Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][NH:4][C:3]1=[O:14].Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.O.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]>[CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[CH2:5][N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)[C:3]1=[O:14]
Reactant: CN1C(=O)NCC1C(=O)OC(C)(C)C
Reactant: Cc1cccc(Br)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(N2CC(C(=O)OC(C)(C)C)N(C)C2=O)n1
Temperature: 25 °C
Yield: 56.3 %

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (300 mg, 1.5 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2-bromo-6-methylpyridine (258 mg, 1.5 mmol) in 1,4-dioxane (10 ml) was treated with cesium carbonate (733 mg, 2.25 mmol), Xantphos™ (65.1 mg, 0.113 mmol) and tris(dibenzylideneacetone)dipalladium(0) (34.3 mg, 0.038 mmol) and the mixture was heated under reflux under argon for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 3-methyl-1-(6-methyl-2-pyridinyl)-2-oxo-4-imidazolidinecarboxylate (246 mg, 56%). LC/MS [M+H]+=292. (ii) A solution of 1,1-dimethylethyl 3-methyl-1-(6-methyl-2-pyridinyl)-2-oxo-4-imidazolidinecarboxylate (246 mg, 0.84 mmol) in TFA/DCM (1:2, 6 ml) was stirred at room temperature for 6 hours. The solution was evaporated and the residue was dried to give 3-methyl-1-(6-methyl-2-pyridinyl)-2-oxo-4-imidazolidinecarboxylic acid TFA salt (assume ˜0.84 mmol) which was used in the next step. LC/MS [M+H]+=236.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C@@H:13]1[C@H:20]([O:21][C:22](=[O:28])[NH:23][C:24](=[O:27])[CH2:25][Cl:26])[CH2:19][CH2:18][C@@:15]2([O:17][CH2:16]2)[C@@:14]1([OH:33])[C:29]([CH3:32])=[CH:30][CH3:31]>ClCCl>[Br:12][C@@H:13]1[C@H:20]([O:21][C:22](=[O:28])[NH:23][C:24](=[O:27])[CH2:25][Cl:26])[CH2:19][CH2:18][C@@:15]2([O:17][CH2:16]2)[C@@:14]1([OH:33])[C:29]1([CH3:32])[CH:30]([CH3:31])[O:9]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC=C(C)[C@@]1(O)[C@H](Br)[C@H](OC(=O)NC(=O)CCl)CC[C@]12CO2
Solvent: ClCCl
Product: CC1OC1(C)[C@@]1(O)[C@H](Br)[C@H](OC(=O)NC(=O)CCl)CC[C@]12CO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 30.5 %

Procedure:
1.12 g (4.74 mmol) of 72% 3-chloroperbenzoic acid are added to a solution of 0.46 g (1.16 mmol) of the compound obtained in Example 1 in 30 ml of dichloromethane. The reaction mixture is stirred at room temperature for 5 hours. The solid formed during the course of the reaction is filtered off. After conventional treatment of the organic phase and purification by chromatography on silica gel twice (eluant: hexane/ethyl acetate, 3:2), 0.146 mg (0.354 mmol) of the expected compound is obtained in the form of a mousse.
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8]Br)=[CH:5][CH:4]=1.[CH2:12](Br)[CH:13]=[CH2:14]>CCOCC>[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][CH2:14][CH:13]=[CH2:12])=[CH:5][CH:4]=1
Reactant: Clc1ccc(CCBr)cc1
Reactant: C=CCBr
Agent: [Mg]
Solvent: CCOCC
Product: C=CCCCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To a flame-dried flask containing 7.75 g of magnesium turnings under ether was added 4-chlorophenethyl bromide (70 g) in anhydrous ether (250 mL) at such a rate as to maintain a gentle reflux. When the addition was complete, the mixture was heated under reflux for an additional hour and then treated dropwise over one hour with allyl bromide (27.6 mL, 38.6 g) in ether (75 mL) maintaining a gentle reflux. The resulting mixture was stirred overnight at room temperature and then poured onto 600 mL of ice-cold dilute sulfuric acid. The product was extracted with ethyl acetate and the combined extracts were washed with dilute aqueous potassium carbonate, dried (MgSO4) and evaporated. The resulting brown oil was distilled under reduced pressure to give 43 g of 5-(4-chlorophenyl)pent-1-ene, b.p. 74°-80° (2 mmHg) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][CH2:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([C:25]3[S:29]/[C:28](=[N:30]\C(=O)OCC=C)/[N:27]([CH3:37])[CH:26]=3)[CH2:21][CH2:20]1)=[O:18])(=[O:14])=[O:13])[CH:6]=[CH:5]2.CN1C(=O)CC(=O)N(C)C1=O>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][CH2:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([C:25]3[S:29][C:28](=[NH:30])[N:27]([CH3:37])[CH:26]=3)[CH2:21][CH2:20]1)=[O:18])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: C=CCOC(=O)/N=c1\sc(C2CCN(C(=O)CCS(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)cn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: C1CCOC1
Product: Cn1cc(C2CCN(C(=O)CCS(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)sc1=N
Yield: 62.7 %

Procedure:
To a solution of allyl (2Z)-5-(1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-4-piperidinyl)-3-methyl-1,3-thiazol-2(3H)-ylidenecarbamate (0.60 g) obtained in Example 57d) in THF, 1,3-dimethylbarbituric acid (0.25 g) and tetrakis(triphenylphosphine)palladium (0.06 g) were added thereto and mixed for 12 hours under argon atmosphere. The insolubles were filtered off, and the filtrate was concentrated. The residue was purified with a silica gel column to give the title compound (0.32 g) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:22])([C:18]([F:21])([F:20])[F:19])[CH2:3][CH2:4][CH2:5]OC1C=CC=C(C)C=1S([O-])(=O)=O.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:1][C:2]([F:22])([C:18]([F:21])([F:20])[F:19])[CH2:3][CH2:4][CH2:5][NH:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cccc(OCCCC(F)(F)C(F)(F)F)c1S(=O)(=O)[O-]
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: FC(F)(F)C(F)(F)CCCNCc1ccccc1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
4,4,5,5,5-Pentafluoropentyloxytoluenesulfonate (1 g, 3 mmol) was dissolved in acetonitrile (10 ml). Benzylamine (646 mg, 6 mmol) and potassium carbonate (829 mg, 6 mmol) were added. The mixture was refluxed for 10 h under nitrogen atmosphere. When the reaction was completed, the mixture was cooled to room temperature. Water was added to reaction solution which was then extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to column chromatography (dichloromethane:ethyl acetate=19:1) to give 590 mg (yield: 74%) of the title compound as a pale yellow liquid.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:9][N:8]([C@@H:10]2[O:22][C@H:21]([CH2:23][O:24]C(=O)C)[C@@H:16]([O:17]C(=O)C)[C@H:11]2[O:12]C(=O)C)[C:7](=[O:28])[N:6]=1)(=[O:3])[CH3:2].C[O-].[Na+].O>CO>[C:1]([NH:4][C:5]1[S:9][N:8]([C@@H:10]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:16]([OH:17])[C@H:11]2[OH:12])[C:7](=[O:28])[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(=O)n([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)s1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)Nc1nc(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)s1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 5-acetamido-2-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1,2,4-thiadiazol-3-one (4, 0.5 g, 0.0011 mole) in anhydrous methanol (25 ml) was added 1N sodium methoxide in methanol, till the pH of the solution was 8.5 and the resulting solution was stirred at ambient temperature for 2.5 hr. Within 40 min the secondary O-acetyl groups were removed and by the end of 2 hr all the O-acetyl groups were removed as judged by tlc. After the O-deacetylation was complete, the sodium ions were removed by stirring the reaction mixture with Amberlite IRC-50 (H+) resin (7.0 g, dry weight) for 15 min before the neutral solution, free from resin, was evaporated to dryness. The residual gum was chromatographed on a silica gel column (3 × 27 cms) using ethyl acetate:water:n-propanol (4:2:1), v/v, upper phase). The appropriate fractions were pooled, solvent evaporated and the residue crystallized from aqueous ethanol to yield 0.23 g (67.0%), m.p. 204°-205° (dec.); [α]D25 -50.1° (c 1.0, water); 1H nmr (Me2SO-d6) δ2.28 (s, 3H, --NAc), 5.65 (d, J=5.0 Hz, C1'H); uv λmax (pH 1) 235 nm (ε 10,600), 275 (3500); λmax (pH 7) 254 nm (ε 9900), 277 sh (5400); λmax (pH 11) 254 nm (ε 12,700), 277 sh (5,900).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=3)[N:6]=2)[CH2:2]1.[CH3:17][C:18]1[N:19]=[C:20]2[N:25]=[C:24]([C:26]3[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=3)[C:23]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[C:22]([NH:40][CH:41]([CH3:43])[CH3:42])[N:21]2[CH:44]=1>>[CH:41]([NH:40][C:22]1[N:21]2[CH:44]=[C:18]([CH3:17])[N:19]=[C:20]2[N:25]=[C:24]([C:26]2[CH:33]=[CH:32][C:29]([CH2:30][N:1]3[CH2:4][CH:3]([C:5]4[N:6]=[C:7]([C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=5)[NH:8][N:9]=4)[CH2:2]3)=[CH:28][CH:27]=2)[C:23]=1[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([CH3:43])[CH3:42]
Reactant: Cc1cn2c(NC(C)C)c(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Reactant: Cc1cccc(-c2n[nH]c(C3CNC3)n2)n1
Product: Cc1cccc(-c2nc(C3CN(Cc4ccc(-c5nc6nc(C)cn6c(NC(C)C)c5-c5ccccc5)cc4)C3)n[nH]2)n1

Procedure:
The compound is prepared in analogy to example 64. 399.3 mg 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-6-methylpyridine×2HCl (60% pure) are reacted with 280 mg (0.76 mmol) 4-(2-methyl-5-isopropylamino-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-benzaldehyde to yield finally after HPLC purification 10.4 mg (2.34%) of the desired compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH2:7].C(N(CC)CC)C.[CH3:15][O:16][C:17]1[CH:26]=[CH:25][C:20]([CH2:21][N:22]=[C:23]=[S:24])=[CH:19][CH:18]=1>CN(C)C=O.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:23]([NH:22][CH2:21][C:20]1[CH:25]=[CH:26][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[S:24]
Reactant: NCc1ccco1
Reactant: COc1ccc(CN=C=S)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(CNC(=S)NCc2ccco2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.5 %

Procedure:
Furan-2-ylmethylamine (190 mg) was dissolved in dimethylformamide (5 ml) and to the solution were added triethylamine (200 mg) and 4-methoxybenzylisothiocyanate (360 mg), followed by stirring at room temperature for 24 hours. Then, the resulting mixture was diluted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure. The residue was purified by column-chromatography (hexane/ethyl acetate=1/1) to yield the compound 16-1 (0.5 g, 90%) as a liquid.
Reaction SMILES: Cl[CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[C:11]([O:18][CH2:19][CH3:20])[CH:10]=1)[C:3](OCC)=[O:4].[NH2:21][C:22]([NH2:24])=[S:23].C([O-])(=O)C.[Na+]>COCCO>[CH2:19]([O:18][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[O:15][CH2:16][CH3:17])[CH2:8][CH:2]1[S:23][C:22](=[NH:21])[NH:24][C:3]1=[O:4])[CH3:20]
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC)c(OCC)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: COCCO
Product: CCOc1ccc(CC2SC(=N)NC2=O)cc1OCC
Temperature: 110 °C
Reaction time: 15 h
Yield: 65.5 %

Procedure:
In 120 ml of ethylene glycol monomethyl ether is dissolved 11.7 g of ethyl 2-chloro-3-(3,4-diethoxyphenyl)propionate, followed by addition of 4.4 g of thiourea and 3.8 g of sodium acetate. The mixture is stirred at 110° C. for 15 hours. The solvent is distilled off under reduced pressure, water is added to the residue and extraction is carried out with ethyl acetate. The extract is washed with water, dried (over MgSO4) and distilled to remove the ethyl acetate. The above procedure provides 7.5 g (65.2%) of 5-(3,4-diethoxybenzyl)-2-iminothiazolidin-4-one as crystals melting at 171°-172° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][N:15]=2)[C:10]([CH:17]=[O:18])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CCO>[OH:18][CH2:17][C:10]1[C:11]2[C:16](=[N:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:9]=1
Reactant: CC(C)(C)OC(=O)n1cc(C=O)c2cccnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)n1cc(CO)c2cccnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-3-formyl-7-azaindole (2.5 g, 10.2 mmol) in 16 mL EtOH was added NaBH4 (115 mg, 3.05 mmol). The reaction was stirred at ambient temperature for 4 h, concentrated and triturated with 1N NaOH. The basic solution was extracted with ether and ethylacetate. The organics were washed with water and brine, then dried over Na2SO4, filtered and concentrated. The filtrate was concentrated and purified by silica gel chromatography (50% ethylacetate/hexanes) to give tert-butyl 3-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (44%). LCMS [M-tert-Bu]+=191.1.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11](O)(=[O:15])[C:12](O)=[O:13]>Cl.O>[CH3:8][C:7]1[CH:6]=[C:5]2[C:4](=[CH:3][C:2]=1[CH3:1])[NH:10][C:12](=[O:13])[C:11](=[O:15])[NH:9]2
Reactant: Cc1cc(N)c(N)cc1C
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: Cc1cc2[nH]c(=O)c(=O)[nH]c2cc1C
Temperature: 25 °C
Yield: 938.5 %

Procedure:
A mixture of 2.72 g (2.0 mmol) of 4,5-dimethyl-1,2-phenylenediamine and 1.92 g (21.3 mmol) of oxalic acid in 30 mL of 2N HCl was refluxed for 2.5 h and cooled to room temperature. The mixture was diluted with 20 mL of H2O, filtered, washed with water, and dried to leave a pale-brown solid 3.57 g (94%); mp>250° C.; 1H NMR (DMSO-d6), 2.161 (s,6), 6.869 (s,2), 11.78 (s,2).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].B(F)(F)F.CCOCC.[CH3:14][O:15][C:16]([C@@H:18]1[CH2:22][CH2:21][CH:20](OC(=O)C)[N:19]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:17]>CCOCC>[CH3:14][O:15][C:16]([C@@H:18]1[CH2:22][CH2:21][C@@H:20]([CH2:1][CH3:2])[N:19]1[C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])=[O:17]
Reactant: CC[Mg]Cl
Reactant: COC(=O)[C@@H]1CCC(OC(C)=O)N1C(=O)OC(C)(C)C
Agent: FB(F)F
Solvent: CCOCC
Product: CC[C@@H]1CC[C@@H](C(=O)OC)N1C(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of copper bromide-dimethylsulfide complex (2.15 g, 10.4 mmol) in dry Et2O (40 mL), cooled to −40° C., was added dropwise ethyl magnesium chloride (2M in Et2O; 5.22 mL, 10.4 mmol; Aldrich 300330) under an argon atmosphere. After stirring for 45 min, the mixture was cooled to −78° C., followed by dropwise addition of boron trifluoride etherate (1.32 mL, 10.4 mmol) and stirring for 15 min. Then, a solution of (S)-5-acetoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.00 g, 3.48 mmol, prepared as described in Scheme B1) in dry Et2O (10 mL) was added dropwise to result in a black suspension. The reaction mixture was stirred for 15 min and subsequently was allowed to warm up to RT over a period of 1 h. The reaction was quenched by addition of a (1:1)-mixture of a saturated aqueous NH4Cl solution and a concentrated aqueous NH3 solution (10 mL), followed by stirring for 30 min. The organic layer was separated, and the aqueous phase was extracted with Et2O (2×50 mL). The combined organics were dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/c-hexane 2:8) to afford the title compound (contained less than 10% of the minor (2S,5S)-diastereoisomer according to 1H-NMR). TLC Rf (EtOAc/c-hexane 1:3)=0.48.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([C:6](N2C=NC=C2)=[O:7])[CH:2]=1.[C:13]([O:17][C:18](=[O:25])[NH:19][CH:20]1[CH2:24][CH2:23][NH:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14]>C1COCC1.C(Cl)Cl>[C:13]([O:17][C:18](=[O:25])[NH:19][CH:20]1[CH2:24][CH2:23][N:22]([C:6]([N:3]2[CH:2]=[CH:1][N:5]=[CH:4]2)=[O:7])[CH2:21]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)n2ccnc2)C1
Temperature: 57.5 °C
Yield: 88.1 %

Procedure:
To a suspension of CDI (3.8 g, 20.5 mmol) in THF (40 mL) was added pyrrolidin-3-yl-carbamic acid tert-butyl ester (3.99 g, 20.5 mmol) and the reaction mixture was heated at about 55-60° C. for about 4 h. The reaction mixture was cooled at ambient temperature and concentrated in vacuo to afford an yellow oil. The residue was dissolved in DCM (40 mL), washed with water (2×30 mL), and the organic portion was separated, dried over MgSO4, filtered, and concentrated in vacuo to give [1-(imidazole-1-carbonyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (5.06 g, 88%) as a yellow oil which was used in subsequent reactions without further purification. RP-HPLC (Table 1, Method d) Rt 2.08 min; m/z: (M+H)+ 281.
Reaction SMILES: [OH-].[Na+].C([O:7][C:8](=[O:35])/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH3:20])=[C:13]([C:21]2[NH:22][C:23](=[O:34])[C:24]3[N:29]([CH3:30])[N:28]=[C:27]([CH2:31][CH2:32][CH3:33])[C:25]=3[N:26]=2)[CH:12]=1)(C)(C)C>CO>[CH3:30][N:29]1[C:24]2[C:23](=[O:34])[NH:22][C:21]([C:13]3[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=3[O:17][CH2:18][CH2:19][CH3:20])/[CH:10]=[CH:9]/[C:8]([OH:35])=[O:7])=[N:26][C:25]=2[C:27]([CH2:31][CH2:32][CH3:33])=[N:28]1
Reactant: CCCOc1ccc(/C=C/C(=O)OC(C)(C)C)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCOc1ccc(/C=C/C(=O)O)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 77.4 %

Procedure:
2N Aqueous sodium hydroxide solution (2.28 ml, 0.0046 mol) was added to a solution of (E)-3-(1-methyl-7-oxo-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-5-yl)-4-n-propoxycinnamic acid t-butyl ester (0.40 g, 0.00088 mol) in methanol (2.3 ml) and the mixture was heated under reflux for 18 hours. The methanol was removed by evaporation under vacuum, the residue dissolved in water (25 ml), and the solution extracted with ethyl acetate (4×15 ml). The aqueous layer was separated, acidified to pH 1 with hydrochloric acid, and then extracted with a mixture of methanol and ethyl acetate (3:97, 4×20 ml). The organic extracts were combined, dried (Na2SO4) and evaporated under vacuum, then the residue crystallised from ethyl acetate to give the title compound as a white solid (0.27 g, 77%), m.p. 229°-230° C. Found C,63.64; H,5.98; N,14.14. C21H25N4O4 requires C,63.46; H,6.34; N,14.10%.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@H:10]([C:14]2[NH:15][C:16](=[O:29])[C:17]3[CH:22]=[N:21][N:20]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:18]=3[N:19]=2)[CH2:9]1)C1C=CC=CC=1.Cl>CO.[OH-].[Pd+2].[OH-]>[CH3:13][C@@H:11]1[CH2:12][NH:8][CH2:9][C@H:10]1[C:14]1[NH:15][C:16](=[O:29])[C:17]2[CH:22]=[N:21][N:20]([CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:18]=2[N:19]=1
Reactant: C[C@@H]1CN(Cc2ccccc2)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Reaction time: 18 h
Yield: 103.5 %

Procedure:
6-[(3S,4S)-1-benzyl-4-methylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (5.6 g) was dissolved in 100 mL of methanol and added to a Parr bottle. Palladium hydroxide (3.76 g) was added along with 3.56 mL of concentrated hydrochloric acid. The reaction mixture was placed on a hydrogenator under 40 psi of H2 for 18 h. The reaction mixture was filtered through Celite and concentrated to provide 4.47 g of the title compound as the hydrogen chloride salt. 400 MHz 1H NMR (CD3OD) δ 8.03 (s, 1H), 4.49 (m, 1H), 4.09-4.06 (m, 2H), 3.74-3.57 (m, 4H), 3.24 (m, 1H), 3.05 (m, 1H), 2.89 (m, 1H), 2.77 (m, 1H), 2.30 (m, 2H), 1.90 (m, 2H), 1.22 (d, J=6.6 Hz, 3H). MS: (M+H m/z=304.2).
Reaction SMILES: [C:1]12([C:11]3[CH:23]=[CH:22][C:14]([O:15][CH2:16][CH:17]=[CH:18][C:19]([OH:21])=[O:20])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C12(C3C=CC(OC=CCC(O)=O)=CC=3)CC3CC(CC(C3)C1)C2.[H][H]>CO.[Pd]>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:22][CH:23]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=C(O)C=CCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C(O)CC=COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Solvent: CO
Product: O=C(O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reaction time: 24 h

Procedure:
A solution of 0.9 g of the mixture of 4-[4-(1-adamantyl)-phenoxy]-2-butenoic acid and 4-[4-(1-adamantyl)-phenoxy]-3-butenoic acid in 30 ml of absolute methanol is hydrogenated with 0.3 g of palladium (5% strength on charcoal) until 1 equivalent of hydrogen has been taken up (normal pressure, about 25° C). The catalyst is then filtered off, and the filtrate is mixed with 10 ml of 2 N sodium hydroxide solution and left to stand for 24 hours at about 25° C. It is then evaporated in vacuo to half its volume. The evaporation residue is partitioned between 50 ml of 2 N hydrochloric acid and 3 times 50 ml of methylene chloride. The organic phases are washed until neutral, dried over sodium sulphate and evaporated in vacuo. Crystallisation of the evaporation residue from ethanol gives 4-[4-(1-adamantyl)-phenoxy]butyric acid of melting point 170°-172° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C:12]1[N:13]([CH3:23])[C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([O:21][CH3:22])[CH:15]=2)[CH3:2].[Cl:26]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:26][C:20]1[C:19]2[C:14](=[CH:15][C:16]([O:21][CH3:22])=[CH:17][CH:18]=2)[N:13]([CH3:23])[C:12]=1[C:5]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:4]=1[N:3]([CH2:1][CH3:2])[CH2:24][CH3:25]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCN(CC)c1cc(OC)ccc1-c1cc2ccc(OC)cc2n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)c1cc(OC)ccc1-c1c(Cl)c2ccc(OC)cc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a solution of diethyl [5-methoxy-2-(6-methoxy-1-methyl-1H-indol-2-yl)phenyl]amine (110 mg) in tetrahydrofuran (5 ml) was added N-chlorosuccinimide (50 mg), and the solution was stirred for 1 hour at room temperature. To the reaction solution was added a saturated aqueous solution of sodium bicarbonate, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate-methanol system) to provide the title compound (96 mg).