Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=[C:4]2[CH:3]=1.C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[CH2:33]([C:35]1[C:43]2[C:42]([NH2:44])=[CH:41][CH:40]=[CH:39][C:38]=2[N:37]([CH2:45][C:46]2[CH:50]=[CH:49][N:48]([CH2:51][CH3:52])[N:47]=2)[N:36]=1)[CH3:34]>CN1CCCC1=O>[CH2:33]([C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][C:42]=2[NH:44][C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]3=[N:10][CH:9]=2)=[O:13])[N:37]([CH2:45][C:46]2[CH:50]=[CH:49][N:48]([CH2:51][CH3:52])[N:47]=2)[N:36]=1)[CH3:34]
Reactant: CCc1nn(Cc2ccn(CC)n2)c2cccc(N)c12
Reactant: O=C(O)c1cnc2cc(F)ccn12
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCc1nn(Cc2ccn(CC)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
7-Fluoroimidazo[1,2-a]pyridine-3-carboxylic acid (Preparation I; 224 mg, 1.25 mmol) was dissolved in anhydrous N-methylpyrrolidinone (0.2 M) and treated with triethylamine (0.35 mL, 2.5 mmol). When the mixture was homogeneous 2,4,6-trichlorobenzoyl chloride (0.20 mL, 1.31 mmol) was added dropwise. The mixture was stirred for 30 minutes at ambient temperature. 3-Ethyl-1-((1-ethyl-1H-pyrazol-3-yl)methyl)-1H-indazol-4-amine (0.30 mg, 1.11 mmol) was added in one portion and the sides of the flask were washed with anhydrous N-methylpyrrolidinone (2 mL). The mixture was heated to 90° C. and stirred for 16 hours. The mixture was allowed to cool and filtered through GF/F paper washing with ethyl acetate. The filtrate was concentration under reduced pressure and diluted with water to give a beige precipitate which was collected by filtration, washed with water and dried under high vacuum to give N-(3-ethyl-1-((1-ethyl-1H-pyrazol-3-yl)methyl)-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide (259 mg). MS m/z 432.1 (M+1, APCI+).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH:10]([CH3:25])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=C=O)=[CH:36][CH:35]=1>C(Cl)Cl>[Cl:24][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([NH:40][C:37]4[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=4)=[O:5])[CH2:9][CH:10]3[CH3:25])=[CH:15][CH:16]=[N:17]2)=[CH:22][CH:21]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccnc2cc(Cl)ccc12
Reactant: O=C=Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CN(C(=O)Nc2ccc(F)cc2)CCN1c1ccnc2cc(Cl)ccc12

Procedure:
4-[4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl]-7-chloroquinoline (0.30 g, 0.8 mmol) is deprotected with TFA in CH2Cl2 and transformed after being washed with base into the product according to method C using 4-fluorophenyl isocyanate (61 μL, 0.54 mmol) to give the title product a colorless solid.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=CC=1.Cl[CH:9]([C:15]([CH3:17])=[CH2:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].O1CCCC1.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[S:7]1[CH:1]=[CH:6][CH:5]=[C:4]1[C:9](=[C:15]([CH3:17])[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: C=C(C)C(Cl)C(=O)OCC
Reactant: Sc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(=C(C)C)c1cccs1
Reaction time: 2 h

Procedure:
A mixture of thiophenol (0.7 g, 6.36 millimole), ethyl 2-chloro-3-methyl-3-butenoate (1.05 g, 6.5 millimole), tetrahydrofuran (2 ml), and tetrabutyl ammonium bromide (50 mg) was stirred at room temperature while one equivalent (1.5 ml) of 4N NaOH was added rapidly. Stirring of the resulting two-phase system was continued for two hours (at room temperature). The reaction mixture was diluted with 50 ml of water and extracted twice with 20 ml proportions of ether. Evaporation of the ether left 1.4 g of a crude yellow oil. Flash column chromatography on silica gel gave the desired product, ethyl 2-thiophenyl-3-methyl-2-butenoate in 66% overall yield. The identity of the product was confirmed by proton NMR, carbon 13 NMR, and mass spectrum analysis.
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[S:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1>>[CH3:17][C:4]1([CH3:18])[C:3](=[O:19])[C:2]([C:22]2[CH:23]=[CH:24][S:20][CH:21]=2)=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[O:5]1
Reactant: OB(O)c1ccsc1
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2ccsc2)C1=O
Yield: 5 %

Procedure:
200 mg of 4-bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone was coupled with 100 mg of thiophene-3-boronic acid according to a procedure similar to the synthetic procedure in Example 2 to yield 10 mg of 2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-4-(3-thienyl)-3(2H)-furanone as a solid. NMR: δ1.56 (s, 6H), 3.09 (s, 3H), 6.92-6.93 (m, 1H), 7.32-7.35 (m, 1H), 7.51-7.52 (m, 1H), 7.90-7.93 (m, 2H), 7.97-8.00 (m, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH:31][C:32]2[CH:33]=[C:34]([CH:40]=[CH:41][CH:42]=2)C(OCC)=O)=O)=[CH:24][CH:23]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:43](OCC)(=[O:45])C.S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC.O1CCCC1>[CH2:7]([O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][NH:31][C:32]2[CH:42]=[CH:41][CH:40]=[CH:34][C:33]=2[CH2:43][OH:45])=[CH:26][CH:27]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCOC(C)=O
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2cccc(C(=O)OCC)c2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCOc1ccc(CCNc2ccccc2CO)cc1
Temperature: 0 °C

Procedure:
To a solution of 42.36 ml of 1 molar lithium aluminum hydride in ether is added dropwise under argon over 20 minutes a solution of ethyl 3-[[[4-(tetradecyloxy)phenyl]acetyl]amino]benzoate in 50 ml of ether and 50 ml of tetrahydrofuran. The mixture is refluxed for 3 hours, cooled to 0° C. and ethyl acetate added. Saturated sodium sulfate is added followed by ether. The mixture is filtered and the cake washed with ether. The filtrate is evaporated and the residue chromatographed on silica gel using 9:1 chloroform:ethyl acetate. The product fractions are combined and evaporated to a residue which is crystallized from hexane to give 4.5 g of the desired product as a white solid, m.p. 67°-70° C.
Reaction SMILES: O1[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[CH:8]1([NH2:11])[CH2:10][CH2:9]1>CN(C)C=O>[CH:8]1([N:11]2[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]2)[CH2:10][CH2:9]1
Reactant: NC1CC1
Reactant: O=c1ccocc1
Solvent: CN(C)C=O
Product: O=c1ccn(C2CC2)cc1
Temperature: 100 °C
Yield: 158 %

Procedure:
990 mg of 4H-pyran-4-on and 1.5 g of cyclopropylamine were dissolved in 15 ml of N,N-dimethylformamide, and reacted by heating in a sealed tube at 100° C. for 6 hours. The reaction mixture was concentrated to dryness, dissolved in 80 ml of chloroform and washed with 40 ml of water. The chloroform layer was concentrated to obtain 2.2 g of 1-cyclopropyl-4-pyridone.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][C:6]1([OH:20])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[CH3:3].[BH4-].[Na+].[Cl-].[NH4+].[OH-].[Na+]>O1CCCC1.C(O)C>[CH3:3][N:2]([CH2:4][CH:5]1[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)([OH:20])[CH2:7][CH:8]([OH:11])[CH2:9][CH2:10]1)[CH3:1]
Reactant: COc1cccc(C2(O)CC(=O)CCC2CN(C)C)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cccc(C2(O)CC(O)CCC2CN(C)C)c1
Reaction time: 1.25 h
Yield: 99.4 %

Procedure:
A solution of 10 g (0.036 mol) of the crude product (IV) in 36.5 ml tetrahydrofuran was added dropwise at +2° C. with stirring to a solution of 1.36 g (0.036 mol, 1 equiv.) sodium borohydride in 15 ml ethanol and 36.5 ml tetrahydrofuran. Once the crude product solution had been completely added the mixture was then stirred for 60 to 90 minutes at +15° C. 25 ml aqueous ammonium chloride solution (10% w/w) were then added and alkalized with 5 ml sodium hydroxide solution (32%) to pH 12. After being extracted twice with 50 ml ethyl acetate, the combined phases were dried over magnesium sulfate and evaporated in vacuo. 10 g crude mixture was obtained in this case.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=2[CH:24]=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.[BH4-].[Na+]>CO>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=2[CH2:24][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(C(F)(F)F)c2C=O)CC1
Reactant: C1CCNC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(C(F)(F)F)c2CN2CCCC2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of N-boc-4-(2-formyl-3-trifluoromethyl-phenyl)piperazine (358 mg, 1 mmol, 1.0 eq.) in MeOH (10 mL) was added pyrrolidine (0.093 mL, 1.1 mmol, 1.1 eq.). The mixture was refluxed overnight. The reaction was cooled to about 0° C., and NaBH4 on alumina (10 wt % on basic alumina, 570 mg, 1.5 mmol, 1.5 eq.) was added. After the addition was compete, the ice bath was removed, and the mixture was stirred at r.t. for about 2 hours. The mixture was filtered through celite, washed with methanol and concentrated. The solution was diluted with EtOAc (50 mL) and washed with saturated NaHCO3 and brine. The aqueous layers were extracted with EtOAc (2×). The combined organic extracts were dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (35 g SiO2, 40 mL/min, linear gradient 0-10% MeOH/CH2Cl2 for 25 minutes and 10% MeOH/CH2Cl2 for 7 minutes) gave the title compound (298 mg, 0.72 mmol, 72%). LRMS (ESI+): 414.3 (M+1)
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH:17]([CH3:19])[CH3:18])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:14][CH2:13][CH2:12][C:11]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)[CH2:29][CH2:28]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CC(C)Cc1cc(CCC=O)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Cc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccccc2)n1

Procedure:
121 mg (92%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-isobutyl-1H-pyrazol-5-yl)propanal (80 mg, 0.312 mmol), 1-(2-fluorophenyl)piperazine (56 mg, 0.312 mmol), DIPEA (0.082 mL, 0.468 mmol) and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]([C:19]1[CH:31]=[CH:30][C:22]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=1)=[O:18])#[N:2].ClC1C=CC=C(C(OO)=[O:40])C=1>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]([C:19]1[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=1)=[O:18])=[O:40])#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2C#N)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1ccc(C(=O)Nc2ccccc2S(=O)c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 1.51 g of ethyl 4-[2-(2-cyanophenylthio)phenylcarbamoyl]phenoxyacetate (prepared in accordance with Reference Example 6, Step 2) in 5 ml of chloroform was added dropwise a solution of 0.87 g of 70% m-chloroperbenzoic acid in 20 ml of chloroform and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then washed with aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate and the solvent was distilled off. The residue was recrystallized from ethyl acetate-n-hexane to give 1.3 g of the title compound as white crystals, m.p. 128°-130° C. .
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([O:23]CC)=[O:22])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:10].[OH-].[Na+]>C1COCC1.Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:23])=[O:22])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:10]
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2c[nH]c3ccccc23)c(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(NC(=O)c2c[nH]c3ccccc23)c(Br)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.4 %

Procedure:
Ethyl (3-bromo-4-((3-indolylcarbonyl)amino)phenyl)acetate (664 mg, 1.65 mmol) was dissolved in THF (17 ml). To the resulting solution was added 0.25N NaOH (10.0 ml, 2.48 mmol). After stirring at room temperature for 24 hours, the reaction mixture was poured in 1N HCl to acidify the mixture. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water, and dried under reduced pressure to give (3-bromo-4-((3-indolylcarbonyl)amino)phenyl)acetic acid (341 mg, 55%) as a brown solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:43][C:44]([N:46]([CH3:48])[CH3:47])=[O:45]>C1COCC1.C(Cl)Cl>[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[C:23]4[CH:26]=[CH:27][C:28]([CH:30]5[CH2:35][CH2:34][N:33]([CH2:43][C:44]([N:46]([CH3:48])[CH3:47])=[O:45])[CH2:32][CH2:31]5)=[CH:29][C:22]=4[O:21][CH2:20][CH2:19][N:18]3[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(CC(=O)N(C)C)CC3)cc1OCC2
Reaction time: 4 h
Yield: 27.9 %

Procedure:
To a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetic acid salt (300 mg, 0.61 mmol) in THF (5 mL) was added potassium carbonate (295 mg, 2.13 mmol) and 2-chloro-N,N-dimethyl-acetamide (82 mg, 0.67 mmol). The reaction was stirred for 4 hours before being diluted with DCM and the mixture washed with water (2×30 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2, gradient 0-5% MeOH in DCM). The resultant material was triturated with diethyl ether then petroleum ether to give 278 as a white solid (85 mg, 0.17 mmol, 29%). LCMS: RT=2.72 min, [M+H]+=464. 1H NMR δ (ppm)(DMSO-d): 8.28 (1 H, d, J=8.29 Hz), 7.86 (1 H, d, J=0.64 Hz), 7.85 (1 H, s), 7.01 (1 H, dd, J=8.35, 1.78 Hz), 6.86 (1 H, d, J=1.73 Hz), 5.89-5.79 (1 H, m), 4.48-4.41 (4 H, m), 3.10 (2 H, s), 3.00 (3 H, s), 2.89 (2 H, d, J=10.79 Hz), 2.77 (3 H, s), 2.11 (2 H, dd, J=12.35, 10.20 Hz), 1.71 (2 H, d, J=12.52 Hz), 1.61 (2 H, td, J=12.15, 3.73 Hz), 1.44 (6 H, d, J=6.60 Hz). 1H obscured by solvent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:17]=[C:18]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=3)[C:19]3[CH2:25][NH:24][CH2:23][CH2:22][C:20]=3[N:21]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:17]=[C:18]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=3)[C:19]3[CH2:25][N:24]([C:35](=[O:37])[CH3:36])[CH2:23][CH2:22][C:20]=3[N:21]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cccc(Cc2nc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc3c2CNCC3)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COc1cccc(Cc2nc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc3c2CN(C(C)=O)CC3)c1
Yield: 16.7 %

Procedure:
N-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-(3-methoxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (137 mg, 0.3 mmol, example 95a) was dissolved in DCM (3 mL) and acetic anhydride (0.028 mL, 0.30 mmol) was added. The crude product was purified by preparative HPLC yielding 1-(2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-4-(3-methoxybenzyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (25.00 mg, 16.7%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].Cl.[NH2:9][CH:10]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[OH:12].C(N(CC)CC)C.[OH-].[Na+].[I-].[K+].P([O-])(O)(O)=O.[Na+]>CN(C=O)C>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH:10]([N:9]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:6])[CH:11]([OH:12])[C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)=[CH:28][CH:27]=1
Reactant: O=C(Cl)CCCCl
Reactant: NC(c1ccc(F)cc1)C(O)c1cccc2ccccc12
Agent: Cl
Agent: O=P([O-])(O)O
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCCN1C(c1ccc(F)cc1)C(O)c1cccc2ccccc12
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 12 %

Procedure:
2.15 ml (18.1 mmol) of 4-chlorobutyryl chloride (95%) were slowly added dropwise to a solution of 5.5 g (17.3 mmol) of 2-amino-2-(4-fluorophenyl)-1-naphthalen-1-ylethanol hydrochloride and 7.2 ml (51.7 mmol) of triethylamine in 55 ml of DMF cooled to −10° C. After stirring at room temperature for 2.5 h, 8.3 g (208 mmol) of sodium hydroxide pellets and 862 mg (5.2 mmol) of potassium iodide were added, and the mixture was stirred at room temperature overnight. The mixture was poured into an aqueous sodium dihydrogen phosphate solution (80 g/l). Extraction twice with diisopropyl ether was followed by drying over magnesium sulfate. The residue after concentration in vacuo was purified by chromatography with petroleum benzene/ethyl acetate 50:50. 3.8 g of 1-[1-(4-fluorophenyl)-2-hydroxy-2-naphthalen-1-ylethyl]pyrrolidin-2-one (diastereoisomer A) (yield: 63%) and 728 mg of 1-[1-(4-fluorophenyl)-2-hydroxy-2-(1-naphthyl)ethyl]pyrrolidin-2-one (diastereomer B) (yield: 12%) were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:17][CH2:18][N:19]([C:33](=[O:34])[NH:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][CH3:24])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: COc1ccccc1N=C=O
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Solvent: ClCCl
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)Nc3ccccc3OC)CC2)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.4 %

Procedure:
To a solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester (which may be prepared as described above; 83.6 mg, 0.265 mmol) in methylene chloride (8.0 mL) was added 2-methoxyphenyl isocyanate (71 μL, 0.53 mmol) at room temperature under nitrogen. The resulting light brown solution was stirred at room temperature for 10 minutes. The reaction mixture was diluted with water (˜25 mL) and the resulting mixture was extracted with methylene chloride (2×30 mL). The combined organic layers were washed with saturated aqueous NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated to a light yellow film. Flash chromatography (0-60% ethyl acetate in hexanes) provided {6-fluoro-4-[1-(2-methoxy-phenylcarbamoyl)-piperidin-4-yl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (107.6 mg, 87%) as a colorless film. MS cald. for C27H30FN2O4 [(M+H)+]: 465, obsd. 465.3.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O[CH2:13][NH:14][C:15](=[O:18])[CH2:16][Cl:17].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:13][NH:14][C:15](=[O:18])[CH2:16][Cl:17])=[C:7]([OH:11])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CCl)NCO
Reactant: CC(C)(C)c1cccc(O)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(CNC(=O)CCl)c(O)c1
Temperature: 25 °C

Procedure:
A finely powdered mixture of 15 g (0.10 mol) of 3-tert-butylphenol and 12.4 g (0.10 mol) of N-hydroxymethyl-2-chloroacetamide was added in portions to a vigorously stirred solution of 90 mL acetic acid and 10 mL (98%) sulfuric acid at 0° C. The reaction mixture was allowed to warm to room temperature over several hours, and stirring was maintained for a total of 20 hours. The reaction mixture was poured into ice-water, neutralized with saturated aqueous NaHCO3 solution and extracted into CH2Cl2. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 10-30% EtOAc in hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [CH3:1][NH:2][CH:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][OH:5].[CH:15](O)=O>>[CH3:1][N:2]([CH3:15])[CH:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][OH:5]
Reactant: O=CO
Reactant: CNC(CO)CCOc1ccccc1
Product: CN(C)C(CO)CCOc1ccccc1

Procedure:
2-(methylamino)-4-phenoxy-1-butanol, described in Example 4, with formic acid, followed by reduction, gives 2-(dimethylamino)-4-phenoxy-1-butanol,
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:16][OH:17])=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.O=[Mn]=O>[CH3:15][C:12]1[N:11]=[C:10]([CH:16]=[O:17])[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(OCc2ccccc2)c(CO)n1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1ccc(OCc2ccccc2)c(C=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A mixture of 3-(benzyloxy)-6-methyl-2-pyridinemethanol (0.0314 mol) and MnO2 (29.52 g) in CH2Cl2 (100 ml) was stirred at room temperature overnight and then purified over silica gel on a glass filter (eluent: CH2Cl2 100%). The pure fractions were collected and the solvent was evaporated, yielding 6.71 g of 6-methyl-3-(phenyl-methoxy)-2-pyridinecarboxaldehyde (94%) (interm. 6).
Reaction SMILES: C(Cl)(C(Cl)=O)=O.OCC1(CO)O[C@@H]([N:14]2[CH:22]=[C:20]([CH3:21])[C:18](=[O:19])[NH:17][C:15]2=[O:16])CC1.ON=C[C@]1(CO)O[C@@H](N2C=C(C)C(=O)NC2=O)CC1>C(Cl)Cl.CS(C)=O>[NH:14]1[CH:22]=[C:20]([CH3:21])[C:18](=[O:19])[NH:17][C:15]1=[O:16]
Reactant: Cc1cn([C@H]2CCC(CO)(CO)O2)c(=O)[nH]c1=O
Agent: Cc1cn([C@H]2CC[C@@](C=NO)(CO)O2)c(=O)[nH]c1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1c[nH]c(=O)[nH]c1=O
Temperature: -55 °C
Reaction time: 0.25 h

Procedure:
To a solution of DMSO (170μl, 2.34 mM) and CH2Cl2 (0.5 ml) at -60° C., was added 135 ml of (COCl)2 in 1 ml of CH2Cl2 dropwise over a period of 5 minutes. After 15 minutes, 3'-deoxy-4'-hydroxymethylthymidine (0.3 g, 1.17 mM), prepared, e.g., as described in Preparation 15, in 0.5 ml DMSO/0.5 ml CH2Cl2 was added slowly and the mixture stirred at -55° C. for 3 hours. After the addition of 0.65 ml TEA, the solution was removed from the cooling bath and allowed to warm to 24° C. at which temperature it was stirred for 15 minutes. The solution was filtered and the solvent was removed by evaporation. The residue was dissolved in pyridine; treated with H2NOH HCl (0.2 g, 2.9 mM), and stirred at 24° C. for 48 hours. The solvent was removed by evaporation and the residue was chromatographed on silica gel using 8% CH3OH/CH2Cl2, yielding a mixture of the 4'-α and 4'-β isomers of 3'-deoxy-4'-hydroxyiminomethylthymidine (140 mg, 0.52 mM).