Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]3[N:22]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:21]4[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=4[N:19]=3)[CH2:13][CH2:12]2)[C:3]=1[NH2:35].N[C:37](N)=[O:38]>O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[NH:35][C:37](=[O:38])[N:8]2[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:21]3[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=3[N:19]=2)[CH2:13][CH2:12]1
Reactant: NC(N)=O
Reactant: Nc1c(Cl)ncnc1NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Solvent: O
Product: O=c1[nH]c2c(Cl)ncnc2n1CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Yield: 49.9 %

Procedure:
7.5 Parts of 6-chloro-N4 -[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-4,5-pyrimidinediamine and 3.6 parts of urea were heated together till about 220° C. during 10 minutes. The resulting melt was cooled and suspended in water. The solid was filtered off, washed with water and ethanol and recrystallized from a mixture of N,N-dimethylacetamide, ethanol and water, yielding 3.9 parts (49.9%) of 6-chloro-9-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-7,9-dihydro-8H-purin-8-one; mp. 266.2° C. (compound 144).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[CH3:15][C:16]([CH3:18])=O.N1CCCC1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:15][C:16]1([CH3:18])[CH2:2][C:1](=[O:3])[C:4]2[C:13](=[CH:12][CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=2)[O:14]1
Reactant: CC(C)=O
Reactant: COC(=O)c1ccc(O)c(C(C)=O)c1
Solvent: CCOC(C)=O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)C(=O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 3-acetyl-4-hydroxybenzoate (200 mg, 1.03 mmol), acetone (151 μL, 2.06 mmol) and pyrrolidine (25.6 μL, 0.31 mmol) were mixed in toluene (515 μL) and stirred at room temperature for 1 hour. It was then heated to 100° C. for 5 hours, allowed to cool to room temperature, diluted with EtOAc (50.0 mL) and poured into ice. The two layers were separated. The organic layer was washed with 2 N aqueous HCl (10.0 mL), 2 N aqueous NaOH (10.0 mL), water (10.0 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude mixture was purified by silica gel chromatography eluting with 0-30% EtOAc/hexanes to give the desired product as a pale-yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]2[C:28]([F:29])=[CH:27][C:18]([C:19]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])=[C:17]([F:30])[C:16]=2[F:31])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32]OC(OC)N(C)C.[CH3:40][CH:41]([NH2:44])[CH2:42][OH:43]>C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]2[C:28]([F:29])=[CH:27][C:18]([C:19]([C:21](=[CH:32][NH:44][CH:41]([CH3:40])[CH2:42][OH:43])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])=[C:17]([F:30])[C:16]=2[F:31])[CH2:13][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(N)CO
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1cc(F)c(C2(NC(=O)OCc3ccccc3)CC2)c(F)c1F
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNC(C)CO)C(=O)c1cc(F)c(C2(NC(=O)OCc3ccccc3)CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 17 h
Yield: 86.2 %

Procedure:
In 30 ml of benzene was dissolved 3.00 g of ethyl 4-(1-benzyloxycarbonylaminocyclopropyl)- 2,3,5-trifluorobenzoylacetate. To the resulting solution was added 3.69 g of N,N-dimethylformamide-dimethylacetal. The resulting mixture was refluxed for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in 15 ml of toluene. To the resulting solution was added 518 mg of DL-2-amino-1-propanol. The resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure. The residue obtained was purified by a column chromatography (eluant: toluene/ethyl acetate=5/1) to obtain 3.09 g (yield: 86.1%) of ethyl 2-[4-(1-benzyloxycarbonylaminocyclopropyl)-2,3,5trifluorobenzoyl]-3-(2-hydroxy-1-methylethylamino)acrylate.
Reaction SMILES: [CH2:1]1[C@H:5]2[CH2:6][CH2:7][C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C@H:4]2[CH2:3][NH:2]1.C(N(CC)CC)C.[F:24][C:25]([F:37])([F:36])[C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>ClCCl>[F:37][C:25]([F:24])([F:36])[C:26]1[CH:27]=[C:28]([S:32]([N:2]2[CH2:3][C@@H:4]3[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:7][CH2:6][C@@H:5]3[CH2:1]2)(=[O:33])=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@@H]21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylcarbamate (0.71 g, 3.14 mmol) from Step B, triethylamine (0.656 mL, 4.71 mmol), and 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.552 mL, 3.45 mmol) were combined in dichloromethane (10.0 mL). The reaction was stirred at room temperature for 16 hours and quenched with saturated aqueous NaHCO3. The organic layer was separated and concentrated in vacuo. The resultant crude material was applied to a SF-25-60 g cartridge (Analogix®, Burlington, Wis.) and purified with a gradient of 0-2% methanol/dichloromethane over 20 minutes to give tert-butyl(3aR,4S,6aS)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-ylcarbamate: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.30 (s, 1H), 8.14 (d, J=7.8, 1H), 7.84 (d, J=7.8, 1H), 7.65 (t, J=7.8, 1H), 6.83-6.71 (m, 1H), 3.88-3.76 (m, 1H), 3.61 (dd, J=10.1, 3.3, 1H), 3.24 (dd, J=9.8, 8.1, 1H), 3.12 (d, J=5.6, 2H), 2.64-2.44 (m, 2H), 1.99-1.78 (m, 2H), 1.55 (tt, J=12.4, 7.7, 1H), 1.48 (s, 9H), 1.38-1.20 (m, 1H); MS (ESI−) m/z 433 (M−H)−.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH:18]([C:20]2[CH:25]=[CH:24][C:23]([C@@H:26]([NH:28][C:29]3[N:34]=[C:33]([C:35]4[N:39]5[CH:40]=[CH:41][CH:42]=[C:43]([CH3:44])[C:38]5=[N:37][CH:36]=4)[C:32]([C:45]#[N:46])=[CH:31][N:30]=3)[CH3:27])=[CH:22][CH:21]=2)[OH:19])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>O1CCCC1.CO.[OH-].[Pd+2].[OH-]>[OH:19][CH:18]([C:20]1[CH:21]=[CH:22][C:23]([C@@H:26]([NH:28][C:29]2[N:34]=[C:33]([C:35]3[N:39]4[CH:40]=[CH:41][CH:42]=[C:43]([CH3:44])[C:38]4=[N:37][CH:36]=3)[C:32]([C:45]#[N:46])=[CH:31][N:30]=2)[CH3:27])=[CH:24][CH:25]=1)[CH2:17][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1
Reactant: Cc1cccn2c(-c3nc(N[C@@H](C)c4ccc(C(O)CC5CCN(C(=O)OCc6ccccc6)CC5)cc4)ncc3C#N)cnc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccn2c(-c3nc(N[C@@H](C)c4ccc(C(O)CC5CCNCC5)cc4)ncc3C#N)cnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.5 %

Procedure:
21 mg of the compound [17-1] was dissolved in a mixed solvent of 3 mL of tetrahydrofuran and 3 mL of methanol, then 20 mg of a carbon catalyst of 20% palladium hydroxide was added thereto, and the mixture was stirred for 2 hours at room temperature under hydrogen atmosphere. The catalyst was filtered through celite, and the filtrate was concentrated under reduced pressure. Diethylether was added to the resulting residue, and thus produced solid was taken by filtration to obtain 6 mg of 2-({(1S)-1-[4-(1-hydroxy-2-piperidin-4-ylethyl)phenyl]ethyl}amino)-4-(8-methylimidazo[1,2-a]pyridin-3-yl)pyrimidine-5-carbonitrile [17-2] (hereinafter, referred to as the compound [17-2]).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([NH:13][C:14]1[CH:19]=[C:18]([NH:20][C:21](=[O:33])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=2)[CH:17]=[CH:16][C:15]=1[CH3:34])=[O:12].[CH2:35]([Sn](CCCC)(CCCC)C=C)[CH2:36]CC>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:31]([C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:18]1[CH:17]=[CH:16][C:15]([CH3:34])=[C:14]([NH:13][C:11]([C:3]2[S:4][C:5]3=[N:6][CH:7]=[CH:8][N:9]=[C:10]3[C:2]=2[CH:35]=[CH2:36])=[O:12])[CH:19]=1)=[O:33])([CH3:30])[CH3:29])#[N:32]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1sc2nccnc2c1Br
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=Cc1c(C(=O)Nc2cc(NC(=O)c3cccc(C(C)(C)C#N)c3)ccc2C)sc2nccnc12
Yield: 10.1 %

Procedure:
A solution of 7-bromo-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 42 (22 mg, 0.041 mmol), bis(triphenylphosphine)palladium(II) chloride (1.445 mg, 2.058 μmol) and tributyl(vinyl)tin (0.024 mL, 0.082 mmol) in toluene (1 mL) was stirred for 30 min at 110° C. in microwave. After filtration, diluted with toluene and washed with water, brine, dried and evaporated. Purification by HPLC gave the title compound N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-7-vinylthieno[2,3-b]pyrazine-6-carboxamide 43c (2 mg, 10.09%). NMR (400 MHz, DMSO-d6) 2.27 (s, 3H), 5.76 (dd, J=12.0 and 2.3 Hz, 1H), 8.85-8.91 (dd, J=17.6 and 1.9 Hz, 1H), 7.28-7.38 (m, 2H), 7.58-7.68 (m, 2H), 7.76 (d, J=7.8 Hz, 1H), 7.91 (d, J=1.9 Hz, 1H), 7.96 (d, J=7.8 Hz, 1H), 8.05 (t, J=1.9 Hz, 1H), 8.80 (d, J=2.3, 1H), 8.94 (d, J=2.3 Hz, 1H), 10.37 (s, 1H), 10.38 (s, 1H). (m/z)=482 (M+H)+.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[F:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:23]1[CH:24]=[C:19]([F:18])[CH:20]=[CH:21][C:22]=1[F:25])[CH3:5])=[N+:2]=[N-:3]
Reactant: OB(O)c1cc(F)ccc1F
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3cc(F)ccc3F)c(=O)n12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.080 g, 0.25 mmol) and (2,5-difluorophenyl)boronic acid (0.048 g, 0.30 mmol) in 1,4-dioxane (2 mL) was added a 1N solution of sodium carbonate in water (0.38 mL, 0.38 mmol) and dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (0.011 g, 0.015 mmol). The mixture was stirred at 100° C. overnight. After cooled to room temperature, the mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, then concentrated and purified on silica gel (0-25% ethyl acetate/hexane) to give the desired product as a diastereoisomer mixture (54 mg). LCMS calculated for C15H12F2N5OS (M+H)+: m/z=348.1. Found: 348.0.
Reaction SMILES: [CH2:1]=O.Cl.[CH3:4][NH:5][CH3:6].[C:7]1([CH2:13][CH2:14][C:15]2[C:16]3[N:17]([CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:19][N:20]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>CC#N>[CH2:12]([C:7]1[CH:13]=[C:14]([C:15]2[C:16]3[N:17]([C:21]([CH2:4][N:5]([CH3:1])[CH3:6])=[CH:22][CH:23]=3)[CH:18]=[CH:19][N:20]=2)[CH:10]=[CH:9][CH:8]=1)[CH3:11]
Reactant: C=O
Reactant: c1ccc(CCc2nccn3cccc23)cc1
Reactant: CNC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCc1cccc(-c2nccn3c(CN(C)C)ccc23)c1
Temperature: -78 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
A 500 mL round bottom flask was half-filled with paraformaldehyde (~200 g) and then connected by means of a rubber hose to an acetone-dry ice trap. The trap was fitted with a 100 mL round bottom flask that contained dry dimethylamine hydrochloride (880 mg, 18 mmol. 1.2 eq. with respect to 1-(2-phenylethyl)pyrrolo[1,2-a]pyrazine). The flask containing the dimethylamine hydrochloride was then cooled to -78° C. and the flask containing the paraformaldehyde was heated between 180°-200° C. until an excess of paraformaldehyde had been distilled. The reaction mixture was then allowed to warm to room temperature. The solid mixture was cooled again to -20° C. and a solution of 1-(2-phenylethyl)pyrrolo[1,2-a]pyrazine (2 g., 9 mmol) in 20 mL of dry CH3CN was added. The reaction mixture was allowed to reach room temperature and left stirring at this temperature for 8 hours. A solution of NaOH (5M, 40 mL) was then added. The resulting solution was extracted with ethyl acetate (3×30 mL). The organic extracts were extracted with a solution of HCl (0.1M, 50 mL). The aqueous acid phase was then separated, neutralized with a solution of NaOH (2M, 50 mL) and extracted with ethyl acetate (2×50 mL). The organic extracts were combined, dried over MgSO4 and evaporated to give 1.8 g (73%) of the title compound,
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][N:28]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[C:17]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=2[N:13]=1)=[O:7].[I-].[Na+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(#N)C.C(OCC)(=O)C>[CH3:25][O:24][C:14]1[C:12]2[N:13]=[C:9]([NH:8][C:6]([C:5]3[CH:26]=[CH:27][N:28]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:3](=[O:2])[CH:4]=3)=[O:7])[S:10][C:11]=2[C:17]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:16][CH:15]=1
Reactant: COc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Reactant: BrCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccn(Cc4ccccc4)c(=O)c3)nc12
Temperature: 25 °C
Yield: 32 %

Procedure:
To a stirred solution of 85 mg (0.21 mmol) 2-methoxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide in 2 ml acetonitrile were added 73 mg (0.43 mmol) sodium iodide and 0.05 ml (0.43 mmol) benzyl bromide. The mixture was heated at reflux for 16 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, and washed sequentially with water and saturated brine. The organic phase was then dried over sodium sulfate and concentrated in vacuo. Flash chromatography (2/1 EtOAc/toluene) afforded 32 mg (32%) 1-benzyl-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide as a yellow crystalline solid. ES-MS m/e (%)): 499 (M+Na+, 14), 477 (M+H+, 100).
Reaction SMILES: O.[SH2:2].[Na].Cl[C:5]1[C:9]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:8][S:7][N:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]#[N:29]>CN(C=O)C.O>[C:28]([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][S:2][C:5]1[C:9]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:8][S:7][N:6]=1)#[N:29]
Reactant: N#CCCCCCBr
Reactant: Clc1nsnc1-c1cccnc1
Reactant: S
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCCCCSc1nsnc1-c1cccnc1
Reaction time: 1 h

Procedure:
Sodium hydrogen sulfide monohydrate (0.25 g, 3.3 mmol) was added to a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (0.59 g, 3.0 mmol) in DMF (20 ml) at room temperature and the reaction mixture was stirred for 1 h. Potassium carbonate (1.24 g, 9 mmol) and 6-bromocapronitrile (0.80 g, 4.5 mmol) were added and the reaction mixture was stirred for additionally 24 h. Water (50 ml) was added and extracted with ether. The combined ether phases were dried and evaporated to give the title compound.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)#[N:2].C(O[C:12]1(O[Si](C)(C)C)[CH2:14][CH2:13]1)C.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:12]1([N:6]2[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]2)[CH2:14][CH2:13]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: N#CC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#CC1CCN(C2CC2)CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
5.0 g (45.4 mmol) of 4-cyanopiperidine were dissolved in 83 ml of methanol, and 11.9 g (68.1 mmol) of [(1-ethoxy-1-cyclopropyl)oxy]trimethylsilane, 2.9 ml (3.0 g, 49.9 mmol) of acetic acid and 6.0 g (91.0 mmol) of sodium cyanoborohydride were added. The reaction mixture was stirred at 60° C. for 16 h, cooled to RT and then filtered through kieselguhr, the filter cake was washed with methanol and the filtrate was concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed twice with 1 N aqueous sodium hydroxide solution and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. Yield: 6.0 g (88% of theory)
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:12]=[C:11]([OH:13])[C:10]([C:14]([OH:16])=O)=[CH:9][N:8]=2)[CH:6]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:48][C@H:49]([C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=1)[C:50]1[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=1.Cl.N[C@H](C1C=CC(F)=CC=1)C1C=CC(P(C)(=O)OCC)=CC=1>CC#N>[F:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:12]=[C:11]([OH:13])[C:10]([C:14]([NH:48][C@H:49]([C:62]3[CH:63]=[CH:64][C:65]([F:68])=[CH:66][CH:67]=3)[C:50]3[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=3)=[O:16])=[CH:9][N:8]=2)[CH:6]=1
Reactant: O=C(O)c1cnc(-n2cc(F)cn2)nc1O
Reactant: CCOP(C)(=O)c1ccc([C@H](N)c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOP(C)(=O)c1ccc([C@H](NC(=O)c2cnc(-n3cc(F)cn3)nc2O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 15.7 %

Procedure:
To a stirred solution of 28-g (2.8 g, 12 mmol) and Et3N (3.5 g, 34 mmol) in MeCN (30 ml) was added HATU (4.8 g, 12 mmol). The mixture was stirred for 5 min at room temperature and then ethyl 4-((R)-amino(4-fluoro phenyl)methyl)phenyl(methyl)phosphinate, 18-e, (3.5 g, 11 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with 1N HCl. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel chromatography (petroleum ether:ethyl acetate=1/1) to provide the product, 29-a, (1 g, 15.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:14]([O:16][CH3:17])=[O:15])([CH3:13])[CH2:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>CCOCC>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([N:10]2[CH2:11][C:12]([C:14]([O:16][CH3:17])=[O:15])([CH3:13])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9]2)=[O:27])=[CH:21][CH:20]=1
Reactant: COC(=O)C1(C)CNN=C1c1ccc(Cl)cc1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CCOCC
Product: COC(=O)C1(C)CN(C(=O)Nc2ccc(Cl)cc2)N=C1c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
An ether solution of 3-(4-chlorophenyl)-4-carbomethoxy-4-methyl-4,5-dihydro-1H-pyrazole (Example O) (approximately 1.8 mole) is treated with 286 g (1.86 mole) of 4-chlorophenyl isocyanate at a rate sufficient to maintain a mild reflux. After stirring for 30 minutes solvent is removed to 2/3 of the volume to afford a semisolid. After cooling in an ice bath solid product is filtered and washed with cold hexane and dried yielding 702 g (95%) of N,3-bis-(4-chlorophenyl)-4-carbomethoxy-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide. NMR data was consistent with the structure.
Reaction SMILES: C([N:8]([CH2:37]C1C=CC=CC=1)[C@@H:9]([C@H:20]([CH2:28][CH:29]([OH:36])COS(C)(=O)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10]([O:12]CC1C=CC=CC=1)=[O:11])C1C=CC=CC=1.Cl>CO.[Pd]>[C:24]([O:23][C:21]([C@H:20]1[CH2:28][CH:29]([OH:36])[CH2:37][NH:8][C@@H:9]1[C:10]([OH:12])=[O:11])=[O:22])([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)[C@@H](CC(O)COS(C)(=O)=O)[C@@H](C(=O)OCc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)[C@H]1CC(O)CN[C@@H]1C(=O)O

Procedure:
To a solution of 1-benzyl 4-tert-butyl (2S,3S)-2-(dibenzylamino)-3-{2-hydroxy-3-[(methylsulfonyl)oxy]propyl}succinate from step 1k (5.02 g, 8.2 mmol) in methanol (40 mL) was added Pd-Black and 1M HCl (4 mL) solution. The mixture was hydrogenated under H2 at 50 psi overnight. The catalyst was filtered off and the solution was concentrated to dryness. The residue was dissolved in ethanol and triethyl amine (2 mL) was added. The solution was refluxed for three hours and then concentrated to dryness to provide the crude compound (2S,3S)-3-(tert-butoxycarbonyl)-5-hydroxypiperidine-2-carboxylic acid, the compound was directly used in the next step. MS (ESI): 189.9 (M+H+-t-Bu); 246.0 (M+H+); 268.0 (M+Na+).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=[O:4].[CH3:14][Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[Br:1][CH2:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:14])=[O:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(C(=O)CBr)cc1

Procedure:
4-(Bromoacetyl)benzoic acid (10 g, 41.3 mmol) was dissolved in 75 mL of MeOH and 75 mL of methylene chloride. Trimethylsilyl diazomethane (2.0 M in ether) was slowly added at 0° C. until a yellow color persisted. The volatiles were evaporated to give the title compound. 1H NMR (500 MHz, (CD3OD): 8.18 (d, 2H), 8.16 (d, 2H), 4.68 (s, 2H), 3.96 (s, 3H). LCMS: m/z 258 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=C(C(C)C(O)=O)C=C[CH:7]=1.B.[CH2:14]1[CH2:18][O:17][CH2:16][CH2:15]1.[CH2:19]1COC[CH2:20]1>>[F:1][C:2]1[CH:7]=[C:14]([CH:18]([OH:17])[CH2:19][CH3:20])[CH:15]=[CH:16][CH:3]=1
Reactant: C1CCOC1
Reactant: CC(C(=O)O)c1cccc(F)c1
Agent: B
Product: CCC(O)c1cccc(F)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
3-Fluorophenylpropionic acid (39, 0.500 g, 2.97 mmol) was diluted in anhydrous THF (2 mL) under argon, and cooled to 0° C. Borane-THF (1 M, 4.16 mL, 4.16 mmol) was added dropwise, and the mixture was allowed to warm to room temperature and stirred for 18 h. The reaction was quenched by the addition of 1:1 THF/H2O (5 mL). When gas evolution ceased, solid K2CO3 was added until the mixture separated into two layers, which were separated. The aqueous layer was extracted with EtOAc (2×5 mL), and the combined organic layers were washed with H2O (15 mL) and sat. aq. NaCl (15 mL), dried over anhydrous sodium sulfate, and concentrated to yield the product as a clear oil (0.446 g, 97%) after drying in vacuo. 1H-NMR (500 MHz; CDCl3): δ 7.29-7.25 (m, 1 H), 7.00 (d, J=7.6 Hz, 1 H), 6.95-6.89 (m, 2 H), 3.71 (t, J=6.4 Hz, 2 H), 2.74 (t, J=7.7 Hz, 2 H), 1.95-1.89 (m, 2 H), 1.39 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>CN(C=O)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:30])=[CH:24][CH:23]=1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(Cl)cc4)CC3)c2cc1OC
Yield: 29.4 %

Procedure:
A solution of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (20 mg, 0.0733 mmol), as prepared in Example 1d, in DMF (1 mL) was treated with 1-chloro-4-isocyanato-benzene (16.8 mg, 0.110 mmol) at RT overnight. The reaction was then partitioned between EtOAc (10 mL) and H2O (10 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a yellow solid (9.2 mg, 29%). 1H NMR (300 MHz, CDCl3) δ 9.08 (s, 1H), 7.38-7.33 (m, 4H), 7.26 (m, 2H), 6.44 (br s, NH), 4.29-4.26 (m, 2H), 4.07 (s, 6H), 3.62 (m, 1H), 3.19 (m, 2H), 2.16 (m, 2H), 2.02-1.99 (m, 2H); LC/MS (ESI) calcd mass 426.2, found 427.2 [M+1]+.