Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([C:9]#[N:10])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.ClCCCl.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2C(=O)C3(CCOCC3)N(CCCC(O)=O)[C:24]2=[O:40])=[CH:19][C:18]=1[C:41]([F:44])([F:43])[F:42])#[N:16]>C(N(CC)CC)C>[NH:10]=[C:9]1[C:2]2([CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)[NH:1][C:24](=[O:40])[N:23]1[C:20]1[CH:21]=[CH:22][C:17]([C:15]#[N:16])=[C:18]([C:41]([F:42])([F:43])[F:44])[CH:19]=1
Reactant: N#Cc1ccc(N2C(=O)N(CCCC(=O)O)C3(CCOCC3)C2=O)cc1C(F)(F)F
Reactant: CN1CCC(N)(C#N)CC1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN1CCC2(CC1)NC(=O)N(c1ccc(C#N)c(C(F)(F)F)c1)C2=N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Using the procedure of Stage 2 of Example 20, 153 mg of the product of Stage 1 of Example 20, 1.5 ml of 1,2-dichlorethane and 0.1 ml of triethylamine were reacted and the solution was placed in an ice-cooled water bath. 1 ml of the product of Example 7 of European Patent Application EP 0,494,819 was added and the mixture was allowed to return to ambient temperature. The reaction medium stood for one hour, was dried and the residue was purified on silica with methylene chloride-methanol: 7-3 as eluant to obtain 277 mg of the expected product (white crystals) melting at 199-200° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4](O)[CH:3]=1.P(Br)(Br)([Br:14])=O>ClCCl>[Br:14][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=1
Reactant: Cc1cc(O)ncc1[N+](=O)[O-]
Reactant: O=P(Br)(Br)Br
Solvent: ClCCl
Product: Cc1cc(Br)ncc1[N+](=O)[O-]

Procedure:
A solution of 4-methyl-5-nitropyridin-2-ol (82 g, 0.53 mol) and POBr3 (229 g, 0.8 mol, 1.5 eq.) in dichloromethane (2 L) was heated under a nitrogen atmosphere in a 3 L 3-neck flask with overhead stirrer for 24 h. The mixture was filtered cold. The solid consisted of a 1:1 mixture of desired product 2 and unreacted starting material 4-methyl-5-nitropyridin-2-ol, the filtrate contained the desired product and unreacted POBr3. The solid (46 g) and fresh POBr3 were dissolved in dichloromethane and refluxed for 10 h. The liquid was decanted and combined with the filtrate of the first reaction. The combined solutions were concentrated to a volume of 1.5 L. The mixture was cooled in an ice bath and stirred while ice (500 g) was added to quench the excess POBr3. The organic layer was separated, and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried (magnesium sulfate) and concentrated. The product was recrystallized from hexanes. Yield: 104 g (90%). 1H NMR (300 MHz, CDCl3) δ ppm 2.63 (s, 3H) 7.52 (s, 1H) 8.95 (s, 1H). LCMS: (APCI, M-H)=215 and 217 u/e (bromine isotope pattern); Retention Time: 3.01 min; Purity by TIC: 95%; Purity by UV: 95%.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1/[CH:11]=[C:12](/[N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)\[C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].Cl.O>CN(C)C=O.ClCCCl>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1/[CH:11]=[C:12](/[N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)\[CH:13]([OH:18])[C:14]([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)C(=O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1
Reaction time: 21 h
Yield: 99.4 %

Procedure:
Reaction was carried out on a scale of ten times that of Example 6. In a nitrogen atmosphere, a solution of 0.681 g (0.018 mole) of sodium borohydride in 9.44 g of dimethylformamide was added dropwise at -20° C. to a suspension of 3.38 g (0.018 mole) of (+)-norephedrine hydrochloride in 62.8 g of 1,2-dichloroethane, and the temperature of the resulting mixture was raised from -20° C. to room temperature over 2 hours. Thereafter, a solution of 3.89 g (0.012 mole) of (E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one (E/Z=97.6/2.4) in 50.24 g of 1,2-dichloroethane was added, and stirring was carried out at room temperature for 21 hours and then at 40° C. for 3 hours. The reaction solution was decomposed with addition of 7.22 g of 10% hydrochloric acid and 2.1 g of water, and the organic layer was separated, washed with water and concentrated under reduced pressure to obtain 3.89 g of (-)-(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol as a crystal. The conversion of 99.9%, and the composition of the product obtained was: E-form alcohol, 95.8%; saturated alcohol, 0.2%; Z-form alcohol, 3.5%; and others, 0.5%. The enantiomer ratio of the E-form alcohol was: (-)-isomer, 85.2% and (+)-isomer, 14.8%. The optical yield was 70.4%.
Reaction SMILES: O[CH:2]1[O:6][C@H:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.[CH2:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([CH3:29])([F:28])[CH3:27])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCOC(C)=O>[CH2:18]([N:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([F:28])([CH3:29])[CH3:27])[CH2:2][CH2:3][CH2:4][C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=1)[OH:6])[CH3:19]
Reactant: CS(=O)(=O)Nc1ccc([C@@H]2CCC(O)O2)cc1
Reactant: CCNCCCCCC(C)(C)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCN(CCCCCC(C)(C)F)CCC[C@H](O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
N-[4-[(2S)-Tetrahydro-5-hydroxy-2-furanyl]phenyl]methanesulfonamide (10.0 g, 38.9 mmol) from Preparation 4 and N-ethyl-6-methyl-6-fluoroheptane amine (99% pure, 6.8 g, 38.9 mmol) from Preparation 7 were stirred with EtOAC (25 ml) in a flask for 1 hour. The slurry became clear solution, indicating formation of the iminium salt. Sodium triacetoxyborohydride (11.5 g, 54.4 mmol) was placed in a separate flask with EtOAc (50 ml). The mixture was cooled to 0° C. The first solution (iminium salt) was added slowly to the second mixture with vigorous stirring. The temperature was maintained at 0 to 4° C. After the addition was complete, the flask was rinsed with EtOAc (10 ml), and that was added also. The mixture was stirred overnight at 0° C. Water (100 ml) was added to quench the excess reagent, while the temperature was maintained at 0 to 4° C. While cooling was maintained, the pH was raised to 6.5 using a 10% aqueous sodium hydroxide solution. The layers were separated, and the aqueous was extracted with EtOAc (2×50 ml). The aqueous layer was then adjusted to pH 8.2, and the product was extracted with EtOAc (3×100 ml). The solvent was removed under reduced pressure to provide the title product as a colorless oil (14.9 g) in 92% yield. TLC 100% EtOAc, Rf=0.15.
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:6]Cl.[Si:12]([O:19][CH:20]([CH3:23])[CH:21]=[O:22])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[Cl-].[NH4+]>BrCCBr.C(OCC)C>[Si:12]([O:19][CH:20]([CH3:23])[CH:21]([OH:22])[CH2:6][C:5]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:3]([Cl:2])[CH:4]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: CC(C=O)O[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: CCOCC
Product: CC(O[Si](C)(C)C(C)(C)C)C(O)Cc1ccc(Cl)c(Cl)c1
Reaction time: 3 h
Yield: 33.7 %

Procedure:
2.45 g of magnesium (turnings) was added to 100 ml of ethyl ether, and a few drops of 1,2-dibromoethane were added thereto to activate magnesium. Then, 100 ml of an ethyl ether solution of 19.2 g of 3,4-dichlorobenzyl chloride was dropwise added thereto over a period of 3 hours with stirring under cooling with ice. Then, 50 ml of an ethyl ether solution of 6.11 g of 2-(tert-butyldimethylsilyloxy)propionaldehyde (which was produced by silylating ethyl 2-hydroxypropionate with tert-butyldimethylchlorosilane, followed by reducing with diisobutylaluminum hydride) was dropwise added to this solution over a period of 30 minutes with stirring under cooling with ice, and the mixture was stirred at the same temperature for 1 hour. Then, a saturated ammonium chloride aqueous solution was added thereto, and the mixture was further stirred at room temperature for 10 minutes. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.82 g (yield: 33%) of 3-(tert-butyldimethylsilyloxy)-1-(3,4-dichlorophenyl)-2-butanol.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:15]2[NH:16][C:17](=[O:30])[C:18]3[C:19](=[C:21]([CH2:28][CH3:29])[N:22]([CH2:24][CH2:25][O:26][CH3:27])[N:23]=3)[N:20]=2)[C:7](OCCCC)=[N:8][CH:9]=1)(=[O:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[CH3:41][O:42][CH2:43][CH:44]([OH:46])[CH3:45]>>[C:1]([C:4]1[CH:5]=[C:6]([C:15]2[NH:16][C:17](=[O:30])[C:18]3[C:19](=[C:21]([CH2:28][CH3:29])[N:22]([CH2:24][CH2:25][O:26][CH3:27])[N:23]=3)[N:20]=2)[C:7]([O:46][CH:44]([CH3:45])[CH2:43][O:42][CH3:41])=[N:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCCCOc1ncc(C(C)=O)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Reactant: COCC(C)O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCc1c2nc(-c3cc(C(C)=O)cnc3OC(C)COC)[nH]c(=O)c2nn1CCOC
Yield: 29 %

Procedure:
5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (Example 16) (150 mg, 0.36 mmol) was dissolved in 1-methoxypropan-2-ol (3 mL) and the solution heated at reflux for 5 minutes to degas the solution. After cooling potassium hexamethyldisilazide (360 mg, 1.80 mmol) was added and the solution reheated to reflux for 8 h. The cooled reaction mixture was evaporated to dryness and partitioned between ethyl acetate and water after 1N hydrochloric acid had been used to adjust the pH to 8. The organic phase was separated and washed with brine, dried (MgSO4) and evaporated. The crude product was purified by flash column chromatography (gradient elution from 100% dichloromethane 0.5% ammonia to 99% dichloromethane:1% methanol:0.5% ammonia) to give the title compound (45 mg, 29%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([NH:21][C:22](=[O:24])[CH3:23])[CH3:20])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2].[Na].[H-].[Na+].[CH3:28]I>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([N:21]([CH3:28])[C:22](=[O:24])[CH3:23])[CH3:20])=[CH:14][CH:13]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(C#Cc2ccc(CC(C)NC(C)=O)cc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: CCOc1ccc(C#Cc2ccc(CC(C)N(C)C(C)=O)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
32.1 mg (100 μmol) N-{2-[4-(4-ethoxy-phenylethynyl)-phenyl]-1-methyl-ethyl}-acetamide are added to an ice cooled mixture of 40.0 mg (1.00 mmol) sodium NaH and 2.50 mL THF. The reaction mixture is stirred at 0° C. for 10 min. Then 25.0 μL (0.40 mmol) methyliodide are added dropwise and the mixture is stirred at r.t. for 2 h. The reaction is quenched by the addition of water and sat. NH4Cl solution, and is extracted with DCM. The organic layer is separated and the solvent is removed in vacuo. The residue is lyophilised from ACN/water.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH3:17])[N:3]=1.[NH3:18]>CS(C)=O>[NH2:18][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH3:17])[N:3]=1
Reactant: Cc1nc(Cl)c(C#N)c(C)c1-c1ccccc1
Reactant: N
Solvent: CS(C)=O
Product: Cc1nc(N)c(C#N)c(C)c1-c1ccccc1
Temperature: 0 °C

Procedure:
2-Chloro-4,6-dimethyl-5-phenyl-3-pyridinecarbonitrile (8.3 grams) was dissolved in 110 ml DMSO and treated with gaseous NH3 at a temperature of 100°-110° C. After about 66 hours of heating and treatment with NH3, the reaction mixture was cooled and poured into ice water. A solid precipitate formed which was collected, washed with water, and then dried in an oven desicator. The identity of the desired product was confirmed by NMR.
Reaction SMILES: [C:1]([NH:9][C:10](N)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S-]C#N.[NH4+].C(Cl)(=O)C1C=CC=CC=1>ClCCl>[C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)NC(=O)c1ccccc1
Agent: N#C[S-]
Agent: [NH4+]
Solvent: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: O=C(N=C=S)c1ccccc1
Temperature: 12.5 °C

Procedure:
Benzoyl isothiocyanate was prepared as a starting material for benzoyl thiourea and derivatives thereof. In a 500 mL three-neck round-bottom flask (“RBF”), fitted with a condenser, thermo-probe, sealed system nitrogen purge, pressure-equilibrated addition funnel and mechanical stirrer, were placed solid ammonium thiocyanate (16.9 g, 0.22 mol) and dichloromethane (100 mL). The stirred mixture was cooled in an ice-water bath to a temperature of about 10-15° C. To the stirred mixture was added a solution of benzoyl chloride (28.4 g, 0.2 mol) in dichloromethane (50 mL) over a period of time of 20 minutes and the reaction mixture was warmed to a temperature near reflux (39° C.) for a period of time of 1 hour. Reaction completion was confirmed by FT-IR analysis. The solution was then cooled to a temperature of about 10-15° C. The solution can be concentrated to an oil to provide the benzoyl isothiocyanate. A boiling point of 128-131° C. at 15 mm Hg was measured.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[C:27]([Si:31]([C:43]([CH3:46])([CH3:45])[CH3:44])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[O:32][CH2:33][CH:34](O)[CH3:35])([CH3:30])([CH3:29])[CH3:28].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>O1CCCC1>[C:43]([Si:31]([C:27]([CH3:28])([CH3:30])[CH3:29])([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[O:32][CH2:33][CH:34]([CH3:35])[O:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2)([CH3:44])([CH3:45])[CH3:46]
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O)c2[nH]1
Reactant: CC(O)CO[Si](c1ccccc1)(C(C)(C)C)C(C)(C)C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OC(C)CO[Si](c3ccccc3)(C(C)(C)C)C(C)(C)C)c2[nH]1
Temperature: 50 °C
Reaction time: 18 h
Yield: 60.1 %

Procedure:
A mixture of ethyl 7-hydroxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (2.3 g), 1-{[di-tert-butyl(phenyl)silyl]oxy}propan-2-ol (3.9 g), 1,1′-(azodicarbonyl)dipiperidine (3.1 g), tributylphosphine (3.1 mL) and tetrahydrofuran (20 mL) was stirred at 50° C. for 18 hr. The reaction solution was allowed to cool to room temperature, and the precipitated white solid was filtered off. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography (ethyl acetate:hexane=0:100 to 30:70, volume ratio) to give the title compound (2.4 g, yield 57%) as an orange oil. MS 672 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[CH2:15](Br)[CH:16]=[CH2:17]>CN(C)C=O.CCCCCC.O.ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH2:17][CH:16]=[CH2:15])=[CH:4][CH:3]=1
Reactant: O=Cc1cc(O)ccc1Br
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: C=CCOc1ccc(Br)c(C=O)c1

Procedure:
To a dry 5 L three necked round bottom flask fitted with a condensor, temperature port, and stirrer, was added 6-bromo-meta hydroxyl benzaldehyde (2, 250 g, 1.23 moles) in dimethyl formamide (1250 mL). To the resulting solution was added anhydrous pottasium carbonate (538 g, 3.81 moles) under stirring. To this mixture was added slowly allyl bromide and reaction mixture maintained under stirring until the reaction was complete (monitored by thin layer chromatography (TLC) in hexane:dichlor-methane:ethyl acetate::7:4:0.5). After reaction completion dichloromethane and water were added and resulting solution stirred and layer separation carried out. The organic layer treated with 10% NaOH solution and layer separation repeated. The organic layer obtained was distilled out under reduced pressure to obtain 6-bromo-3-allyloxy benzaldehyde as a brownish liquid mass; yield 290 g (98%), purity by HPLC>95%. 1HNMR (CDCl3): 4.55-4.65 (s, 2H), 5.15-5.40 (m, 2H), 6.00-6.10 (m, 1H), 7.0-7.10 (dd, 1H), 7.18-7.24 (d, 1H), 7.52-7.56 (d, 1H), 10.1 (s, 1H, CHO)
Reaction SMILES: [OH-].[Na+].[N:3]1([C:9]2[N:10]=[C:11]([CH2:16][C:17]([NH:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25]C)=[O:24])=[O:18])[NH:12][C:13](=[O:15])[CH:14]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1>CO>[N:3]1([C:9]2[N:10]=[C:11]([CH2:16][C:17]([NH:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([OH:25])=[O:24])=[O:18])[NH:12][C:13](=[O:15])[CH:14]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(C(=O)O)c1
Temperature: 60 °C

Procedure:
1.8 ml of 2 M sodium hydroxide are added to a solution of 335 mg of methyl 3-({[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetyl}amino)-benzoate in 25 ml of methanol. The reaction mixture is heated at 60° C. for 2 h 30, and it is then concentrated under reduced pressure. The evaporation residue is taken up in 50 ml of water. The aqueous phase is extracted with ethyl acetate and then acidified (pH=6) by adding a 1N solution of hydrochloric acid. The precipitate formed is filtered off and then washed with ml of water, 5 ml of ethyl acetate and, finally, 20 ml of ethyl ether. The solid is dried under vacuum and 175 mg of 3-({[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetyl}amino)benzoic acid are thus obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [H-].[Na+].[CH:3]1([C:9]([O:11]CC)=O)[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4]1.[C:14](#[N:16])[CH3:15]>C1(C)C=CC=CC=1>[CH:3]1([C:9]([CH2:15][C:14]#[N:16])=[O:11])[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4]1
Reactant: CCOC(=O)C1CC=CCC1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CCC(=O)C1CC=CCC1
Temperature: 85 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a suspension of 1.25 g (2.60 mM) of 50% sodium hydride in 10 ml of toluene is added dropwise a solution of 2.01 g (1.30 mM) of ethyl 3-cyclohexenylcarboxylate 11 and 0.96 g (2.34 mM) of acetonitrile in 4 ml of toluene under nitrogen atmosphere in an hour and the mixture is stirred at 85° C. for 8 hours. After cooling, ice-cold water is added to the mixture. The aqueous phase is separated, washed with toluene, made acid with 10% hydrochloric acid and extracted with toluene. The extracted solution is washed with a dilute aqueous sodium hydrogencarbonate, and then with water, dried on magnesium sulfate and evaporated under reduced pressure. The resulting residue is chromatographed over silica gel and eluted with chloroform to give 1.91 g of the titled compound 8 as an yellow oil in 98.4% yield,
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:9]([OH:11])=O)=[N:5][CH:6]=[CH:7][CH:8]=1.[NH2:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1>S(Cl)(Cl)=O>[NH:14]1[C:13]([NH:12][C:9]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=2)=[O:11])=[N:17][N:16]=[N:15]1
Reactant: Nc1nnn[nH]1
Reactant: COc1cccnc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COc1cccnc1C(=O)Nc1nnn[nH]1
Yield: 8.6 %

Procedure:
1.45 g of 3-methoxy-2-pyridinecarboxylic acid, 30 ml of thionyl chloride and 0.95 g of 5-aminotetrazole are treated in the same manner as described in Example 1. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and water, whereby 0.18 g of N-(5-tetrazolyl)-3-methoxy-2-pyridinecarboxamide is obtained.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[NH:9][C:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:7])C>CO>[CH2:13]([C:10]1[NH:9][C:8]([C:6]([OH:7])=[O:5])=[CH:12][CH:11]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1ccc(Cc2ccccc2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(Cc2ccccc2)[nH]1

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 4.78 mmol) was added to a stirring, room temperature solution of 31 (0.2190 g, 0.955 mmol) in MeOH (2.4 mL, 0.4 M) under N2. The reaction was heated to reflux until the reaction was judged complete by HPLC (40 min). The product was concentrated and then dissolved in 1.9 mL H2O. 10% aq. HCl was added dropwise until the pH=2. The white solid that precipitated from the reaction was filtered off and washed with cold H2O. The solid was dried under vacuum overnight to obtain 32 as a pale pink, impure solid (0.0845 g). 32 was further purified by adding CHCl3, stirring, and filtering off pure white 32 (0.0445 g). Note. The undesired impurity has a retention time of 9.643 min by HPLC. Also, the 13C NMR of 32 at room temperature showed doublets for the peaks corresponding to the pyrrole carbons, benzyl carbon, and acid carbon. When the NMR probe was heated to 28° C., all doubled peaks collapsed into single peaks as reported below. 1H (CD3OD, 400 MHz): δ 11.04 (1H, broad s), 7.27-7.13 (5H, m), 6.80 (1H, d, J=3.4 Hz), 5.87 (1H, d, J=3.4 Hz) 3.93 (2H, s) ppm. 13C (CD3OD, 100 MHz): δ 164.52, 140.71, 139.04, 129.56, 129.42, 127.27, 122.77, 117.59, 109.66, 34.65 ppm. DEPT (CD3OD, 100 MHz): CH2 carbons: 34.65; CH carbons: 129.56, 129.42, 127.27, 117.59, 109.66 ppm. HPLC: 8.698 min.
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][Si](C(C)(C)C)(C)C.[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O.C1(C)C=CC=CC=1>[F:17][C:3]1[C:4]([CH2:5][OH:6])=[CH:14][CH:15]=[CH:16][C:2]=1[N:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Br)c1F
Reactant: CCOC(=O)C1CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(c2cccc(CO)c2F)CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
Under argon atmosphere, [(3-bromo-2-fluorobenzyl)oxy](tert-butyl)dimethylsilane (2 g) and ethyl piperidine-4-carboxylate (1.6 g) were mixed with toluene (30 ml), and Pd2(dba)3 (150 mg), BINAP (300 mg), and cesium carbonate (3.2 g) were added thereto, followed by stirring at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, and EtOAc was added thereto, followed by filtration using Celite as a filtration adjuvant. The filtrate was concentrated under reduced pressure, the residue was then mixed with THF (30 ml), and a 1 M TBAF/THF solution (12 ml) was added thereto, followed by stirring at room temperature for 1 hour. To the reaction mixture were added EtOAc and water, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain ethyl 1-[2-fluoro-3-(hydroxymethyl)phenyl]piperidine-4-carboxylate (1.02 g).