Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:13])[NH:7][NH:8]2)([O-:3])=[O:2].[CH3:14]I.Cl>CN(C)C(=O)C>[CH3:14][N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[C:6](=[O:13])[NH:7]1
Reactant: CI
Reactant: O=c1[nH][nH]c2cccc([N+](=O)[O-])c12
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cn1[nH]c(=O)c2c([N+](=O)[O-])cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
306 mg (1.7 mmol) 4-nitro-1,2-dihydro-indazol-3-one are dissolved in 1 ml N,N-dimethyl-acetamide, combined with 150 μl (2.4 mmol) methyl iodide and 500 μl (2.32 mmol) of N-ethyldiisopropylamide and stirred for 2 h at ambient temperature. Then the reaction mixture is combined with 40 ml of a 1 N aqueous hydrochloric acid and extracted twice with 50 ml dichloromethane. Then the organic phase is dried with MgSO4, the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and 5% water and 95% acetonitrile at the finishing point.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:8])[S:5][CH:6]=1.[Cl:18][S:19](O)(=[O:21])=[O:20]>>[Br:1][C:2]1[CH:3]=[C:4]([C:7](=[O:8])[NH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[S:5][C:6]=1[S:19]([Cl:18])(=[O:21])=[O:20]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(NCCN1CCOCC1)c1cc(Br)cs1
Product: O=C(NCCN1CCOCC1)c1cc(Br)c(S(=O)(=O)Cl)s1
Temperature: 95 °C

Procedure:
To a flask containing 4-bromo-N-[2-(morpholin-4-yl)ethyl]thiophene-2-carboxamide (1.6 g, 5.1 mmol) was added chlorosulfonic acid (10 ml, 30 equiv). The reaction was heated to 95° C. for 90 minutes before careful addition to ice. The resulting solid was filtered and dried in vacuo. The crude material was trituated with heptane:ethyl acetate to afford the title compound without need for further purification (0.62 g, 29%). δH (500 MHz, DMSO-d6) 9.01 (1H, t, 5.5 Hz), 7.76 (1H, s), 3.97 (2H, d, 10.4 Hz), 3.78 (2H, t, 11.5 Hz), 3.63 (2H, q, 6.0 Hz), 3.51 (2H, d, 12.3 Hz), 3.29 (2H, q, 5.7 Hz), 3.03-3.17 (2H, m), TR=1.22 min.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:13])[N:5]=[C:4]([SH:14])[N:3]=1.[CH3:15]I>[OH-].[Na+]>[OH:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1
Reactant: CI
Reactant: COC(=O)Cc1c(C)nc(S)nc1O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)Cc1c(C)nc(SC)nc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.6 %

Procedure:
Methyl (4-hydroxy-6-methyl-2-mercapto-5-pyrimidinyl)-acetate (40 g, 0.19 mol) is dissolved in an aqueous solution of NaOH (8 g in 400 ml H2O). Methyl iodide (29.5 g, 0.2 mol) is added and the mixture is stirred at room temperature for 4 hours. Filtration and drying at high vacuum gives methyl (4-hydroxy-6-methyl-2-methylmercapto-5-pyrimidinyl)-acetate (25.4 g, 60%) as a crystalline solid, having a m.p. of 200° C.
Reaction SMILES: [C:1]([N:4]1[C:8]([CH3:9])=[C:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:6]([C:20](=[O:22])[CH3:21])[C:5]1=[O:23])(=[O:3])[CH3:2].[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:24][CH2:9][C:8]1[N:4]([C:1](=[O:3])[CH3:2])[C:5](=[O:23])[N:6]([C:20](=[O:22])[CH3:21])[C:7]=1[C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(C(=O)c2c(C)n(C(C)=O)c(=O)n2C(C)=O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(C(=O)c2c(CBr)n(C(C)=O)c(=O)n2C(C)=O)cc1

Procedure:
A mixture of 55.5 g (0.176 mole) of 1,3-diacetyl-1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one, 37.4 g (0.210 mole) of N-bromosuccinimide and about 100 mg of benzoyl peroxide in 500 ml of carbon tetrachloride is stirred at reflux temperature for 4 hours. The mixture is then cooled and filtered to remove the succinimide which formed. The solvent is evaporated from the filtrate and the resulting residue is crystallized from a mixture of 300 ml of ethyl acetate and 300 ml of hexane to give 5-(bromomethyl)-1,3-diacetyl-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-one melting at about 135°-136° C.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][NH2:22])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[Cl:23][C:24]1[C:29]([CH:30]=O)=[C:28](Cl)[N:27]=[CH:26][N:25]=1>C1(C)C=CC=CC=1>[C:8]([O:12][C:13]([N:15]1[CH2:16][CH2:17][CH:18]([N:21]2[C:28]3=[N:27][CH:26]=[N:25][C:24]([Cl:23])=[C:29]3[CH:30]=[N:22]2)[CH2:19][CH2:20]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(NN)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Yield: 34 %

Procedure:
Triethylamine (19.5 mL, 140 mmol) was added to a stirred solution of 4-hydrazino-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 9; 15.0 g, 69.7 mmol) and 4,6-dichloro-pyrimidine-5-carbaldehyde (Intermediate 16; 12.34 g, 69.7 mmol) in toluene (100 mL) at room temperature under nitrogen and the resulting mixture was heated to reflux for 6 hours. The solvent was removed in vacuo and the crude reaction mixture was purified by column chromatography (silica gel, 100-200 mesh; 5% ethyl acetate/hexanes) to give 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (8.0 g, 34%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 1.97-2.00 (m, 2H), 2.19-2.29 (m, 2H), 2.90-3.00 (br s, 2H), 4.25-4.35 (m, 2H), 4.92-5.00 (m, 1H), 8.15 (s, 1H), 8.74 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 28.3, 31.1, 42.8, 55.3, 79.8, 113.8, 131.8, 152.4, 154.1, 154.4, 154.7. HRMS Calcd. for C15H21ClN5O2 (MH+): 338.1379. Found: 338.1377.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21](=[O:36])[N:22]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][C:27]=2[CH3:35])[CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C1COCC1.[Pd]>[NH2:32][C:29]1[CH:30]=[CH:31][C:26]([N:22]2[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][O:18][Si:1]([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:21]2=[O:36])=[C:27]([CH3:35])[CH:28]=1
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])ccc1-n1cccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(N)ccc1-n1cccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O

Procedure:
555 mg (1.11 mmol) of the compound from Example 7A are dissolved in 15 ml of THF, 150 mg of palladium on carbon are added and the mixture is hydrogenated in a hydrogen atmosphere at atmospheric pressure until the theoretical amount of hydrogen has been taken up. The catalyst is filtered off, which gives, after concentration under reduced pressure, 520 mg (99% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13]([CH2:17][CH2:18][C:19](OCC)=[O:20])=[N:14][O:15][N:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13]([CH2:17][CH2:18][CH2:19][OH:20])=[N:14][O:15][N:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)CCc1nonc1C(=O)Nc1ccc(F)c(Cl)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CCCO
Temperature: 25 °C
Yield: 82 %

Procedure:
To a solution of ethyl 3-(4-[(3-chloro-4-fluorophenyl)amino]carbonyl-1,2,5-oxadiazol-3-yl)propanoate (97.5 mg, 0.285 mmol) in THF (1.2 mL) was added lithium tetrahydroborate (14.3 mg, 0.656 mmol) at 0° C. under an atmosphere of nitrogen. The reaction solution was allowed to warm to rt for 2 h. The reaction was quenched with MeOH and concentrated. The residue was purified by flash chromatography (60% ethyl acetate/hexane) to give the desired product (70 mg, 80%). LCMS for C12H12ClFN3O3 (M+H)+: m/z=300.1.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][C:10](=O)[C:4]=2[CH:3]=1.Cl.[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][SH:23].B(F)(F)F.CCOCC.[OH-].[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[C:10]([S:23][CH2:22][CH2:21][N:20]([CH3:24])[CH3:19])[C:4]=2[CH:3]=1
Reactant: CN(C)CCS
Reactant: O=C1Cc2ccccc2Sc2ccc(F)cc21
Agent: Cl
Agent: FB(F)F
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CN(C)CCSC1=Cc2ccccc2Sc2ccc(F)cc21
Temperature: 90 °C
Reaction time: 72 h

Procedure:
To a solution of 5.0 g of 10,11-dihydro-2-fluoro-11-oxodibenzo[b,f]thiepin in 52 ml of glacial acetic acid is added 5.81 g of β-dimethylaminoethanethiol hydrochloride. After the addition is complete, the mixture is heated at 90° C. whereupon it becomes homogenous. The solution is cooled to 25° C. and 15.4 ml of boron trifluoride etherate is added. After stirring for 3 days at 25° C., an additional 8 ml of boron trifluoride etherate is added and the solution is heated at 60° C. for 5 hours. The reaction mixture is poured into 150 ml of 20% sodium hydroxide solution at 0° C. The mixture is extracted with ether and the combined extracts are washed with 20% sodium hydroxide solution, water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Chromatography of the filtrate on silica gel with 5% methanol/dichloromethane elution provides 2-fluoro-11-[β-(dimethylamino)ethylthio]dibenzo[b,f]thiepin which is converted to its hydrochloride, mp 209°-211° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.[NH2:20][CH2:21][CH2:22][CH2:23][OH:24]>CC#N.C(O)(C(F)(F)F)=O>[CH2:18]([C:15]1[CH:16]=[CH:17][C:12]([C:4]2[N:3]=[C:2]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=2)=[CH:13][CH:14]=1)[CH3:19]
Reactant: CCc1ccc(-c2ccc(C(F)(F)F)c(Cl)n2)cc1
Reactant: NCCCO
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCc1ccc(-c2ccc(C(F)(F)F)c(NCCCO)n2)cc1
Yield: 51.8 %

Procedure:
To a solution of 2-chloro-6-(4-ethylphenyl)-3-(trifluoromethyl)pyridine (Example 315, 0.36 g, 1.25 mmol) and 3-amino-1-propanol (0.38 g, 5.00 mmol) in CH3CN (2 mL), TFA (0.5 mL) was added. The mixture was stirred at reflux for 18 h, and then concentrated under reduced pressure. The product (0.21 g, 52%) was isolated after silica gel flash chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD3OD) δ 7.95 (d, 2H), 7.72 (d, 1H), 7.27 (d, 2H), 7.10 (d, 1H), 3.72 (t, 2H), 3.66 (t, 2H), 2.69 (q, 2H), 1.90 (q, 2H), 1.27 (t, 3H).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25]O)=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1>>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][N:27]4[CH:31]=[N:30][CH:29]=[N:28]4)=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1nc[nH]n1
Reactant: OCCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Product: C(=C/c1nc(COc2ccc(CCCCn3cncn3)cc2)co1)\c1ccccc1
Yield: 71 %

Procedure:
In substantially the same manner as in Working Example 1, 4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butanol was allowed to react with 1,2,4-triazole to give 1-[4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butyl]-1,2,4-triazole. The yield was 71%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 94-95° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[C:13](=[O:23])[N:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[C:11]([CH3:34])=[C:10]2[C:35]([CH:37]2[CH2:40][CH2:39][CH2:38]2)=[O:36])=[CH:5][CH:4]=1)#[N:2]>FC(F)(F)C(O)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[N:14]([CH2:15][C:16]([OH:18])=[O:17])[C:13](=[O:23])[N:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:25]=3)[C:11]([CH3:34])=[C:10]2[C:35]([CH:37]2[CH2:38][CH2:39][CH2:40]2)=[O:36])=[CH:7][CH:8]=1)#[N:2]
Reactant: CC1=C(C(=O)C2CCC2)C(c2ccc(C#N)cc2)N(CC(=O)OC(C)(C)C)C(=O)N1c1cccc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(C(=O)C2CCC2)C(c2ccc(C#N)cc2)N(CC(=O)O)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.08 h

Procedure:
tert.-Butyl [6-(4-cyanophenyl)-5-(cyclobutylcarbonyl)-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-yl]acetate (Example 26) (35 mg, 0.063 mmol) is dissolved in trifluoroacetic acid (1 ml). After 5 minutes stirring, the solution is concentrated in vacuo and the residue is purified by HPLC (RP18 column; eluent: acetonitrile/0.1% aq. formic acid 10:90→90:10).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][C@H:20]([CH3:24])[CH2:19]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[OH-:25].[Na+]>CO>[OH:25][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][C@H:20]([CH3:24])[CH2:19]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C[C@H]1CCCN(CCCOc2ccc(-c3ccnc(Cl)c3)cc2)C1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1CCCN(CCCOc2ccc(-c3ccnc(O)c3)cc2)C1
Yield: 33.7 %

Procedure:
A A mixture of 2-chloro-4-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyridine (345 mg), sodium hydroxide (288 mg) and methanol (1.55 mL) is heated overnight at a temperature close to 170° C. in a sealed tube. The mixture is cooled to a temperature close to 0° C. and neutralized with a cold concentrated aqueous hydrochloric solution. Methanol (1.3 mL) is added and the precipitate separated by filtration. The filtrate is concentrated under reduced pressure and purified by chromatography over silica gel (eluent dichloromethane/methanol from 100/0 to 80/20). Fraction containing the expected product are pooled and concentrated under reduced pressure. The crude base is dissolved in ethanol; oxalic acid (118 mg) is added followed by diethyl ether. The precipitate that appears is separated by filtration, washed with ethanol and dried under reduced pressure to give 110 mg of 2-hydroxy-4-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyridine, oxalate as a white powder melting at 110° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:40])[CH:15]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]C)=[O:24])=[CH:19][C:18]=2[CH2:27][CH:28]([CH3:30])[CH3:29])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+].C(Cl)(Cl)Cl.CO.[NH4+].[OH-].Cl>CO>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14](=[O:40])[CH:15]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][C:18]=2[CH2:27][CH:28]([CH3:30])[CH3:29])(=[O:11])=[O:12])=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(OC(C(=O)NS(=O)(=O)c2ccc(C(C)C)cc2)c2ccc3c(c2)OCO3)c(CC(C)C)c1
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)Cc1cc(C(=O)O)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Temperature: 60 °C
Yield: 82.7 %

Procedure:
To a solution of 0.294 g (0.52 mmol) of the product of Example 60 dissolved in 3.0 mL of methanol was added 1.0 mL of a 5.0N aqueous solution of sodium hydroxide. The reaction mixture was magnetically stirred at 60° C. After 3 hours TLC analysis (CHCl3 --MeOH--NH4OH 80:15:1) indicated complete hydrolysis of the ester. The reaction was cooled to room temperature, adjusted to pH=5 with dropwise addition of 1.0N HCl, then partitioned between EtOAc and water. The organic layer was separated, washed with saturated aqueous NaCl, dried (MgSO4), filtered and evaporated. The residue was dried in vacuo to afford 0.238 g (83%) of the title compound as an amorphous powder.
Reaction SMILES: C([O:5][C:6](=[O:24])[CH:7]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])CCC.CO.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O>[CH2:12]([O:11][C:9]([NH:8][CH:7]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:6]([OH:24])=[O:5])=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCCOC(=O)C(NC(=O)OCc1ccccc1)OCCCC
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCOC(NC(=O)OCc1ccccc1)C(=O)O

Procedure:
A solution of 0.002 mol. of N-benzyloxycarbonyl-2-n-butoxyglycine n-butyl ester is stirred with 10 ml. of methanol and 10 ml. of 5% aqueous sodium bicarbonate-sodium carbonate solution for five hours at 25°. The reaction mixture is then diluted with water and shaken with ethyl acetate. The layers are separated and the aqueous layer is acidified to pH 2.0 and extracted with ethyl acetate containing 10% ethanol. The extracts are dried (Na2SO4) and concentrated in vacuo to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH2:21])=[CH:17][CH:16]=1.O=[C:25]([C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(O)(=O)C.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.CCCCCC.O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][N:21]=[C:25]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:22][CH:23]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CON)cc1
Reactant: CCOC(=O)CCC(=O)c1cccnc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)CCC(=NOCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1cccnc1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (500 mg), ethyl 4-oxo-4-(3-pyridyl)butyrate (367 mg), acetic acid (0.276 ml), sodium acetate (264 mg) and ethanol (20 ml) was heated to reflux for 20 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl 4-[4(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(3-pyridyl)butyrate (590 mg, yield 73%) as a colorless oil from an ethyl acetate-hexane (3:2, v/v)-eluted fraction.
Reaction SMILES: [OH:1]/[CH:2]=[C:3]1/[CH:4]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[C:23]#[C:24][Si](C)(C)C)[CH:5]2[N:6](C(OC(C)(C)C)=O)[C:7]/1=[O:8].O/C=C1/C2CC3C(=CC=CC=3C#C[Si](C)(C)C)C2NC/1=O.FC(F)(F)C(O)=O.[Na]>ClCCl>[C:23]([C:20]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:21]=1[CH2:22][CH:4]1[CH:5]2[NH:6][C:7](=[O:8])/[C:3]/1=[CH:2]\[OH:1])#[CH:24]
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\O)C2Cc3c(C#C[Si](C)(C)C)cccc3C21
Agent: C[Si](C)(C)C#Cc1cccc2c1CC1/C(=C/O)C(=O)NC21
Agent: [Na]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#Cc1cccc2c1CC1/C(=C/O)C(=O)NC21
Temperature: 0 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of tert-butyl (3Z)-3-(dimethylaminomethylene)-2-oxo-5-(2-trimethylsilylethynyl)-4,8b-dihydro-3aH-indeno[1,2-b]pyrrole-1-carboxylate D2 (Example 2, Step 2, 0.13 g, 0.3 mmol) in dioxane (5 mL) was added HCl (37%, 0.321 mL). The solution was stirred 2 h at room temperature and was then diluted with water, extracted with ethyl acetate, washed with brine, dried and concentrated to give 0.130 g of a mixture of tert-butyl (3Z)-3-(hydroxymethylene)-2-oxo-5-(2-trimethylsilylethynyl)-4,8b-dihydro-3aH-indeno[1,2-b]pyrrole-1-carboxylate and (3Z)-3-(hydroxymethylene)-5-(2-trimethylsilylethynyl)-1,3a,4,8b-tetrahydroindeno[1,2-b]pyrrol-2-one. A solution of 0.13 g of a mixture of tert-butyl (3Z)-3-(hydroxymethylene)-2-oxo-5-(2-trimethylsilylethynyl)-4,8b-dihydro-3aH-indeno[1,2-b]pyrrole-1-carboxylate and (3Z)-3-(hydroxymethylene)-5-(2-trimethylsilylethynyl)-1,3a,4,8b-tetrahydroindeno[1,2-b]pyrrol-2-one in dichloromethane (18 mL) was added trifluoroacetic acid (2 mL) at 0° C. The solution was stirred for 1 h at 0° C. A saturated solution of sodium hydrogenocarbonate was added and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with a saturated solution of sodium hydrogenocarbonate, dried and concentrated in vacuo to give ((3Z)-5-ethynyl-3-(hydroxymethylene)-1,3a,4,8b-tetrahydroindeno[1,2-b]pyrrol-2-one C2 (70 mg, 72%). LC-MS (Method C) RT 0.67 min, ES− 224 (M−H+), ES+226 (M+H+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27]CC4C=CC=CC=4)=[CH:23][C:22]=3[F:35])[N:18]=[C:17]3[N:36]([CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][O:41]4)[N:37]=[C:38]([CH3:39])[C:16]=23)[C:10]([CH3:47])([CH3:46])[CH2:9]1)C1C=CC=CC=1>CO>[CH3:46][C:10]1([CH3:47])[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[CH2:14][C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=2[F:35])[N:18]=[C:17]2[N:36]([CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][O:41]3)[N:37]=[C:38]([CH3:39])[C:16]=12
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(CN3CCN(Cc4ccccc4)CC3(C)C)c12
Solvent: CO
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3F)cc(CN3CCNCC3(C)C)c12
Reaction time: 16 h
Yield: 90.8 %

Procedure:
200 mg 4-(4-benzyl-2,2-dimethyl-piperazin-1-ylmethyl)-6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine was dissolved in 6 ml methanol and purged with argon. 18 mg Palladium (10% on charcoal) was added and the mixture was hydrogenated at 3 bar and r.t. for 16 h. The catalyst was filtered off and the solvents were evaporated. 130 mg (45%) of the title compound were obtained.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17](Cl)[CH:18]=2)[C:13]=1[O:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH:32]([Sn](CCCC)(CCCC)CCCC)=[CH2:33].C([O-])(O)=O.[Na+]>CN(C=O)C.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH:32]=[CH2:33])[CH:18]=2)[C:13]=1[O:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(Cl)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd+]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: NCCc1[c-]cccc1
Solvent: CN(C)C=O
Product: C=Cc1ccc2c(OS(=O)(=O)C(F)(F)F)c([C@H](OC(C)(C)C)C(=O)OCC)c(C)cc2c1
Temperature: 120 °C

Procedure:
A solution of (S)-ethyl 2-tert-butoxy-2-(6-chloro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (1.0 g, 2.1 mmol) in DMF (10 mL) at room temperature is treated with BrettPhos precatalyst (Strem, 0.23 g, 0.31 mmol), vinyl tributyltin (0.68 mL, 2.3 mmol) and solid NaHCO3 (0.026 g, 0.31 mmol). The reaction mixture is sealed and sparged with Ar for 10 minutes prior to heating at 120° C. for 90 minutes. The reaction mixture is allowed to cool to room temperature, loaded directly onto silica gel and purified via Yamazen column chromatography to afford (S)-ethyl 2-tert-butoxy-2-(3-methyl-1-(trifluoromethylsulfonyloxy)-6-vinylnaphthalen-2-yl)acetate. 1H-NMR: 400 MHz, (CDCl3) δ: 8.00 (d, J=8.8 Hz, 1H); 7.72 (d, J=8.8 Hz, 1H); 7.70 (s, 1H); 7.64 (s, 1H); 6.87 (dd, J=17.2, 11.2 Hz, 1H); 5.92 (d, J=17.2 Hz, 1H); 5.41 (d, J=11.2 Hz, 1H); 4.27-4.08 (m, 2H); 2.55 (s, 3H); 1.22 (s, 9H); 1.18 (t, J=7.2 Hz, 3H).