Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][NH2:11])=[CH:5][CH:4]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].Cl>C(OCC)(=O)C.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[N:12]([CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:23](=[O:24])[NH:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCN[C@@H](CN)c2ccc(OC)cc2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CCN2C(=O)NC[C@H]2c2ccc(OC)cc2)cc1
Yield: 96.9 %

Procedure:
A solution of 1-(R)-(4-methoxyphenyl)-N1-[2-(4-methoxyphenyl)ethyl]ethane-1,2-diamine (446 g, 1.48 mol) in ethyl acetate (2.25 L) is placed in a water bath and 1,1′-carbonyldiimidazole (264 g, 1.62 mol) is added in portions. The reaction is then heated to reflux for 1.5 hours after which the solution is cooled, treated with 1N HCl (2×1.5 L), brine (2×1.5 L), dried over Na2SO4 and set aside in the cold. After standing the precipitate which forms is removed by filtration and the solvent removed under reduced pressure to afford 468 g (96% yield) of the desired product. Chiral HPLC of the product thus obtained to have 99.5% of the desired (R) enantiomer present.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@:7]1([CH2:17][CH2:18][NH2:19])[CH2:16][C:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.C(NCC[C@]1(C2C=CC(F)=CC=2)CC2(CCCC2)OCC1)C1C=CC=CC=1.Br[CH2:48][C:49]1[S:50][CH:51]=[CH:52][C:53]=1[CH2:54]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[S:50]1[C:49]2[CH2:48][N:19]([CH2:18][CH2:17][C@:7]3([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:16][C:11]4([CH2:15][CH2:14][CH2:13][CH2:12]4)[O:10][CH2:9][CH2:8]3)[CH2:54][C:53]=2[CH:52]=[CH:51]1
Reactant: BrCc1ccsc1CBr
Reactant: NCC[C@@]1(c2ccccn2)CCOC2(CCCC2)C1
Agent: Fc1ccc([C@]2(CCNCc3ccccc3)CCOC3(CCCC3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc([C@]2(CCN3Cc4ccsc4C3)CCOC3(CCCC3)C2)nc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethan-1-amine (0.030 g, 0.115 mmol; prepared by following a sequence described for Compound 81 in dried ACN (5.8 mL) was added 2,3-bis(bromomethyl)thiophene (31.1 mg, 0.115 mmol) followed by addition of K2CO3 (79.62 mg, 0.576 mmol). After 30 min, LCMS showed that the reaction was done and the major peak had the corresponding mass to the desired product. It was then subjected to HPLC purification. HPLC purification method: Luna acid medium column, 10-50% acetonitrile in H2O over 15 min, followed by flashing with 100% acetonitrile, 0.1% TFA modifier was employed. The fractions containing the desired product were pooled, basified with 2N NaOH and extracted with DCM (3×20 mL). The combined organics were concentrated and purified with flash chromatography (10 g silica gel column, eluted by 0-10% MeOH in DCM, based upon TLC measurement: DCM/MeOH (10/1) Rf=0.60) to afford 5 mg of 2-[(9R)-9-(2-{4H,5H,6H-thieno[2, 3-c]pyrrol-5-yl}ethyl)-6-oxaspiro[4.5]decan-9-yl]pyridine as a colorless oil in 12% yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][F:30]>CS(C)=O.[I-].[K+]>[F:30][CH2:29][CH2:28][O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: FCCBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(OCCF)cc2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
To a solution of tert-butyl 4-(4-hydroxyphenyl)-piperazine-1-carboxylate (1.0 g, 3.59 mmol) in DMSO (12 mL) was added potassium carbonate (745 mg, 5.39 mmol), potassium iodide (18 mg, 0.11 mmol) and 1-bromo-2-fluoroethane (294 μL, 3.95 mmol). The reaction stirred at 50° C. overnight. The next day, additional amounts of potassium carbonate (745 mg, 5.39 mmol), 1-bromo-2-fluoroethane (134 μL, 1.79 mmol), and potassium iodide (18 mg, 0.11 mmol) were added. The reaction mixture continued to stir at 50° C. After 5 h the reaction mixture was cooled to room temperature, quenched with water (10 mL), and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (100 mL), brine (50 mL), dried over Na2SO4, and concentrated to obtain a brown solid. The crude material was purified using silica gel chromatography (1:4 hexanes:EtOAc) to obtain tert-butyl 4-(4-(2-fluoroethoxy)phenyl)piperazine-1-carboxylate as a white solid (440 mg, 38% yield). 1H NMR (300 MHz, DMSO-d6): δ 6.92-6.84 (m, 4H), 4.78 (m, 1H), 4.62 (m, 1H), 4.20 (m, 1H), 4.10 (m, 1H), 3.45 (dd, 4H, J=5.2, 5.0 Hz), 2.96 (dd, 4H, J=5.3, 5.0 Hz), 1.42 (s, 9H); 19F NMR (282.4 MHz, DMSO-d6): δ−222.04 (m, 1F); 13C NMR (75.5 MHz, DMSO-d6): δ 153.8, 152.1, 145.5, 117.9, 115.1, 83.2 (81.1), 78.9, 67.4 (67.2), 49.7, 43.2, 28.0; HRMS calcd. for C17H25FN2O3: 325.19220 found 325.19230.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[OH:12])[NH:8][C:7](=[O:13])[C:6]2([CH3:15])[CH3:14].[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=O)=[CH:18][CH:17]=1.N>>[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]2[O:12][C:11]3[CH:10]=[C:9]4[NH:8][C:7](=[O:13])[C:6]([CH3:15])([CH3:14])[C:5]4=[CH:4][C:3]=3[N:2]=2)=[CH:18][CH:17]=1
Reactant: CC1(C)C(=O)Nc2cc(O)c(N)cc21
Reactant: O=C(O)Cc1ccncc1
Agent: Cl
Agent: N
Product: CC1(C)C(=O)Nc2cc3oc(Cc4ccncc4)nc3cc21

Procedure:
4.52 g. 5-Amino-1,3-dihydro-3,3-dimethyl-6-hydroxy-2H-indol-2-one hydrochloride and 3.65 g. 4-pyridylacetic acid were heated in 20 g. polyphosphoric acid for 30 minutes to 170° C. and the reaction mixture subsequently poured on to ice. A concentrated aqueous solution of ammonia was added thereto to give a pH of 10, the precipitate obtained was filtered off with suction, successively washed with water, methanol and diethyl ether and then dried to constant weight to give 3.20 g. (55% of theory) of the title compound; m.p. 208°-211° C.
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:13]3[C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][NH:4][CH2:3]1.Cl.Cl[CH2:21][CH2:22][N:23]([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH3:24][N:23]([CH3:25])[CH2:22][CH2:21][N:4]1[CH2:3][C:2](=[O:1])[C:14]2[C:13]3[C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5]1
Reactant: CN(C)CCCl
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CNC3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CN(CCN(C)C)C3
Temperature: 50 °C
Yield: 38.1 %

Procedure:
Methyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate (183 mg, 0.75 mol) was dissolved in DMF (20 ml) and 2-chloro-N,N-dimethylethanamine hydrochloride (107 mg, 0.75 mmol), and K2CO3 (207 mg, 1.5 mmol) were subsequently added. The reaction was stirred at 50° C. until the starting material was disappeared. The reaction mixture was then diluted with CH2Cl2 (15 ml) and washed with water three times. The organic layer was dried with MgSO4. Evaporation of most of the solvent and the crude product was purified by chromatography column on silica gel (elution with CH2Cl2/MeOH/NH3.H2O) to provide 0.09 g of methyl 2-(2-(dimethylamino)ethyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate. MS (ESI) m/e [M+1]+ 316.
Reaction SMILES: [NH2:1][CH:2]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])[CH:23]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH2:19][CH3:20])[CH:13]=2)=[CH:7][CH:6]=1)[OH:4].[C:35]1([C:46](O)=[O:47])[CH:36]=[CH:37][CH:38]=[C:39]2[CH2:45][CH2:44][CH2:43][CH:42]=[CH:41][C:40]=12.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:46]([C:35]3[CH:36]=[CH:37][CH:38]=[C:39]4[CH2:45][CH2:44][CH2:43][CH:42]=[CH:41][C:40]=34)=[O:47])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])[CH:23]=3)=[CH:6][CH:7]=2)=[CH:13][C:14]=1[CH2:19][CH3:20]
Reactant: CCc1cc(Oc2ccc(C(O)C(N)Cc3cccc(OC(F)(F)C(F)F)c3)cc2)ccc1Cl
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: CCc1cc(Oc2ccc(C(O)C(Cc3cccc(OC(F)(F)C(F)F)c3)NC(=O)c3cccc4c3C=CCCC4)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-3-(3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)-1-propanol (300 mg, 0.60 mmol) in acetonitrile (16 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (114 mg, 0.60 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (174 mg, 0.91 mmol) and 1-hydroxy-1H-benzotriazole (92 mg, 0.60 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (318 mg, 79%).
Reaction SMILES: C(O)(C)C.[S:5](=[O:9])(=[O:8])([OH:7])[OH:6].COS([O-])(=O)=O.[CH2:16]([N+:34]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])([CH3:36])[CH3:35])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>O>[S:5](=[O:7])(=[O:6])([OH:9])[O-:8].[CH2:37]([N+:34]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([CH3:36])[CH3:35])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: O=S(=O)(O)O
Agent: CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC
Agent: COS(=O)(=O)[O-]
Solvent: CC(C)O
Solvent: O
Product: O=S(=O)([O-])O
Temperature: 840 °C
Reaction time: 4 h

Procedure:
Seventy-five (75) kilograms of isopropyl alcohol and 25 kilograms of deionized water were charged in a 50 gallon glass lined reactor. The reactor agitator (three armed retrieve curve impeller) was started at 100 RPM and full cooling (water at 8° to 10° C.) was applied to the reactor jacket. Eighteen (18) kilograms of 93 percent sulfuric acid (technical grade) were added slowly to the reactor, after which 30 kilograms of technical grade distearyl dimethyl ammonium methylsulfate (obtained from Zeeland Chemical Co., d Cambrex Company formerly Hexcel Company of Zeeland, Mich.) were charged in the reactor. The reactor loading port was closed and cooling water was applied to the reactor reflux condenser and the agitator speed adjusted to 150 RPM. The reactor was heated to approximately 840° C. using hot water supplied to the reactor jacket. The reaction was effected for 4 hours under a slight reflux after which cooling was applied to initiate the crystallization. The mixture was agitated for two hours under full cooling at 16° to 18° C. before transferring to a 70 gallon agitated Nutsche vacuum filter. The filtrate was drained and collected in a storage vessel for solvent recovery or disposal. The wet cake was reslurried with 100 kilograms of the second wash filtrate from the previous batch (containing an approximate 75:25 ratio of isopropanol and water) for 30 minutes, after which the filtrate (about 100 kilograms) was drained by vacuum filtration and collected in order to be used as the solvent system for the next synthesis batch. After additional reslurry washes were performed using wash filtrates from a previous batch, the wet cake was discharged from the filter and recrystallized from 100 kilograms of isopropanol In a 50 gallon glass lined reactor. This was performed by dissolving the materials under agitation at 600° C., cooling and recovering the wet dimethyl distearyl ammonium bisulfate cake by filtration. After vacuum drying, 22.27 kilograms (75.8 percent yield) of recrystallized distearyl dimethyl ammonium bisulfate were recovered. Analyticals: melting point (DSC) 91.4° C., H2O content 0.65 percent, bisulfate content (by titration) 14.65 percent.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[N+:8]([O-])=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12]>ClCCl>[Cl:3][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)[n+]([O-])c1C
Solvent: ClCCl
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Temperature: 25 °C
Yield: 11.2 %

Procedure:
Phosphorous oxychloride (0.72 mL, 7.8 mmol) was added dropwise to an oven-dried 100 mL pear-shaped flask charged with 18.1 (1.8 g, 7.00 mmol) and dichloromethane (20 mL). The reaction was refluxed under nitrogen atmosphere for 30 minutes and then cooled to room temperature. The reaction was washed with water (2×250 mL) and the combined aqueous layers were back extracted with DCM (2×25 mL). The combined organic layers were washed with brine and dried (Na2SO4). The solvent was removed under reduced pressure and the resulting residue was purified via radial chromatography (15% diethyl ether in hexanes) to yield 216 mg (15%) of 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole as a white solid. LC/MSD m/e: 276.0 (M+H); 1H NMR (400 MHz) (CDCl3) δ 8.15 (2H, d, J=8.0 Hz), 7.73 (2H, d, J=8.0 Hz), 4.59 (2H, s), 2.48 (2H, s).
Reaction SMILES: [CH2:1]1[CH2:11][CH2:10]N2C(=NCCC2)[CH2:3][CH2:2]1.BrCCCCCBr.[NH2:19][C:20]1[CH:21]=[C:22]([C:26]2[C:27]([C:44]([O:46][CH2:47][CH3:48])=[O:45])=[C:28]3[C:37]4[C:32](=[CH:33][C:34]([O:40][CH3:41])=[C:35]([O:38][CH3:39])[CH:36]=4)[CH2:31][CH2:30][N:29]3[C:42]=2[CH3:43])[CH:23]=[CH:24][CH:25]=1>CN(C=O)C>[CH3:41][O:40][C:34]1[CH:33]=[C:32]2[C:37](=[CH:36][C:35]=1[O:38][CH3:39])[C:28]1=[C:27]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([N:19]4[CH2:10][CH2:11][CH2:1][CH2:2][CH2:3]4)[CH:21]=3)=[C:42]([CH3:43])[N:29]1[CH2:30][CH2:31]2
Reactant: CCOC(=O)c1c(-c2cccc(N)c2)c(C)n2c1-c1cc(OC)c(OC)cc1CC2
Reactant: C1CCC2=NCCCN2CC1
Agent: BrCCCCCBr
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2cccc(N3CCCCC3)c2)c(C)n2c1-c1cc(OC)c(OC)cc1CC2
Temperature: 120 °C
Reaction time: 20 h

Procedure:
168.5 mg (1.11 mmol) of DBU and 84.9 mg (0.37 mmol) of 1,5-dibromopentane were added to a solution of 150 mg (0.37 mmol) of ethyl 2-(3-aminophenyl)-8,9-dimethoxy-3-methyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-1-carboxylate (Example 28) in 3 mL of DMF. The mixture was stirred at 120° C. for 20 hours, then evaporated under reduced pressure, and the residue was taken up in an ethyl acetate/water mixture. The layers were separated, the aqueous layer was extracted with ethyl acetate, and the combined organic phases were washed with water, dried over Na2SO4, and the solvent was evaporated under reduced pressure. Chromatography on a short silica gel column using a dichloromethane/ethyl acetate 10:1 mixture as eluant, followed by crystallization from diethyl ether gave the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[C:22]([C:23]2[CH:28]=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:26]=[CH:25][C:24]=2[F:38])=[CH:21][C:20]([C:39]#[N:40])=[CH:19][CH:18]=1>>[F:16][C:17]1[C:22]([C:23]2[CH:28]=[C:27]([C:2]3[C:3]4[C:8](=[N:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=4)[N:9]=[CH:10][CH:11]=3)[CH:26]=[CH:25][C:24]=2[F:38])=[CH:21][C:20]([C:39]#[N:40])=[CH:19][CH:18]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3cc(C#N)ccc3F)c2)OC1(C)C
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Product: N#Cc1ccc(F)c(-c2cc(-c3ccnc4nc(C(F)(F)F)ccc34)ccc2F)c1
Yield: 26.5 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 6,2′-difluoro-5′-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)biphenyl-3-carbonitrile (96 mg, 0.28 mmol) as described in Example 7 part g), affording 6,2′-difluoro-5′-(7-trifluoromethyl[1,8]naphthyridin-4-yl)biphenyl-3-carbonitrile (24 mg, 27%). δH (400 MHz, CDCl3) 7.35 (1H, t, J 9.0), 7.45 (1H, t, J 9.0), 7.52-7.61 (3H, m), 7.74-7.78 (1H, m), 7.83 (1H, dd, J 1.4 and 6.5), 7.87 (1H, d, J 8.6), 8.54 (1H, d, J 8.2), 9.30 (1H, d, J 4.3). m/z (ES) 412 [MH]+.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][CH2:20][O:21][CH2:22][CH3:23])[C:7]2=[O:24])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:39]=[N:40][C:41]([NH2:44])=[CH:42][CH:43]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C1(C)C=CC=CC=1>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:39]=[N:40][C:41]([NH:44][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([CH2:19][CH2:20][O:21][CH2:22][CH3:23])[C:7](=[O:24])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:42][CH:43]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: CCOCCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Solvent: Cc1ccccc1
Product: CCOCCc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Yield: 20.3 %

Procedure:
8-Cyclopentyl-6-(2-ethoxy-ethyl)-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.86 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.10 g, 3.95 mmol) were heated to reflux in toluene (10 mL) for 16 hours. The mixture was cooled to room temperature and purified by silica gel chromatography to give 4-{6-[8-cyclopentyl-6-(2-ethoxy-ethyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester as an orange solid (0.328 g, 20.4%). 1H NMR δ (400 MHz, CDCl3) 8.54 (s, 1H), 8.26 (d, J=9.0 Hz, 1H), 7.98 (d, J=2.9 Hz, 1H), 7.45 (s, 1H), 7.38 (dd, J=2.9, 9.3 Hz, 1H), 5.90 (m, 1H), 3.70 (t, J=6.3, 1H), 3.61 (m, 4H), 3.51 (q, J=7.1, 1H), 3.11 (m, 4H), 2.84 (t, J=5.9, 1H), 2.33 (m, 2H), 2.08 (m, 2H), 1.87 (m, 2H), 1.69 (m, 2H), 1.48 (s, 9H), 1.19 (t, J=7.1, 1H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]#[C:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:3].[CH3:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>ClCCl>[CH2:15]([N:14]([CH3:13])[C:2]([O:4][CH2:5][C:6]#[C:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CNCc1ccccc1
Reactant: CCOC(=O)C#CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C#CCOC(=O)N(C)Cc1ccccc1
Temperature: 0 °C
Yield: 28.6 %

Procedure:
2.85 g (15 millimoles) of ethyl 4-(chlorocarbonyloxy)-2-butynoate obtained in the first step of Example VI-9 was dissolved in 20 ml of dichloromethane, and 9 ml of a dichloromethane solution containing 3.1 ml (24 millimoles) of N-methylbenzylamine was rapidly added under cooling with ice. The mixture was reacted for 1 hour under stirring and cooling with ice. The reaction mixture was poured into ice water, adjusted to pH 2 with dilute hydrochloride acid and subjected to extraction treatment. The dichloromethane extraction solution was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (with use of 30 g of silica gel). The desired fraction eluted by hexane-benzene (1:0→3:1), was collected and concentrated under reduced pressure, whereby 1.18 g (yield: 28.5%) of colorless oily ethyl 4-(N-benzyl-N-methylcarbamoyloxy)-2-butynoate was obtained.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([CH3:35])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[N:31][CH:32]=[N:33][CH:34]=4)=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])C.[OH-].[Na+]>C(O)C.C1COCC1>[CH3:35][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:24]=[CH:25][C:26]([C:29]4[CH:30]=[N:31][CH:32]=[N:33][CH:34]=4)=[CH:27][CH:28]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)([CH3:6])[C:4]([OH:36])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cncnc4)cc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(-c3cncnc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Under nitrogen, 2-methyl-2-(4-{2-[5-methyl-2-(4-pyrimidin-5-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-propionic acid ethyl ester (0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1 h and concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1 N HCl, and partitioned. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to yield the desired product. 1H NMR (400 MHz, CDCl3) δ9.23 (s, 1 H), 9.20 (s, 2 H), 8.16 (d, 2 H), 7.65 (d, 2 H), 6.86 (d, 2 H), 6.76 (d, 2 H), 4.20 (t, 2 H), 3.00 (t, 2 H), 2.39 (s, 3 H), 1.48 (s, 6 H); MS (EI) 460.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@:5]1([CH3:18])[C@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C(Cl)Cl>[CH3:1][O:2][C:3]([C@:5]1([CH3:18])[C@H:9]([O:10][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@]1(C)[C@H](O)CCN1C(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)[C@]1(C)[C@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
To a solution of (2S,3R)-3-Hydroxy-2-methylpyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester-2-methyl ester (25A) (362 mg, 1.39 mmol) in CH2Cl2 (4 mL) was added imidazole (284 mg, 4.17 mmol) then tert-butydimethylsilyl chloride (1.05 g, 6.95 mmol). After stirring overnight, the reaction was partitioned between H2O and CH2Cl2. The CH2Cl2 layer was washed with 1M H3PO4 (2×) and brine, dried (MgSO4), then filtered and concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with 30% EtOAc/hexane to yield the title compound (456 mg) as a white solid.
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]2=[N:10][C:9]=1[CH:19]([N:23]([CH2:33][CH2:34][CH2:35][N:36]1C(=O)C2C(=CC=CC=2)C1=O)[C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.C(O)(C(F)(F)F)=O>C(O)C>[NH2:36][CH2:35][CH2:34][CH2:33][N:23]([CH:19]([C:9]1[N:10]=[C:11]2[CH2:18][CH2:17][CH2:16][CH2:15][N:12]2[C:13](=[O:14])[C:8]=1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:20]([CH3:21])[CH3:22])[C:24](=[O:32])[C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=1
Reactant: Cc1ccc(C(=O)N(CCCN2C(=O)c3ccccc3C2=O)C(c2nc3n(c(=O)c2Cc2ccccc2)CCCC3)C(C)C)cc1
Agent: NN
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)N(CCCN)C(c2nc3n(c(=O)c2Cc2ccccc2)CCCC3)C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from Step 12 (22), 50 mg (0.08 mmol) was dissolved in 1 ml of anhydrous ethanol. Hydrazine 18 μl (0.57 mmol) was added and the reaction stirred at room temperature for 2 h. The precipitate was filtered through a PTFE filter and washed with ethyl acetate. The solvent was evaporated and the crude material was purified by reverse phase HPLC resulting to 11 mg (0.023 mmol) of N-(3-aminopropyl)-N-[1-(3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-2-yl)-2-methylpropyl]-4-methylbenzamide (2) as the TFA salt.