Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=2)=[O:5])C.[H-].[Na+].I[CH3:21]>CN(C=O)C.CCCCCCC>[CH3:21][N:7]1[C:8]2[C:13](=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=2)[CH:14]=[C:6]1[C:4]([OH:3])=[O:5]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: Cn1c(C(=O)O)cc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-Nitro-1H-indole-2-carboxylic acid ethyl ester (234 mg, 1 mmol) was dissolved in DMF (2 ml). NaH (32 mg, 1.4 mmol) was added as a suspension in heptane (0.5 ml) and the mixture was stirred at room temperature for 10 min. Iodomethane (170 mg, 1.2 mmol) was added drop-wise and the solution was left stirring for 1 h. During this reaction, hydrolysis occurred. The reaction mixture was quenched with H2O (2 ml) and washed with EtOAc (3×1 ml). The aqueous layer was acidified to pH 1 with conc. HCl until a white precipitate formed and extracted with EtOAc (3×1 ml). These organic layer were combined, dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][CH2:10][CH:11]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([CH2:18][CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:15][CH2:16][CH3:17])=[O:14]>>[CH3:19]/[C:18](=[CH:11]\[CH2:10][CH2:9][C:8]#[C:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)/[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCCC#Cc1ccccc1
Product: CCOC(=O)/C(C)=C/CCC#Cc1ccccc1
Yield: 98 %

Procedure:
5-phenyl-pent-4-yn-1-al (1 g, 6.33 mmol) (Example 1) and carboethoxymethylmethylene triphenylphosphorane were used with the same method as in Example 1 to give 1.5 g (98% of theory) of ethyl 2-methyl-7-phenyl-(2E)-hepten-6-ynoate as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=[O:18].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:26][CH2:27][O:28][CH3:29]>CN(C)C=O.C(OCC)(=O)C>[CH3:29][O:28][CH2:27][CH2:26][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=[O:18]
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(O)cc12
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(c1)c(C=O)nn2C1CCCCO1
Yield: 89.9 %

Procedure:
A solution of 5-hydroxy-1-(oxan-2-yl)-1H-indazole-3-carbaldehyde (120 mg, 0.49 mmol, 1.00 equiv), Cs2CO3 (180 mg, 0.55 mmol, 2.00 equiv) and 1-bromo-2-methoxyethane (500 mg, 3.60 mmol, 3.00 equiv) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 10 h. The reaction was diluted with 50 mL of ethyl acetate and then washed with 4×10 mL of brine. The organic layer was dried over anhydrous sodium sulfate then concentrated under vacuum to give 134 mg (90%) of (R/S) 5-(2-methoxyethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde as a yellow oil. LCMS (method D, ESI): RT=1.48 min, m/z=305.1 [M+H]+.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22](I)=[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][N:16]3[N:15]=2)=[CH:10][CH:9]=1.CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([NH:38][C:39](=[O:42])[CH2:40][CH3:41])[CH:33]=2)O1.C(OCC)(=O)C>O1CCOCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([NH:38][C:39](=[O:42])[CH2:40][CH3:41])[CH:33]=3)=[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][N:16]3[N:15]=2)=[CH:10][CH:9]=1
Reactant: Fc1ccc(-c2nn3c(c2I)CCCC3)cc1
Reactant: CCC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCC(=O)Nc1cc(-c2c(-c3ccc(F)cc3)nn3c2CCCC3)ccn1
Temperature: 120 °C
Yield: 79.3 %

Procedure:
Under argon, 1.39 ml of a 2M aqueous Na2CO3 solution are added dropwise to a solution of 200 mg (0.55 mmol) of 2-(4-fluorophenyl)-3-iodo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine, 168 g (0.61 mmol) of N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]propanamide in 2 ml of dioxane, and 32 mg (0.04 mmol) of Pd(PCy3)2Cl2 are added. In a microwave reactor, the reaction mixture is heated at 120° C. for 15 min. After cooling, 50 ml of ethyl acetate are added, the reaction mixture is filtered through kieselguhr and the filtrate is extracted with ethyl acetate. The combined organic phases are washed with water, dried over MgSO4 and freed from the solvent under reduced pressure. Purification by column chromatography on silica gel (cyclohexane/ethyl acetate) gives 159 mg (78%) of the desired product; log P(HCOOH): 1.97; 1H-NMR (MeCN-d3): 8.54 (br.s, 1H), 8.11 (d. 1H), 8.02 (s, 1H), 7.42 (dd, 2H), 7.04 (dd, 2H), 6.77 (d, 1H), 4.16 (dd, 2H), 2.81 (dd, 2H), 2.40 (q, 2H), 1.77 (m, 2H), 1.11 (t, 3H).
Reaction SMILES: O.[ClH:2].Cl.[NH2:4][C:5]1[N:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:8]2[CH2:14][NH:13][CH2:12][CH2:11][C:9]=2[N:10]=1.NC1N=[C:25]([C:33]2C=CC(F)=CC=2)[C:26]2CNCCC=2N=1.Cl.Cl.C(Br)C=C>>[ClH:2].[ClH:2].[CH2:33]([N:13]1[CH2:12][CH2:11][C:9]2[N:10]=[C:5]([NH2:4])[N:6]=[C:7]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:8]=2[CH2:14]1)[CH:25]=[CH2:26]
Reactant: Nc1nc2c(c(-c3ccc(F)cc3)n1)CNCC2
Agent: Cl
Solvent: O
Solvent: C=CCBr
Product: C=CCN1CCc2nc(N)nc(-c3ccc(F)cc3)c2C1
Yield: 117.4 %

Procedure:
The title compound was prepared as described in Example 17 starting with 2-amino-4-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine dihydrochloride hemihydrate (1.0 g, 3.1 mmol) and allyl bromide (0.3 mL, 3.1 mmol) instead of iodoethane to produce 0.65 g (59%) of 6-allyl-2-amino-4-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine dihydrochloride. m.p. 241°-243° C. MS: 285 (MH+). IR(KBr): 3305, 3118, 2476, 1651 cm-1.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([N:7]1[CH2:12][CH2:11][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]([NH2:21])[CH2:13]2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].C(N(CC)CC)C.Cl[S:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])(=[O:33])=[O:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:3][C:2]([CH3:22])([O:4][C:5]([N:7]1[CH2:8][CH2:9][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]([NH:21][S:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])(=[O:33])=[O:32])[CH2:13]2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(N)c1ccccc12
Reactant: COC(=O)CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CS(=O)(=O)NC1CC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21

Procedure:
A sample of 1'-(1,1-dimethylethyloxycarbonyl)-3-amino-2,3-dihydrospiro(1H-indene-1,4'-piperidine), prepared by hydrogenation of 500 mg of oxime (1.58 mmole) as in Example 135, in 2 mL methylene chloride containing 475 mg of DMAP (2.46×1.58 mmole), and 550λ of triethylamine (2.51×1.58 mmole), was stirred under nitrogen in an ice bath while adding a solution of 400λ of 8.4M methyl chlorosulfonylacetate (2.13×1.58 mmole) in 2 mL methylene chloride dropwise over 2-3 minutes. The suspension was stored over night in the refrigerator. It was then washed twice with water, then with 5% citric acid. Atypically, solid material was still present in suspension; this was s removed by filtration, the filtrate dried with magnesium sulfate and concentrated under reduced pressure. Again, solid formed and was removed by filtration. Finally, preparative TLC on four 8"×8"×1,000μ GF silica gel plates using 2:1 ethyl acetate:hexane afforded 389 mg of the title compound
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[C:4]([CH3:11])[C:3]=1[C:12]1[C:13]([O:20][CH3:21])=[C:14]([OH:19])[CH:15]=[C:16]([F:18])[CH:17]=1.[CH2:22]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][C:31]=1[CH3:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(=O)C>[CH3:8][C:7]([N:6]1[C:2]2[N:1]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([O:29][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[C:31]([CH3:38])[CH:32]=3)[C:17]3[C:16]([F:18])=[CH:15][C:14]([OH:19])=[C:13]([O:20][CH3:21])[C:12]=3[C:3]=2[C:4]([CH3:11])=[N:5]1)([CH3:9])[CH3:10]
Reactant: COc1c(O)cc(F)cc1-c1c(C)nn(C(C)(C)C)c1N
Reactant: Cc1cc(C=O)ccc1OCc1ccccc1
Solvent: CC(=O)O
Product: COc1c(O)cc(F)c2c(-c3ccc(OCc4ccccc4)c(C)c3)nc3c(c(C)nn3C(C)(C)C)c12
Temperature: 120 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To 3-[5-amino-1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-4-yl]-5-fluoro-2-(methyloxy)phenol (150 mg, 0.51 mmol) was added 4-benzyloxy-3-methylbenzaldehyde (115 mg, 0.51 mmol) and acetic acid (2 mL). The mixture was heated to 120° C. and stirred overnight. The acetic acid was removed in vacuo. The residue was purified by flash chromatography (70% hexanes, 30% ethyl acetate) to provide 3-(1,1-dimethylethyl)-6-fluoro-1-methyl-9-(methyloxy)-5-{3-methyl-4-[(phenylmethyl)oxy]phenyl}-3H-pyrazolo[3,4-c]isoquinolin-8-ol (207 mg, 0.42 mmol, 81% yield) as an orange foam. 1H NMR (400 MHz, CDCl3): δ 7.52-7.35 (m, 7H), 6.99 (br d, 1H), 6.85 (d, 1H), 5.17 (s, 2H), 3.82 (s, 3H), 2.89 (s, 3H), 2.39 (s, 3H), 1.88 (s, 9H); MS (EI) for C30H30FN3O3: 500 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]([CH2:13][S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[NH2:17])[C:6]2[O:7][CH2:8][O:9][CH2:10][C:5]=2[CH:4]=1.[CH3:22][C:23]([CH3:28])([CH3:27])[C:24](Cl)=[O:25].C(O)C(N)(CO)CO>ClCCl.C(N(C(C)C)CC)(C)C.CN(C1C=CN=CC=1)C>[Cl:2][C:3]1[CH:12]=[C:11]([CH2:13][S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[NH:17][C:24](=[O:25])[C:23]([CH3:28])([CH3:27])[CH3:22])[C:6]2[O:7][CH2:8][O:9][CH2:10][C:5]=2[CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccccc1SCc1cc(Cl)cc2c1OCOC2
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccccc1SCc1cc(Cl)cc2c1OCOC2
Reaction time: 24 h
Yield: 63.8 %

Procedure:
The product from step 1 (75 mg, 0.22 mmol) was dissolved in a mixture of dichloromethane and diisopropyl ethyl amine (4 mL , ˜40:1), PS DMAP resin (0.10 g, Argonaut 1.41 mmol/g) was added in followed by 2,2-dimethylpropanoyl chloride (0.15 mL, 1.25 mmol). The reaction was agitated for 24 hours and then treated with PS trisamine (Argonaut 4.27 mmol/g) for 6 h filtered and the solvent removed under a stream of nitrogen. The residue was chromatographed on silica to give the title product 55 mg (65%). 1H NMR (CDCl3) δ 9.87 (s, 1 H), 8.45 (dd, 1 H), 7.39 (dd, 1 H), 7.33 (dt, 1 H), 7.00 (dt, 1 H), 6.80 (dd, 2 H), 4.98 (s, 2 H), 4.77 (s, 2 H), 3.84 (s, 2 H), 1.28 (s, 9 H); MS (ESI+) for C20H22ClNO3S m/z 392 (M+H)+.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@H:21]([OH:38])[CH2:22][N:23]1[C@H:27]([C:28]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][C@@H:25]2[CH2:35][CH2:36][CH2:37][C@H:24]12)=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@H:21]([OH:38])[CH2:22][N:23]1[C@H:27]([C:28]([NH:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:26][C@@H:25]2[CH2:35][CH2:36][CH2:37][C@H:24]12)=[O:18])[CH2:13][C:14](=[O:16])[NH2:15]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCC[C@@H]2N1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCC[C@@H]2N1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Yield: 100.2 %

Procedure:
A solution of 397 mg of 1-[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-octahydro-(3aS,6aS)-cyclopenta[b]pyrrole-2(S)-carboxamide in 20 ml of ethanol was hydrogenated over 10% palladium-on-carbon at 20° C. and under atmospheric pressure for 4 hours. The catalyst was removed by filtration and the filtrate was evaporated to give 312 mg of 1-[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-octahydro-(3aS,6aS)-cyclopenta[b]pyrrole-2(S)-carboxamide as a pale yellow gum; MS: m/e 488 [M+H]+.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:12]2[CH:11]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(OCC)(=O)C>C1COCC1>[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:12]2[CH:11]=1
Reactant: COC(=O)c1cnn2ccc(CO[Si](C)(C)C(C)(C)C)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cnn2ccc(CO)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 5-((tert-butyldimethylsilyloxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxylate Y-5 (2.9 g, 9.1 mmol) in dry THF (20 mL) was added TBAF (3.5 g, 13.7 mmol). The reaction mixture was stirred at room temperature for 10 mins, then treated with ethyl acetate. The resulting mixture was washed with brine, dried over Na2SO4 and concentrated to afford the title compound (1.9 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:43])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36]4([C:40](O)=[O:41])[CH2:39][CH2:38][CH2:37]4)[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[NH4+].O[N:46]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN(C)C=O>C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]2[C:17](=[O:43])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36]4([C:40]([NH2:46])=[O:41])[CH2:37][CH2:38][CH2:39]4)[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:13][CH:14]=1)#[N:2]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(C(=O)O)CCC3)CC2)c2ncnn12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(C(N)=O)CCC3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 1-{[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]methyl}cyclobutanecarboxylic acid (0.4 g), 1-hydroxybenzotriazole ammonium salt (0.24 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.37 g, 93%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:4]2[N:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1>C(O)C>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]3=[N:12][N:13]=[C:14]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[N:4]3[N:3]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(N)cc1
Reactant: COc1ccc(-c2nnc3c4ccccc4c(Cl)nn23)cc1
Solvent: CCO
Product: COc1ccc(Nc2nn3c(-c4ccc(OC)cc4)nnc3c3ccccc23)cc1
Yield: 81.3 %

Procedure:
5.0 g of 6-chloro-3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine (compound B1), and 20 g p-anisidine are stirred at 170° C. for 5 h. The reaction mixture is diluted with 40 ml ethanol and the precipitate is filtered with suction. The solid is recrystallized from N,N-dimethylformamide to yield 5.2 g of the title compound. M.p.: 301-304° C.
Reaction SMILES: C(N(CC)CC)C.[C:8]([Si](C)(C)C)#[N:9].[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([C:26]2[S:27][CH:28]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N+:32]=3[O-])[N:30]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[CH3:15]>C(#N)C>[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([C:26]2[S:27][CH:28]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:8]#[N:9])[N:32]=3)[N:30]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[CH3:15]
Reactant: C[Si](C)(C)C#N
Reactant: CCOc1ccc(-c2nc(-c3cccc[n+]3[O-])cs2)cc1OCC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOc1ccc(-c2nc(-c3cccc(C#N)n3)cs2)cc1OCC

Procedure:
21.3 ml of triethylamine and 30.7 ml of cyanotrimethylsilane were added to a suspension of 26.3 g of 2-[2-(3,4-diethoxyphenyl)-4-thiazolyl]pyridine-1-oxide in 500 ml of acetonitrile. The mixture was refluxed for 62 hours. The solvent in the reaction mixture was removed by distillation. To the residue was added an aqueous sodium carbonate solution. The mixture was subjected to extraction with methylene chloride. The methylene chloride layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by silica gel column chromatography (elutant: methylene chloride) and recrystallized from ethanol to obtain 22.2 g of 2-(3,4-diethoxyphenyl)-4-(6-cyano-2-pyridyl)thiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[CH:13]=[O:14])[CH:3]=1.[BH4-].[Na+].O>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[CH2:13][OH:14])[CH:3]=1
Reactant: O=Cc1sccc1-c1cc(Cl)ccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1sccc1-c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(4-chloro-pyridin-2-yl)-thiophene-2-carbaldehyde (30 mg, 0.13 mmol) in EtOH (1 mL) was added NaBH4 (50 mg, 1.3 mmol) at 0° C. The resulting mixture was stirred at room temperature overnight, then was poured into water and extracted with CH2Cl2. The organic layer was dried and concentrated to yield [3-(4-chloro-pyridin-2-yl)-thiophen-2-yl]-methanol as an oil.
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[S:4].[C:6]([CH2:14][C:15](OCC)=[O:16])(=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[SH:4][C:3]1[N:5]=[C:15]([OH:16])[CH:14]=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:2]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: NC(N)=S
Agent: [Na]
Solvent: CCO
Product: Oc1cc(-c2ccccc2)nc(S)n1
Yield: 559.5 %

Procedure:
To ethanol (100 mL) was added sodium (3.3 g, 14 mmol). After dissolution, thiourea (10.7 g, 14 mmol) and ethyl benzoylacetate (24 mL, 14 mmol) were added. The reaction was heated for 16 hours and the solvent was removed in vacuo. Water was added to dissolve the residue and hydrochloric acid was added and a precipitate formed. The solid was collected and dried in a vacuum oven to give 16 g (56%) of 2-mercapto-4-hydroxy-6-phenylpyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:7]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[CH2:24]([O:12][C:10]1[CH:9]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1cc(O)cc(C(=O)OCC)n1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(OCc2ccccc2)cc(C(=O)OCC)n1
Temperature: 82 °C
Yield: 96 %

Procedure:
To a solution of 4 (6.88 g, 28 mmol) in acetonitrile and K2CO3 (6.31 g, 45 mmol) was carefully added benzyl bromide (3.34 mL, 27 mmol). The resulting solution was stirred at 82° C. under reflux overnight. The reaction was stopped by filtration of K2CO3 and the solvent was removed under reduced pressure. The solid obtained was recrystallized from hot hexanes to yield 96% of the product as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]([C:10]1[CH:11]=[C:12]([NH2:26])[C:13]([O:24][CH3:25])=[C:14]([S:16]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])=[O:17])[CH:15]=1)([CH3:9])([CH3:8])[CH3:7].C(N(C(C)C)CC)(C)C>ClCCl>[C:6]([C:10]1[CH:11]=[C:12]([NH:26][C:3](=[O:4])[CH2:2][Cl:1])[C:13]([O:24][CH3:25])=[C:14]([S:16]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:17])=[O:18])[CH:15]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: O=C(Cl)CCl
Reactant: COc1c(N)cc(C(C)(C)C)cc1S(=O)(=O)NC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1c(NC(=O)CCl)cc(C(C)(C)C)cc1S(=O)(=O)NC(C)(C)C
Reaction time: 2 h

Procedure:
A solution of chloroacetyl chloride (4.4 ml) in dichloromethane (40 ml) was added dropwise to a cooled and stirred solution of 5-t-butyl-2-methoxy-3-aminophenyl N-t-butyl-sulfonamide (15.6 g) and diisopropylethylamine (9.5 ml) in dichloromethane (100 ml). The solution was left standing at ambient temperature for 2 hours and then washed with a 2% solution of citric acid. The organic phase was dried and evaporated. Recrytallization from aqueous ethanol gave the title compound (16.4 g).
Reaction SMILES: C[O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([CH3:34])[CH:28]=2)[O:24][C:25]=1[CH3:26]>>[CH2:16]([O:15][C@@H:4]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:20][C:21]1[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([CH3:34])[CH:28]=3)[O:24][C:25]=1[CH3:26])[CH:10]=[CH:9]2)[C:3]([OH:2])=[O:18])[CH3:17]
Reactant: Cc1cc(-c2nc(CCl)c(C)o2)ccc1F
Reactant: CCO[C@@H](Cc1ccc2[nH]ccc2c1)C(=O)OC
Product: CCO[C@@H](Cc1ccc2c(ccn2Cc2nc(-c3ccc(F)c(C)c3)oc2C)c1)C(=O)O
Yield: 58 %

Procedure:
Starting from (S)-2-ethoxy-3-(1H-indol-5-yl)-propionic acid methyl ester and 4-chloromethyl-2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazole, the title compound was obtained in 58% yield as a pale yellow solid. MS: (M−H)− 435.2.
Reaction SMILES: [C:1]1([CH:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]2[CH2:11][CH:10](S(C3C(C)=CC=CC=3)(=O)=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:28]#[N:29].[K+].O>CS(C)=O>[C:1]1([CH:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]2[CH2:11][CH:10]([C:28]#[N:29])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1S(=O)(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 100 °C
Yield: 69 %

Procedure:
To a solution of 1.0 g. (2.54 mmoles) of 1-diphenylmethyl-3-toluenesulfonylazetidine in 10 ml of dimethylsulfoxide is added 547 mg (8.4 mmoles; 3.3 equivalents) of potassium cyanide, and the mixture is heated to 100° C. for 15 minutes. After cooling, the mixture is mixed with water and extracted with ether. The extract is washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is dissolved in ether, treated with active carbon, and filtered. The filtrate is evaporated to yield 435 mg of 1-diphenylmethyl-3-cyanoazetidine having mp. 153° to 154° C. as needles in 69% yield. From the mother liquor, the same product having mp. 149° to 152° C. is obtained in 6.3% yield. Total yield is 75.3%. The product is recrystallized from ether to yield the pure product having mp. 158° to 159° C.