Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:27])=[C:4]([C:23]([F:26])=[CH:24][CH:25]=1)[O:5][C:6]1[CH2:10][N:9]([C@@H:11]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:12]([OH:14])=O)[C:8](=[O:22])[CH:7]=1.[NH2:28][C:29]1[CH:33]=[CH:32][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[N:30]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([F:27])=[C:4]([C:23]([F:26])=[CH:24][CH:25]=1)[O:5][C:6]1[CH2:10][N:9]([C@@H:11]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:12]([NH:28][C:29]2[CH:33]=[CH:32][N:31]([CH2:34][C:35]([OH:37])([CH3:36])[CH3:38])[N:30]=2)=[O:14])[C:8](=[O:22])[CH:7]=1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2c(F)ccc(Cl)c2F)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)ccc(Cl)c3F)=CC2=O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.6 %

Procedure:
A solution of (S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (143 mg, 0.36 mmol) in N,N-dimethylformamide (3 mL) was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 70 mg, 0.45 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (350 mg, 0.79 mmol) and N,N-diisopropylethylamine (103 mg, 0.80 mmol). The reaction mixture was stirred for 4 h at 25° C., under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride, water, a saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 0% to 100% ethyl acetate/hexanes) to afford (S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (65 mg, 34%) as a light yellow solid: HR-ES-MS m/z calculated for C26H31ClF2N4O4 [M+H]+ 537.2075, observed 537.2071; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.79-1.31 (m, 6H) 1.05 (s, 3H) 1.06 (s, 3H) 1.52-1.85 (m, 7H) 3.89 (s, 2H) 4.29 (d, J=18.7 Hz, 1H) 4.64 (d, J=18.7 Hz, 1H) 4.68 (s, 1H) 4.90 (dd, J=10.7, 5.0 Hz, 1H) 5.24 (s, 1H) 6.44 (d, J=2.2 Hz, 1H) 7.45 (td, J=9.6, 2.0 Hz, 1H) 7.54 (d, J=2.2 Hz, 1H) 7.67 (td, J=8.7, 5.3 Hz, 1H) 10.81 (s, 1H).
Reaction SMILES: CO[C:3](=[C:14]([C:17]#[N:18])[C:15]#[N:16])[CH2:4][C:5]1[CH:10]=CC=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1.Cl.[CH:20]([NH:23][NH2:24])([CH3:22])[CH3:21].C(N(CC)CC)C.[CH3:32][CH2:33]O>>[N+:11]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:32][CH:33]=1)[CH2:4][C:3]1[C:14]([C:15]#[N:16])=[C:17]([NH2:18])[N:23]([CH:20]([CH3:22])[CH3:21])[N:24]=1)([O-:13])=[O:12]
Reactant: CC(C)NN
Reactant: CCO
Reactant: COC(Cc1cccc([N+](=O)[O-])c1)=C(C#N)C#N
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)n1nc(Cc2cccc([N+](=O)[O-])c2)c(C#N)c1N

Procedure:
The intermediate 2-(1-methoxy-2-(3-nitrophenyl)ethylidene)malononitrile (1.2 g, 4.7 mmol) was combined with isopropylhydrazine-HCl (0.57 g, 5.2 mmol; Sigma-Aldrich), 1.4 mL triethylamine in 50 mL EtOH for 2 hours at RT. The reaction was concentrated in vacuo, suspended in brine, and extracted with chloroform. The organic layer was dried over MgSO4. Following, the organic suspension was filtered, concentrated in vacuo, and purified on silica gel in 1% MeOH:CHCl3 to yield 3-(3-nitrobenzyl)-5-amino-1-isopropyl-1H-pyrazole-4-carbonitrile (ESI-MS m/z [M+H]+ found 286.4, calculated 286.12). The product was combined with formamide (1.5 mL) and heated to 160° C. overnight. H2O was added to the cooled reaction, and the precipitate was filtered and dried to yield 3-(3-nitrobenzyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (ESI-MS m/z [M+H]+ found 313.4, calculated 313.13). This precipitated intermediate was then mixed with excess zinc dust, 5 mL THF, and 0.4 mL HOAc for 12 hours under argon at room temperature. Afterwards the reaction was filtered through Celite®, extracted with EtOAc, and concentrated in vacuo to yield 3-(3-aminobenzyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine ESI-MS m/z [M+H]+ found 283.11, calculated 282.16. To the reduced precursor, molar equivalents of 3-(trifluoromethyl)phenyl isocyanate (Sigma-Aldrich) were added dropwise in ice-cold CH2Cl2. The reaction proceeded until completion as judged by TLC, was concentrated in vacuo, resuspended in 50:50 H2O—CH3CN, and purified on a C18 column in CH3CN/H2O/0.1% TFA (1-100% gradient) to yield final compound AD36 1-(3-((4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)methyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (ESI-MS m/z [M+H]+ found 470.5, calculated 470.18; 1H NMR (400 MHz, DMSO): δ 9.25 (1H, s), 8.97 (s, 1H), 8.36 (s, 1H), 8.05 (s, 1H), 7.48-7.54 (m, 2H), 7.41 (s, 1H), 7.30 (d, J=8 Hz, 2H), 7.20 (t, J=8 Hz, 1H0, 6.88 (d, J=8 Hz, 1H), 5.03 (septet, J=8 Hz, 1H), 1.48 (s, 6H). 13C NMR (400 MHz, DMSO): δ 22.15, 33.44, 49.21, 98.32, 116.48 (d), 117.03, 118.92, 122.16, 122.67, 124.70 (q), 129.33, 129.98 (q), 130.47 (q), 139.50, 140.07, 141.15, 145.31, 150.15, 151.77, 152.94, 154.32, 159.10 (q))
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([O:7][C:8]1[C:9]([F:21])=[C:10]([C:13]([CH2:19]O)=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[C:11]#[N:12])[CH3:6].C(OCC)(=O)C.O>COCCOC>[Br:2][CH2:19][C:13]1[C:10]([C:11]#[N:12])=[C:9]([F:21])[C:8]([O:7][CH2:5][CH3:6])=[C:15]([O:16][CH2:17][CH3:18])[CH:14]=1
Reactant: BrP(Br)Br
Reactant: CCOc1cc(CO)c(C#N)c(F)c1OCC
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOc1cc(CBr)c(C#N)c(F)c1OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 180.4 %

Procedure:
Phosphorus tribromide (PBr3, 1.57 mL, 16.7 mmol) was added to a solution of 3,4-diethoxy-2-fluoro-6-(hydroxymethyl)benzonitrile (38.0 g, 33.4 mmol) in 1,2-dimethoxyethane (DME) (80 mL) on ice, followed by 3 hours of stirring at room temperature. After the reaction solution was cooled on ice, ethyl acetate and water were added. The organic layer was separated, and the aqueous layer was extracted further with ethyl acetate. The combined extract solutions were washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and after addition of activated charcoal, were dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, followed by addition of n-heptane (100 mL) to the residue, and the solvent was distilled off again. n-Heptane (100 mL) was added to the residue, and this was cooled on ice. Precipitated crystals were collected by filtration, and washed with n-heptane to give 9.1 g of the subject compound (yield: 90.1%).
Reaction SMILES: [C:1]([O:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]1)(=[O:21])[C:2]1[C:3](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:4]([O:6][CH:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]([CH3:16])([CH3:15])[CH2:8]1)=[O:5].[C:33]([O:37]O)([CH3:36])([CH3:35])C>[Mo](=O)(=O)=O.C1CCCCC1>[C:4]([O:6][CH:7]1[CH2:8][C:9]([CH3:16])([CH3:15])[N:10]([O:37][CH:33]2[CH2:36][CH2:17][CH2:3][CH2:4][CH2:35]2)[C:11]([CH3:13])([CH3:14])[CH2:12]1)(=[O:5])[C:3]1[C:2](=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:1]([O:22][CH:23]1[CH2:24][C:25]([CH3:32])([CH3:31])[N:26]([O:37][CH:33]2[CH2:36][CH2:20][CH2:2][CH2:1][CH2:35]2)[C:27]([CH3:30])([CH3:29])[CH2:28]1)=[O:21]
Reactant: CC(C)(C)OO
Reactant: CC1(C)CC(OC(=O)c2ccccc2C(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Agent: O=[Mo](=O)=O
Solvent: C1CCCCC1
Product: CC1(C)CC(OC(=O)c2ccccc2C(=O)OC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC1CCCCC1
Temperature: 140 °C
Reaction time: 1.25 h
Yield: 143.3 %

Procedure:
A mixture of 30.0 g (67.5 mmol) of di-(2,2,6,6-tetramethyl-piperidin-4-yl) phthalate, 27.5 g (214 mmol) of 70% aqueous t-butyl hydroperoxide, 2.0 g of molybdenum trioxide, and 200 ml of cyclohexane is heated to reflux. Water is collected in a Dean-Stark trap. After 75 min., the reaction mixture becomes red. Another portion of t-butyl hydroperoxide (42.5 g, 70%, 330 mmol) is added over 30 minutes. After the additional water is collected, the reaction mixture is transferred to a Fischer-Porter bottle and heated at 140° C. for 4.5 hours. The nearly colorless reaction mixture is treated with 6.9 g (90%, 69 mmol) of t-butyl hydroperoxide and heated at 140° C. for 90 minutes to remove the last traces of pink color. The reaction mixture is cooled, filtered, and stirred with a solution of 43 g of sodium sulfite in 530 ml of water for 2 hours. Dichloromethane (600 ml) is added, and the organic layer is separated, dried over magnesium sulfate, and concentrated to obtain a crude solid. Purification (Waters Prep. 500A HPLC, 25:1 heptane:ethyl acetate) affords 31.0 g (72% yield) of a white solid, m.p. 149°-51° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH3:3].[NH2:16][C:17]1[C:20](=[O:21])[C:19](=[O:22])[C:18]=1OC>CO>[NH2:16][C:17]1[C:20](=[O:21])[C:19](=[O:22])[C:18]=1[NH:12][CH2:11][CH2:10][CH2:9][O:8][C:7]1[CH:13]=[CH:14][CH:15]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[CH:6]=1
Reactant: CN(C)Cc1cccc(OCCCN)c1
Reactant: COc1c(N)c(=O)c1=O
Solvent: CO
Product: CN(C)Cc1cccc(OCCCNc2c(N)c(=O)c2=O)c1
Yield: 94.9 %

Procedure:
A mixture of 3-(3-dimethylaminomethylphenoxy)propylamine (1.41 g; 6.77 mmoles) [prepared according to the procedure described in Belgian Pat. No. 867,106] and 1-amino-2-methoxycyclobutene-3,4-dione (0.86 g; 6.77 mmoles) in 40 mL of methanol was stirred at ambient temperature for 20 hours and then filtered to give 1.95 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]2[CH:30]=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[ClH:38].C(O)C.C(=O)([O-])[O-].[NH4+:46].[NH4+]>ClCCl.C(O)C>[ClH:38].[CH3:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]2[CH:30]=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:46])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1cccc(C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1cccc(C)c1
Yield: 79 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-methylphenyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 79% of theory, C29H32N6O3 (512.6) Rf value: 0.10 (silica gel; dichloromethane/ethanol=4:1) ##EQU59##
Reaction SMILES: C[O-].[Na+].[CH3:4][CH2:5][O-:6].[Na+].[C:8]1([CH3:18])[C:9]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=1.[NH2:19][C:20](OCC)=[O:21]>>[CH2:5]([O:6][S:14]([C:9]1[C:8]([CH3:18])=[CH:13][CH:12]=[C:11]([N:19]=[C:20]=[O:21])[CH:10]=1)(=[O:16])=[O:15])[CH3:4]
Reactant: CC[O-]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CCOC(N)=O
Agent: C[O-]
Agent: [Na+]
Product: CCOS(=O)(=O)c1cc(N=C=O)ccc1C

Procedure:
If, instead of sodium methylate, sodium ethylate in solution in alcohol is used for esterifying the urethane toluene-2-sulphonic acid chloride according to Example 1, the 4-isocyanatotoluene-2-sulphonic acid ethyl ester is similarly obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Li]CCCC.[C:17]1(=O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18]1.Cl>C1COCC1>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[CH:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCc2ccccc21
Reactant: Brc1cccc2cccnc12
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C1=CC(c2cccc3cccnc23)c2ccccc21
Temperature: -100 °C
Reaction time: 0.25 h
Yield: 54.3 %

Procedure:
30 8-bromoquinoline (10.4 g, 50 mmol) was first placed in 100 ml of THF and cooled to approximately −100° C. 20 ml of n-BuLi (2.5 M in hexane, 50 mmol) were added dropwise, and the internal temperature was kept below −80° C. After the addition was ended, stirring was continued for a further 15 minutes at −80° C., and then 6.6 g of 1-indanone (50 mmol), dissolved in 30 ml of THF, were added dropwise. The reaction mixture was then allowed to return to room temperature slowly and then heated for three hours. in reflux. Once the mixture had cooled to room temperature, first ice and then hydrochloric acid was added to approximately pH 1, and the mixture was stirred for 30 minutes. The aqueous and organic phases were separated; the aqueous phase was mixed with ammonia solution to a pH of approximately 9 and extracted with ether, and the combined organic phases were then concentrated until dry in a vacuum. The thus-obtained viscous oil (1-(8-quinolyl)-indan-1-ol (8H2O)) was mixed with hydrochloric acid until the pH was 0, heated for two hours in reflux, and then neutralized. After processing and drying, 6.6 g of 1-(8-quinolyl)indene (55%) were obtained in the form of a colorless solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[S:11][C:12]4[C:17]([N:18]=3)=[CH:16][CH:15]=[C:14]([C:19]3([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:21][CH2:20]3)[N:13]=4)=[CH:7][CH:8]=2)[CH2:3][NH:2]1.C(N(C(C)C)CC)(C)C.Br[CH2:38][C:39]([O:41][CH3:42])=[O:40]>C(Cl)Cl>[C:22]1([C:19]2([C:14]3[N:13]=[C:12]4[S:11][C:10]([C:6]5[CH:5]=[C:4]6[C:9](=[CH:8][CH:7]=5)[CH2:1][N:2]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH2:3]6)=[N:18][C:17]4=[CH:16][CH:15]=3)[CH2:20][CH2:21]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)CBr
Reactant: c1ccc(C2(c3ccc4nc(-c5ccc6c(c5)CNC6)sc4n3)CC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CN1Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)cc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(Isoindolin-5-yl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (97 mg, 0.263 mmol) was dissolved in DCM (2.625 mL) and diisopropylethylamine (91 μL, 0.525 mmol) before methyl bromoacetate (48.5 μL, 0.525 mmol) was added and stirred at ambient temperature for 3 h. Methyl 2-(5-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)isoindolin-2-yl)acetate was obtained after purification via flash chromatograpy. MS (ESI) m/z: Calculated: 441.2; Observed: 442.4 (M++H).
Reaction SMILES: [Br-].C([N+:9]12[CH2:17][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH2:14][CH2:15][CH2:16]1)[CH2:12][CH2:11][CH2:10]2)C1C=CC=CC=1.CCO>[Pd].[C].C(Cl)(Cl)Cl>[N:9]12[CH2:17][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH2:14][CH2:15][CH2:16]1)[CH2:12][CH2:11][CH2:10]2
Reactant: CCOC(=O)C12CCC[N+](Cc3ccccc3)(CCC1)C2
Agent: [Pd]
Agent: [Br-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOC(=O)C12CCCN(CCC1)C2
Temperature: 25 °C
Yield: 75.3 %

Procedure:
A mixture of 1-benzyl-5-(ethoxycarbonyl)-1-azoniabicyclo[3.3.1]nonane bromide (932 mg), 10% Pd/Carbon with a 50% hydration (25 mg), and EtOH (15 mL) was stirred at room temperature under a hydrogen atmosphere of 3 atm. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to obtain a colorless solid. To this solid were added CHCl3 and a saturated aqueous NaHCO3 solution, and the organic layer was separated. Furthermore, the aqueous layer was extracted with CHCl3. The organic layer was collected, dried over MgSO4, and then concentrated under reduced pressure to obtain ethyl 1-azabicyclo[3.3.1]nonane-5-carboxylate (376 mg).
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=O.[NH2:6][NH:7][C:8]([NH:10][NH2:11])=[S:9]>O>[NH2:6][N:7]1[C:1](=[O:5])[CH:2]=[N:11][NH:10][C:8]1=[S:9]
Reactant: O=CC(=O)O
Reactant: NNC(=S)NN
Solvent: O
Product: Nn1c(=O)cn[nH]c1=S

Procedure:
A solution of 22 parts glyoxylic acid in 22 parts water is slowly added to a hot, stirred solution of 32 parts thiocarbohydrazide in 350 parts water. The resulting mixture is refluxed until no further precipitate is formed. Upon cooling, essentially pure 4-amino-2,3-dihydro-3-thiono-as-triazin-5(4H)-one having a melting point of 211°-215° C. is obtained by filtration.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:14].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C>[CH2:22]([O:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:14])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc2c(c1O)CCNC2=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: COc1ccc2c(c1OCc1ccccc1)CCNC2=O

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-one (700 mg, 3.62 mmol, 1.00 equiv), Cs2CO3 (2.36 g, 7.22 mmol, 2.00 equiv), ethanol (20 mL) and (bromomethyl)benzene (740 mg, 4.35 mmol, 1.20 equiv). The resulting solution was heated to reflux for 1 hr. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 1 g (97%) of 5-(benzyloxy)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-one as a gray solid. 1H NMR (300 MHz, DMSO-d6) δ: 2.70-2.75 (t, 2H), 3.19-3.23 (t, 2H), 3.90 (s, 3H), 4.95 (s, 2H), 7.05-7.08 (m, 1H), 7.33-7.42 (m, 5H), 7.62-7.64 (m, 1H), 7.70 (S, 1H); MS (ESI) m/z 284 ([M+H]+).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[I:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[O:16]1[CH2:20][CH2:19][O:18][CH:17]1[CH2:21]Br>O>[O:16]1[CH2:20][CH2:19][O:18][CH:17]1[CH2:21][O:15][C:12]1[CH:13]=[CH:14][C:9]([I:8])=[CH:10][CH:11]=1
Reactant: Oc1ccc(I)cc1
Reactant: BrCC1OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Ic1ccc(OCC2OCCO2)cc1
Reaction time: 3 h
Yield: 46.5 %

Procedure:
A suspension of 65% sodium hydride (9.3 g)/dimethylformamide (100 ml) was ice-cooled, followed by the addition of 4-iodophenol (50.5 g)/dimethylformamide (200 ml) solution, and the mixture was stirred for 3 hr. To the mixture solution was added (1,3-dioxolan-2-yl)methylbromide (46.0 g), and the mixture was reacted at 60° C. for 1 day. The reaction solution was poured into water, and extracted with ethyl acetate. The resulting organic layer was washed with water and brine, and then dried (over magnesium sulfate). The solvent was removed, and the resulting residue was purified by NH silica gel column chromatography (chloroform), and then recrystallized from ethyl acetate/hexane, to give 32.7 g of the title compound as pale yellow prisms.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:6]([C:13]([O:15][CH3:16])=[O:14])=[C:7]([C:11]#[N:12])[NH:8][C:9]=1[CH3:10])([OH:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl.[CH:32](O)([CH3:34])[CH3:33].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:11]([C:7]1[NH:8][C:9]([CH3:10])=[C:4]([C:1]([O:3][CH:32]([CH3:34])[CH3:33])=[O:2])[CH:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:6]=1[C:13]([O:15][CH3:16])=[O:14])#[N:12]
Reactant: COC(=O)C1=C(C#N)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: CC(C)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1=C(C#N)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
In methylene chloride (30 ml) is suspended methyl (+)-5-carboxy-2-cyano-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate (3.12 g) followed by addition of phosphorus pentachloride (2.46 g) with ice-cooling, and the mixture is stirred for 30 minutes. Then, a solution of isopropyl alcohol (1.4 g) in methylene chloride (10 ml) is added dropwise over a period of 10 minutes. The mixture is stirred for 20 minutes, at the end of which time 5% aqueous sodium carbonate solution (30 ml) is added and the mixture is stirred at ambient temperature for one hour. The organic layer is separated and the water layer is extracted with methylene chloride. The organic layers are combined, washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue is purified by silica gel (75 g) column chromatography, elution being carried out with benzeneethyl acetate (10:1). The solvent is removed from the eluate under reduced pressure and the residue is crystallized from diisopropyl ether to provide 5-isopropyl 3-methyl (+)-2-cyano-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (3.34 g).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1>CN(C=O)C>[Si:12]([O:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:7]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: COC(=O)[C@H]1CC[C@@H](O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
99.0 g (0.63 mol) of the compound from Example 51A are dissolved in 2 liters of dry DMF, and 132.0 g (0.88 mol) of tert-butyldimethylsilyl chloride and 80.9 g (1.19 mol) of imidazole are added at RT. The mixture is stirred at RT for 16 h. The solvent is then removed almost to dryness on a rotary evaporator and the residue is taken up in 2 liters of a 1:1 mixture of tert-butyl methyl ether and saturated aqueous sodium bicarbonate solution. The phases are separated, the organic phase is dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The product is used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][C:10]([O:12]CC)=[O:11])=[CH:7][N:6]([CH2:15][C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:27][C:28]=3[CH3:29])=[CH:20][CH:21]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][N:6]([CH2:15][C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:27][C:28]=3[CH3:29])=[CH:20][CH:21]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)cc1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
After a mixture of ethyl 3-ethoxy-1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-ylacetate (605 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-ethoxy-1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-ylacetic acid (518 mg, yield: 91%). This was recrystallized from ethanol-hexane. Melting point: 126–127° C.