Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:27])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[CH2:11][CH2:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH3:26][O:25][C:18]1[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=1[CH2:16][N:10]1[C:9](=[O:27])[C:8]2[CH:7]=[N:6][C:5]([C:3]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:4])=[C:14]([OH:15])[C:13]=2[CH2:12][CH2:11]1
Reactant: COC(=O)c1ncc2c(c1O)CCN(Cc1ccc(OC)cc1OC)C2=O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(CN2CCc3c(cnc(C(=O)NCC(=O)O)c3O)C2=O)c(OC)c1
Temperature: 25 °C
Yield: 36.8 %

Procedure:
A mixture of 7-(2,4-dimethoxy-benzyl)-4-hydroxy-8-oxo-5,6,7,8-tetrahydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (19 mg, 0.051 mmol), glycine (510 mg, 6.79 mmol), and NaOMe solution (10 mL, 5.11, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water, and 1 M HCl was added with vigorous stirring until pH about 1. The organic layer was dried over MgSO4 and concentrated. The crude was first purified by silica gel chromatography (5-80% EtOAc/hexanes+2% AcOH), and the product isolated was then dissolved in saturated NaHCO3. The aqueous solution was washed with ether, acidified to pH about 1 with 4 M HCl, and the resulting precipitate was collected by filtration and dried under vacuum to give 7.8 mg of the title compound. MS: (+) m/z 416.27 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](O)=O>>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[NH:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: O=C(O)c1cccs1
Reactant: Nc1ccncc1N
Product: c1csc(-c2nc3cnccc3[nH]2)c1
Temperature: 160 °C
Yield: 24.6 %

Procedure:
A mixture of 1.1 g (10 mM) of 3,4-diaminopyridine, 1.3 g (10 mM) of thiophene-2-carboxylic acid, and 50 g of polyphosphoric acid was heated at 160° C. for four hours. The reaction mixture was added to 100 g of ice and stirred for fifteen minutes. The precipitated solid was collected by filtration and dried to give 500 mg of 2-(2-thienyl)-1H-imidazolo[4,5-c]pyridine; mp 265°-268° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][N:11]2[C:12](=[O:23])[C:13]3[C:18]([C:10]2=[C:9]1[CH3:26])=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][N:11]2[C:12](=[O:23])[C:13]3[C:18]([CH:10]2[CH:9]1[CH3:26])=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:21])([F:20])[F:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1=C2c3cccc(C(F)(F)F)c3C(=O)N2CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC1C2c3cccc(C(F)(F)F)c3C(=O)N2CCN1C(=O)OC(C)(C)C
Reaction time: 12 h
Yield: 95 %

Procedure:
To a solution of N-(t-butoxycarbonyl)-3,4-dihydro-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (0.20 g, 0.54 mmol) in methanol (10 mL) was added palladium on carbon (20 mg, 10 wt %; Aldrich). The resulting mixture was degassed (vacuum then argon, ×3) and subjected to a hydrogen atmosphere (60 psi) for 12 hr. The mixture was then filtered, and the filtrate was concentrated. The resulting residue was purified by flash column chromatography (SiO2, 0–50% ethyl acetate in hexanes) to afford N-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (0.19 g, 94%) as a white solid. MS (ESI) 371 (M+H).
Reaction SMILES: I.CS[C:4](=[NH:18])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH3:19][O:20][CH2:21][CH2:22][NH2:23]>C(O)C>[CH3:19][O:20][CH2:21][CH2:22][NH:23][C:4]([NH2:18])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CSC(=N)Nc1ccccc1N1CCOCC1
Reactant: COCCN
Agent: I
Solvent: CCO
Product: COCCNC(N)=Nc1ccccc1N1CCOCC1
Temperature: 25 °C
Reaction time: 336 h

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (7.6 g), 2-methoxyethylamine (2 ml) and ethanol (45 ml) was stirred at ambient temperature for 14 days to give 1-(2-methoxyethyl)-2-(2-morpholinophenyl)guanidine (m.p. 125°-128° C.) which was recrystallised from 1,2-dimethoxyethane and converted into its fumarate salt (m.p. 136°-138° C.) which was recrystallised from a 1:2 mixture of methanol and ether.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][N:16]([C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=5[CH2:39][C:40](O)=[O:41])=[CH:29][CH:28]=4)=[O:26])[C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.CNC.[NH3:46]>>[NH2:46][C:40](=[O:41])[CH2:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:30]1[CH:31]=[CH:32][C:27]([C:25]([N:16]2[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH2:19][N:20]3[C:11]([C:9]([NH:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:10])=[CH:12][CH:13]=[C:14]3[CH2:15]2)=[O:26])=[CH:28][CH:29]=1
Reactant: O=C(O)Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Reactant: N
Agent: CNC
Product: NC(=O)Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Yield: 58 %

Procedure:
The title compound was prepared in essentially the same manner as Example 68, replacing 4′-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl}-1,1′-biphenyl-2-carboxylic acid with (4′-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl}-1,1′-biphenyl-2-yl)acetic acid of Example 36, and dimethylamine with ammonia. Purification by flash chromatography using a solvent gradient of 2 to 8% methanol in dichloromethane gave the title compound (0.138 g, 58%) as a white solid.
Reaction SMILES: [CH:1]([C:4]1[C:12]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[CH:1]([C:4]1[C:12]([CH:13]([OH:17])[CH:14]([CH3:16])[CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)C(=O)c1c(C(C)C)nn2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1nn2ccccc2c1C(O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.4 %

Procedure:
To a solution of 9.2 g of 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one in 25 ml of MeOH was added 1.5 g of NaBH4. The solution was stirred at RT overnight. 10.25 g of oily 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-ol was obtained after workup. 1.05 g of 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-ol in 10 ml of benzene was treated with 0.92 g of PCl5 and 1 ml of pyridine with stirring for 3 hours at RT. The crude 2-isopropyl-3-(2-methylprop-1-enyl)pyrazolo[1,5-a]pyridine obtained was purified on an Al2O3 column to furnish 255 mg of pure compound. Compound 1049.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C@@H:24]3[C@H:29]([C:30]([OH:32])=O)[CH2:28][CH:27]=[CH:26][CH2:25]3)(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:33][N:34]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.NO>CN(C)C=O>[OH:33][NH:34][C:30]([C@H:29]1[C@@H:24]([NH:23][S:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)=[CH:19][CH:18]=2)(=[O:21])=[O:22])[CH2:25][CH:26]=[CH:27][CH2:28]1)=[O:32]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CC=CC[C@H]3C(=O)O)cc2)c2ccccc2n1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CC=CC[C@H]3C(=O)NO)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.4 %

Procedure:
To a solution of 181.0 mg (0.4 mmol) of cis-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohex-3-ene-1-carboxylic acid and 162.2 mg (1.2 mmol) of 1-hydroxybenzotriazole in 3 mL of N,N-dimethylformamide at 0° C. was added 230.0 mg (1.2 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. The reaction mixture was stirred at room temperature for 1.5 h. To the reaction mixture at 0° C. was added 0.2 mL of 50% hydroxylamine solution. The resulting reaction mixture was stirred at room temperature for 18 h. The volatile materials were removed under reduced pressure, below 40° C. The residue was dissolved in 80 mL of ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution (5×30 mL) and a saturated sodium chloride solution (2×30 mL) and dried over sodium sulfate. After removal of the ethyl acetate, the residue was triturated with a 7:3 mixture of hexane:ethyl acetate to give 71.9 mg of cis-N-hydroxy-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohex-3-ene-1-carboxamide as a solid in 38% yield. MS: 468.1 (M+H)+
Reaction SMILES: B(Br)(Br)Br.ClCCl.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:23]C)=[C:13]([CH:22]=1)[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl.C(OCC)(=O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([OH:23])=[C:13]([CH:14]=[CH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:22]=1
Reactant: COc1ccc(Cl)cc1C=Cc1ccccc1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Oc1ccc(Cl)cc1C=Cc1ccccc1
Reaction time: 12 h
Yield: 49.4 %

Procedure:
Under argon atmosphere, 1 mol/L boron tribromide/dichloromethane solution (0.5 mL, 0.5 mmol) was added to a solution of 5-chloro-2-methoxy-β-phenylstyrene (80 mg, 0.3 mmol) in dichloromethane (2 mL) at room temperature, and the mixture was stirred for 12 hours. The reaction mixture was diluted with ethyl acetate (15 mL), and after it was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give the title compound (34.2 mg, 45.4%) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][CH:37]([NH:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH3:38]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:43][CH2:42][CH2:41][CH2:40][NH:39][CH:37]([CH3:38])[CH3:36])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: CC(C)NCCCN
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Solvent: ClCCl
Product: CCCNC(=O)c1ccc(C)c(-c2nc(NCCCNC(C)C)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Yield: 39.3 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (30 mg, 0.06 mmol) in DCM (5 mL) was added N-(1-methylethyl)-1,3-propanediamine (0.042 mL, 0.30 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (13 mg, 39%). LC-MS m/z 554 (M+H)+; 1H-NMR (MeOD) δ 1.00 (m, 9H), 1.65 (m, 4H), 2.31 (s, 3H), 2.50 (m, 2H), 2.78 (m, 2H), 3.16 (m, 2H), 3.43 (m, 1H), 4.11 (s, 2H), 7.17 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.86 (d, 1H).
Reaction SMILES: [OH:1][C:2]1([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C1C(=O)N([Br:25])C(=O)C1.[O-]S([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[Br:25][C:15]1[S:14][C:13]([C:2]2([OH:1])[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)=[N:17][CH:16]=1
Reactant: CCOC(=O)C1CCC(O)(c2nccs2)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(O)(c2ncc(Br)s2)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 83.7 %

Procedure:
The product of Step 1 (23.5 g, 92 mmol) was dissolved in DMF (94 mL) and then treated with NBS (19.66 g, 110 mmol) and stirred at RT for 10 hours. The reaction was then treated with Na2SO3 (5.8 g, 465 mmol) in H2O (150 mL) and then extracted with EtOAc (100 mL) and the oil was purified by flash chromatography on silica gel to afford ethyl 4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxycyclohexanecarboxylate as an oil (31 g, 77 mmol), which was subjected to chiral chromatography to afford ethyl cis-4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxycyclohexane-carboxylate as an oil (15 g, 33 mmol). MS ESI: [M+H]+ m/z 333.
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH:14]=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:16]([Mg]Br)=[CH2:17]>O1CCCC1>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[CH:14]([OH:15])[CH:16]=[CH2:17])=[O:2])([CH3:6])([CH3:5])[CH3:7]
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reaction time: 5 h
Yield: 65 %

Procedure:
To a stirred 0° C. solution of Boc-leucinal (3.00 g, 13.9 mmol) in dry tetrahydrofuran (THF) (70 ml) was added vinyl magnesium bromide (35 ml of a 1.0M solution in THF). After 5 hours, the mixture was quenched with 1.0M NH4Cl (50 ml). Most of the THF was evaporated in vacuo and the residue was extracted with ether several times. The combined extracts were washed (brine), dried (Na2SO4), filtered, and evaporated to give the desired product as a 3:2 mixture of hydroxy diastereomers in 65% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(C)(C)O[C:9]2=[O:15])=[CH:4][CH:3]=1.Cl.[NH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=1.C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[C:9]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=2)=[O:15])=[CH:6][CH:7]=1
Reactant: COc1cc(CCN)ccc1O
Reactant: CC1(C)OC(=O)C(c2ccc(Br)cc2)O1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cc(CCNC(=O)C(O)c2ccc(Br)cc2)ccc1O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-(4-Bromo-phenyl)-2,2-dimethyl-[1,3]dioxolan-4-one (15 g, 55 mmol) is dissolved in 50 ml of ethanol. 4-(2-Amino-ethyl)-2-methoxy-phenol hydrochloride (14 g, 69 mmol) and triethylamine (7.0 g, 69 mmol) are added and the mixture is stirred for 72 hours at room temperature. The solvent is removed in vacuum and the residue is extracted with ethyl acetate and 1N hydrochloric acid. The aqueous layer is extracted twice with ethyl acetate and the combined organic phases are washed with brine, dried over sodium sulfate and evaporated. The remaining 2-(4-bromo-phenyl)-2-hydroxy-N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-acetamide is purified by chromatography on silica gel. 1H-NMR (300 MHz, CDCl3): 2.71 (t, 2H, CH2CH2), 3.54 (t, 2H, CH2CH2), 3.80 (s, 3H, OCH3), 5.59 (s, 1H, CHOH), 6.16 (bs, 1H, NH), 6.52-7.35 (m, 7H, CH arom.).
Reaction SMILES: I[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([O:10][CH3:11])[CH:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])[C:7]([CH:8]=[O:9])=[CH:6][N:5]=1
Reactant: COc1cc(I)c(C=O)cn1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: COc1cc(C#C[Si](C)(C)C)c(C=O)cn1
Yield: 67 %

Procedure:
4-Iodo-6-methoxynicotinaldehyde (0.41 g, 1.6 mmol), trimethylsilylacetylene (0.35 mL, 2.8 mmol), PdCl2(PPh3)2 (catalytic amount), CuI (catalytic amount), TEA (2 mL) and THF (10 mL) were stirred at 60° C. for 2 h. The volatiles were evaporated and the residue was taken up in water and extracted with ether. The organic phase was dried, filtered and concentrated. Purification by column chromatography with EtOAc-heptanes (1:3) as eluent gave 0.25 g (68% yield) of 6-methoxy-4-[(trimethylsilyl)ethynyl]nicotinaldehyde.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]=[C:11]=[O:12].[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][OH:18]>>[Cl:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:10][C:11](=[O:12])[O:18][CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([OH:13])[CH:15]=1
Reactant: Cc1cccc(N=C=O)c1CCl
Reactant: OCc1cccc(O)c1
Product: Cc1cccc(NC(=O)OCc2cccc(O)c2)c1CCl
Temperature: 75 °C
Yield: 29.7 %

Procedure:
A mixture of 2-chloromethyl-1-isocyanato-3-methylbenzene (2 g) and 3-hydroxybenzyl alcohol (1.6 g) is warmed to 75° C. in an oil bath for 1 h and then purified by chromatography on silica gel (eluent: dichloromethane/methanol 19:1). 1 g (30%) of the title compound is obtained as a crude product in the form of an amorphous solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([OH:38])[CH:33]=1.[H-].[Na+]>CN1CCCC1=O>[CH3:21][C:5]1[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[N:7][C:2]([O:38][C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)=[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:4]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Oc2cccnc2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of example 20, [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with pyridin-3-ol and sodium hydride in 1-methyl-pyrrolidin-2-one at reflux to give the title compound as colorless oil. MS: 511.4 (MH+).
Reaction SMILES: [C:1]1([C:7]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:22](I)[CH3:23]>CN(C)C=O>[CH2:22]([N:9]1[CH:10]=[C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:12](=[O:13])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8]1)[CH3:23]
Reactant: O=c1c(-c2ccccc2)c[nH]nc1-c1ccccc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(-c2ccccc2)c(=O)c(-c2ccccc2)n1
Reaction time: 0.5 h

Procedure:
A 1 g. portion of the product of Example 2 was suspended in 40 ml. of dimethylformamide, the suspension was cooled under nitrogen to 0°-5°C., and an 0.3 g. portion of 50 percent NaH in oil was added. The reaction mixture was stirred for 30 minutes, and 3 ml. of ethyl iodide was added. The mixture was stirred at 0°-5°C. for 24 hours, and the mixture was then filtered to separate the precipitated product. The dried product was 1.0 g. of 1-ethyl-3,5-diphenyl-4(1H)-pyridazinone, m.p. 124°-25°C., which was identified by nuclear magnetic resonance analysis, infrared analysis, and mass spectrometry.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]1[C:17]([C:18]2[CH:27]=[CH:26][C:21]([C:22]([NH:24][NH2:25])=[O:23])=[CH:20][CH:19]=2)=[N:16][N:15]=[N:14]1>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:25][NH:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:18]([C:17]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:19][CH:20]=1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: NNC(=O)c1ccc(-c2nnn[nH]2)cc1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(Br)cc2C1=NNC(=O)c1ccc(-c2nnn[nH]2)cc1
Temperature: 100 °C
Yield: 53 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-bromo-1H-indole-2,3dione in acetic acid was added 4-(1H-tetrazol-5-yl)benzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 29 mg of the title compound (53%) as a orange Solid in 89.1% purity by HPLC (Rt: 3.29, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[CH2:3][N:4]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:5]2.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>C(#N)C.O>[OH:1][C@H:2]1[C@H:6]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1
Reactant: O=C(OCc1ccccc1)N1CC2OC2C1
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=C(OCc1ccccc1)N1C[C@@H](O)[C@H](Oc2ccccc2)C1

Procedure:
21.9 g (0.1 mol) of 3,4-epoxy-1-carbobenzyloxypyrrolidine [S. Oida et al., Chem. Pharm. Bull., 18 (12), 2478 (1970)] are dissolved, together with 18.8 g (0.2 mol) of phenol and 100 ml of 2 N sodium hydroxide solution (0.2 mol) in 300 ml of acetonitrile. The reaction mixture is heated under reflux for 5 hours and after cooling is diluted with 600 ml of water and extracted by shaking with methylene chloride. The organic phase is washed with 2 N sodium hydroxide solution and then with water, dried over sodium sulphate and evaporated under a water pump vacuum and trans-3-hydroxy-4-phenoxy-1-carbobenzyloxy-pyrrolidine is obtained in the form of a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[CH2:11]([N:18]1[CH2:26][CH:25]2[CH:20]([CH2:21][CH2:22][CH2:23][C:24]2=[O:27])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[CH2:11]([N:18]1[CH2:26][CH:25]2[CH:20]([CH2:21][CH2:22][CH2:23][C:24]2([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[OH:27])[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccccc1[Mg]Br
Reactant: O=C1CCCC2CN(Cc3ccccc3)CC12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccccc1C1(O)CCCC2CN(Cc3ccccc3)CC21
Yield: 84.1 %

Procedure:
To a suspension of 55.63 g of 2-methoxyphenylmagnesium bromide in 250 cm3 of tetrahydrofuran is added dropwise, at room temperature and with stirring, a solution of 20.16 g of (3aRS,7aSR)-2-Benzyl-4-perhydroisoindolone in 250 cm3 of tetrahydrofuran. The reaction mixture is stirred at room temperature for 18 hours, treated with 300 cm3 of saturated aqueous ammonium chloride solution, taken up in 200 cm3 of ethyl ether and washed with 300 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 8.8 cm, height 41 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 1000 cm3 fractions. Fractions 4 to 27 are combined and then concentrated to dryness under reduced pressure (2.5 kPa). 24.96 g of (3aRS,4RS,7aSR)-2-benzyl-4-(2-methoxyphenyl)-4-perhydroisoindolol are obtained in the form of white crystals melting at 106° C.