5-[4(4-cyanophenyl)phenoxy]pentanoic acid tert-butyl ester (0.91 g, 33%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@H:10]([CH2:14][NH2:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@H:10]([CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1CN(Cc2ccccc2)C[C@H]1CN
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H]1CN(Cc2ccccc2)C[C@H]1CNCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
cis-1-Benzyl-4-methyl-3-aminomethylpyrrolidine (1000 mg) was dissolved in methanol (10 mL). While this solution was chilled in an ice water bath, benzaldehyde (0.50 mL) was added dropwise and the mixture was stirred at room temperature for 1 hour. Subsequently, sodium cyanoborohydride (184 mg) was added and the mixture was stirred at room temperature for 1.5 hours, followed by addition of a second portion of sodium cyanoborohydride (123 mg) and then further stirring for 5.5 hours. To the resulting mixture, a 2 mol/L aqueous solution of sodium hydroxide (5 mL) was added and the mixture was refluxed for 2 hours. Subsequently, the reaction mixture was concentrated under reduced pressure and the residue was extracted with toluene (2×30 mL). The toluene layers were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate=4:1) to give cis-1-benzyl-3-benzylaminomethyl-4-methylpyrrolidine as a pale yellow oil (690 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: [H][H]
Reactant: CCOC(=O)CCCOc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1ccccc1N

Procedure:
A solution of (3) (1.27 g, 5.0 mM) in 15 mL ethyl acetate containing 200 mg of 5% palladium on carbon is reacted in a hydrogen atmosphere (40 psig.) at room temperature until hydrogen uptake ceases. The mixture is then filtered and concentrated in vacuo to yield 1.0+ g of (4) as an oil/low melting solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].O[C:15]1[C:16]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([NH2:27])=[O:26])[C:17]=2[N:18]=[N:19][N:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:15]2[C:16]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([NH2:27])=[O:26])[C:17]=3[N:18]=[N:19][N:20]=2)=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13]
Reactant: NC(=O)c1cccc2c(O)nnnc12
Reactant: NCc1ccc(Cl)c(C(F)(F)F)c1
Product: NC(=O)c1cccc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)nnnc12

Procedure:
Compound 4 was prepared following general synthetic scheme 7 wherein (4-chloro-3-(trifluoromethyl)phenyl)methanamine was reacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the title compound. LC-MS [382 (M+1)], 1H NMR (400 MHz, DMSO-d): δ 9.38-9.32 (m, 2H), 8.54 (d, 1H), 8.48 (d, 1H), 8.05 (s, 1H), 8.02-7.98 (m, 1H), 7.95 (s, 1H), 7.73-7.68 (m, 2H), 4.96 (d, 2H).
Reaction SMILES: [CH2:1]1[CH:8]([N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10]2=[O:11])C(=O)O[C:3](=O)[CH2:2]1.[CH2:20](N)[CH2:21][C:22]1C=CC=C[CH:23]=1>>[CH2:8]([N:9]1[C:10](=[O:11])[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:17]2[C:18]1=[O:19])[CH2:1][C:2]1[CH:3]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCc1ccccc1
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)O1
Product: O=C1c2ccccc2C(=O)N1CCc1ccccc1
Temperature: 177 °C

Procedure:
With reference to Scheme 3 below, a mixture of N-phthaloyl-DL-glutamic anhydride and phenethylamine was heated in a 177° C. oil bath. The reaction mixture was purified by chromatography on a silica gel column to afford N-phenethylthalidomide (8) and N-phenethylphthalimide (9).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6](Cl)[C:7]=1[N:8]1[C:16](=[O:17])[C:15]2[C:10]([C:11]3[S:32][CH:31]=[CH:30][C:12]=3[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH:29]=[CH:28][CH:27]=[N:26]4)=[CH:21][CH:20]=3)[CH:14]=2)=[N:9]1.C([O-])=O.[NH4+]>CO>[N:25]1([C:22]2[CH:23]=[CH:24][C:19]([CH2:18][N:13]3[CH:14]=[C:15]4[C:16](=[O:17])[N:8]([C:7]5[CH:6]=[CH:5][N:4]=[CH:3][CH:2]=5)[N:9]=[C:10]4[C:11]4[S:32][CH:31]=[CH:30][C:12]3=4)=[CH:20][CH:21]=2)[CH:29]=[CH:28][CH:27]=[N:26]1
Reactant: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccsc3c-2nn1-c1c(Cl)cncc1Cl
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccsc3c-2nn1-c1ccncc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2-(3,5-Dichloropyridin-4-yl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[3,4-d]thieno[3,2-b]pyridin-3-one (Example 15, 15 mg, 0.030 mmol), ammonium formate (2.9 mg, 0,046 mmol, 1.5 equiv) and 1,1′-bis(diphenylphosphino)ferroenedichloro palladium (II) dichloromethane complex (4.4 mg, 6.1 lima 0.2 equiv) were combined in methanol (5 mL) and placed into a preheated oil bath at 70° C. for 14 hours. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 85:15; chloroform:methanol), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.28 (1H, s), 8.76 (2H, br d, J=5.5 Hz), 8.57 (2H, br d, J=5.5 Hz), 8.48 (1H, d, J=2.5 Hz), 8.16 (1H, d, J=5.6 Hz), 7.84 (2H, d, J=8.6 Hz), 7.73 (1H, d, J=1.5 Hz), 7.68 (1H, d, J=5.6 Hz), 7.53 (2H, d, J=8.6 Hz), 6.53 (1H, dd, J=2.4, 1.8 Hz), 5.77 (2H, s) ppm; high resolution mass spectrometry (ES+) m/z 425.1184 [(M+H)+; calculated for C23H17N6OS: 425.1179].
Reaction SMILES: C(OC([NH:11][C:12]1[C:13]([C:25]([NH:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][C:33]=2[N:34]2[CH2:39][CH2:38][CH2:37][C@H:36]([NH:40]C(=O)OCC3C=CC=CC=3)[CH2:35]2)=[O:26])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([CH2:22][C:23]#[N:24])[CH:16]=2)=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C:12]1[C:13]([C:25]([NH:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][C:33]=2[N:34]2[CH2:39][CH2:38][CH2:37][C@H:36]([NH2:40])[CH2:35]2)=[O:26])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([CH2:22][C:23]#[N:24])[CH:16]=2
Reactant: N#CCc1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)Nc3cnccc3N3CCC[C@H](NC(=O)OCc4ccccc4)C3)nc2c1
Agent: [Pd]
Solvent: CO
Product: N#CCc1ccc2cc(N)c(C(=O)Nc3cnccc3N3CCC[C@H](N)C3)nc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 8.6 %

Procedure:
To a solution of benzyl {(3S)-1-[3-({[3-{[(benzyloxy)carbonyl]amino}-7-(cyanomethyl)quinolin-2-yl]carbonyl}amino)pyridin-4-yl]piperidin-3-yl}carbamate (65.8 mg, 0.0982 mmol) in MeOH (2.0 mL), 10 wt % Pd on carbon (15.4 mg, 0.0145 mmol) was added. The mixture was stirred at room temperature under hydrogen (1 atm.) for 15 h. The reaction mixture was filtered through a pad of diatomaceous earth (eluted with MeOH), and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to give the title compound as a yellow solid (3.4 mg, 9%). LCMS calc. for C22H24N7O (M+H)+: m/z=402.2. found 402.2. 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.27 (d, J=5.3 Hz, 1H), 7.85 (s, 1H), 7.75 (d, J=8.7 Hz, 1H), 7.57 (s, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.17 (d, J=5.3 Hz, 1H), 6.98 (s, 2H), 4.23 (s, 2H), 3.25-3.18 (m, 1H), 3.18-3.03 (m, 2H), 2.78-2.58 (m, 1H), 2.47-2.41 (m, 1H), 2.08-1.95 (m, 1H), 1.95-1.76 (m, 2H), 1.22 (s, 1H) ppm.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH3:7][O:8][C:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)=[O:10]>>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:15]([C:14]1[CH:18]=[CH:19][C:11]([C:9]([O:8][CH3:7])=[O:10])=[CH:12][CH:13]=1)=[O:16]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: NCCCCO
Product: COC(=O)c1ccc(C(=O)NCCCCO)cc1

Procedure:
The same procedure as a series of reactions of Example 17 was carried out, except that 4-amino-1-butanol was used in place of the compound 16 and 4-(methoxycarbonyl)benzoic acid was used in place of 1H-imidazole-2-carboxylic acid, to obtain the title compound having the following physical properties.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][CH2:16][CH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][O:28][CH3:29])[CH:21]=O.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:15][CH2:16][CH2:17][C:18]1[CH:19]=[C:20]([C:21]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][O:28][CH3:29]
Reactant: COCOc1ccc(C=O)cc1CCO
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COCOc1ccc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)cc1CCO
Temperature: 150 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
A mixture of 2-amino-4,6-dimethoxy-benzamide (0.25 g, 1.27 mmol), 3-(2-hydroxy-ethyl)-4-methoxymethoxy-benzaldehyde (0.268 g, 1.27 mmol), sodium hydrogensulfite (0.146 g, 1:4 mmol) and p-toluenesulfonic acid (0.025 g, 0.127 mmol) in N,N-dimethyl acetamide (8 mL) was stirred at 150° C. overnight under nitrogen atmosphere. The reaction mixture was cooled to room temperature, the solvent evaporated under reduced pressure. Water (70 mL) was added to obtain a solid. The yellow solid was filtered off, washed with water and dried under vacuum to provide crude 2-[3-(2-hydroxy-ethyl)-4-methoxymethoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.182 g, 36.7%) which was used as such in the next step. A solution of 2-[3-(2-hydroxy-ethyl)-4-methoxymethoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.18 g), 50% acetic acid solution (4 mL) and catalytic amount of concentrated sulfuric acid (0.02 mL) was heated at 70° C. for 2.5 h. After cooling to room temperature the reaction mixture was diluted with water (30 mL) to obtain a solid. The solid was filtered off, washed with water and dried under high vacuum to provide crude solid (0.135 g, 85%). The crude was purified by flash column chromatography to give pure 2-(4-hydroxy-3-(2-hydroxyethyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.035 g. 8% over 2 steps). Selected data: MS (ES) m/z: 343.0; MP 249-250.3° C.
Reaction SMILES: [F:1][C:2]1[C:3]([N:11]2[CH2:15][C:14]([CH3:17])([CH3:16])[CH:13]([N:18]([CH3:20])[CH3:19])[CH2:12]2)=[N:4][C:5]([CH3:10])=[N:6][C:7]=1[NH:8][NH2:9].[CH:21]1([CH2:26][C@H:27]([CH2:31][N:32]([CH:41]=[O:42])[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:28](O)=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22]1.CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C>[CH:21]1([CH2:26][C@@H:27]([C:28]([NH:9][NH:8][C:7]2[C:2]([F:1])=[C:3]([N:11]3[CH2:12][CH:13]([N:18]([CH3:20])[CH3:19])[C:14]([CH3:17])([CH3:16])[CH2:15]3)[N:4]=[C:5]([CH3:10])[N:6]=2)=[O:29])[CH2:31][N:32]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:41]=[O:42])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1nc(NN)c(F)c(N2CC(N(C)C)C(C)(C)C2)n1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2CC(N(C)C)C(C)(C)C2)n1
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a solution of racemic 1-(5-fluoro-6-hydrazino-2-methyl-4-pyrimidinyl)-N,N,4,4-tetramethyl-3-pyrrolidinamine (0.0617 g, 0.219 mmol) in DMF (3 mL) was added (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (0.0637 g, 0.209 mmol), N-methylmorpholine (0.120 mL, 1.091 mmol), 1-hydroxy-7-azabenzotriazole (34 mg, 0.250 mmol), and EDC (48 mg, 0.250 mmol). The solution was stirred overnight and then purified directly by Gilson RPLC to give [(2R)-2-(cyclopentylmethyl)-3-(2-{6-[4-(dimethylamino)-3,3-dimethyl-1-pyrrolidinyl]-5-fluoro-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.0775 g, 65% yield, mixture of diastereomers) as a pale yellow oil. LCMS: (M+H)+: 570.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:13]N(C)C)[C:9](OC)=[O:10].[NH2:17][C:18]([NH2:20])=[O:19].[Na+].[I-].C[Si](Cl)(C)C.[OH-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:10])[NH:17][C:18](=[O:19])[NH:20][CH:13]=1
Reactant: COC(=O)C(=CN(C)C)c1ccccc1Cl
Reactant: NC(N)=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=c1[nH]cc(-c2ccccc2Cl)c(=O)[nH]1
Temperature: 25 °C
Yield: 66.5 %

Procedure:
To a mixture of methyl 2-(2-chlorophenyl)-3-(dimethylamino)acrylate 2b (0.26 g, 1.08 mmol), urea (0.2 g, 3.26 mmol) and NaI (0.49 g, 3.26 mmol) in acetonitrile (5 mL) was added TMSCl (0.41 mL, 3.26 mmol). The resulting mixture was refluxed for 16 hours, cooled to room temperature, and 1.0 M NaOH (8 mL) was added. The resultant solution was stirred for 20 hr, and acetonitrile was removed in vacuo. The aq. solution was washed with ether, cooled in ice bath, and neutralized with 1 N HCl (8 mL). The precipitate was filtered, washed with additional H2O, and dried to give 5-(2-chlorophenyl)pyrimidine-2,4(1H,3H)-dione 2c (0.16 g, 66%) as a white solid. MS (CI) m/z 222.9, 224.9 (MH+).
Reaction SMILES: [I:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH2:16][CH2:17][CH3:18])=[N:4][C:3]=1[OH:19].CC(N(C(C)C)CC1C=CC=CC=1)C.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.[C:52]([Si:56](Cl)([CH3:58])[CH3:57])([CH3:55])([CH3:54])[CH3:53]>C(Cl)Cl>[Si:56]([O:19][C:3]1[N:4]=[C:5]([CH2:16][CH2:17][CH3:18])[C:6]2[C:11]([C:2]=1[I:1])=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2)([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:58])[CH3:57]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCc1nc(O)c(I)c2cc(OC)c(OC)cc12
Agent: C=Cc1ccc(C=C)cc1
Agent: CC(C)N(Cc1ccccc1)C(C)C
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: CCCc1nc(O[Si](C)(C)C(C)(C)C)c(I)c2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
To a mixture of 4-iodo-6,7-dimethoxy-1-propylisoquinolin-3-ol CCH 42098-1 (0.60 g, 1.61 mmol) and diisopropylaminomethyl-polystyrene resin (3 mmol/g, 0.80 g, 2.40 mmol) in dry CH2Cl2 (16 mL) in a 50 mL round-bottomed flask equipped with a magnetic stirrer was added tert-butylchlorodimethylsilane (267 mg, 1.77 mmol) and the reaction mixture was stirred for 15 min at RT then for 1 h under reflux. After cooling to RT, the reaction mixture was filtered and the filtrate was washed with brine (5 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 95:5) gave 3-(tert-butyldimethylsilyloxy)-4-iodo-6,7-dimethoxy-1-propylisoquinoline CCH 42098-2 as an off-white solid (0.65 g, 83% yield).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:28]([F:31])([F:30])[F:29])=[N:19][C:20]([C:21]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.[ClH:43]>C(OCC)(=O)C>[ClH:43].[NH2:7][C@H:8]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:28]([F:31])([F:29])[F:30])=[N:19][C:20]([C:21]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])=[C:14]2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)C3CCCC3)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)C3CCCC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 81 %

Procedure:
(R)-[3-(1-Cyclopentanecarbonyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 28c (0.11 g, 0.183 mmol) was dissolved in 2 mL of ethyl acetate under stirring. A solution of 2.4 N hydrochloric acid in 5 mL of ethyl acetate was added to the above solution. The reaction mixture was stirred at room temperature and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-3-amino-1-(1-cyclopentanecarbonyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-4-(2,4,5-trifluoro-phenyl)-butan-1-one hydrochloride 28 (80 mg, yield 81%) as a yellow solid.