Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[N:16][OH:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O1CCCC1.[C:24]([C:26]1[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[CH3:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[CH:25]=[C:24]([C:26]4[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=4)[O:17][N:16]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cc2ccc(CC(Cl)=NO)cc2)o1
Reactant: C#Cc1ccc(N)nc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(Cc2ccc(Cc3cc(-c4ccc(N)nc4)on3)cc2)o1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 11.4 %

Procedure:
To a mixture of (4-(5-methyl-furan-2-ylmethyl)-phenyl)-acetohydroximoyl chloride (38 mg, 0.14 mmol) described in Manufacturing Example 46-1-6 and tetrahydrofuran (1 mL) were added 5-ethynyl-pyridin-2-ylamine (15 mg, 0.13 mmol) described in Manufacturing Example 28-1-3 and triethylamine (35 μL, 0.25 mmol), which was stirred for 3.5 hours at 50° C. The reaction mixture was allowed to room temperature, and water was added to the system at the same temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and was concentrated under a reduced pressure. The residue thus obtained was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid), after which triethylamine was added to a mixture of the resulting target product and the mobile phase, thereby rendering the mobile phase basic, and the eluate was concentrated under a reduced pressure. The residue thus obtained was washed with water to obtain the title compound (5.1 mg, 12%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][OH:28])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.C(OCC)(=O)C>[CH2:29]([N:8]1[C:9](=[O:26])[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]1[CH2:27][OH:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCCCc1nc(CO)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCCc1nc(CO)n(Cc2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 49 %

Procedure:
A solution of 4′-{[4-butyl-2-(hydroxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.4 g), benzyl bromide (0.49 mL) and cesium carbonate (1.3 g) in N,N-dimethylacetamide (14 mL) was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution 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 (0.86 g, 49%) as a colorless liquid.
Reaction SMILES: [N:1]([C@:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:9])[C:5]([O:7]C)=O)=[C:2]=[S:3].[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>O>[CH3:9][C@@:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:1][C:2](=[S:3])[N:23]([NH:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]1=[O:7]
Reactant: NNc1ccccc1
Reactant: COC(=O)[C@@](C)(N=C=S)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: C[C@@]1(c2ccccc2)NC(=S)N(Nc2ccccc2)C1=O
Reaction time: 0.5 h

Procedure:
0.7 g (0.00316 mol) of methyl (+)-(2S)-2-isothiocyanato-2-phenylpropionate, diluted in 15 ml of dry tetrohydrofuran, is introduced into a 100 ml three-necked flask under a dry nitrogen atmosphere. 0.32 ml (0.00316 mol) of phenylhydrazine, diluted in 5 ml of tetrohydrofuran, is run in at 20° C. in a single step. The temperature rises by 2° C. The medium is kept magnetically stirring for 30 minutes. A dark-beige precipitate appears. The medium is neutralized with 0.4 ml of acetic acid and then treated with 20 ml of water. After separating, the aqueous phase is extracted with 3 times 20 ml of ethyl ether. The organic phases are combined, washed with 2 times 30 ml of water, dried over magnesium sulfate and then concentrated under reduced pressure. The solid residue obtained is chromatographed on a silica column, using an eluent mixture composed of heptane and ethyl acetate in the proportions of 50/50.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[N:2]1.[CH3:14]O>Cl>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:2]1
Reactant: O=C(O)Cc1n[nH]c2ncccc12
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1n[nH]c2ncccc12
Reaction time: 0.17 h

Procedure:
To a solution of 1H-pyrazolo[3,4-b]pyridin-3-ylacetic acid (92 mg, 0.520 mmol) in methanol (4 mL) was bubbled in HCl gas for 2 minutes and the resulting solution was allowed to stand for a further 10 minutes. After this time, the solution was concentrated in vacuo and the resulting residue was partitioned between aqueous NaHCO3 (10 mL) and ethyl acetate (2×10 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and the solvent evaporated in vacuo to provide the title compound. LRMS (M+1): 192.0.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:34]=[CH:33][C:18]([CH2:19][N:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)=[CH:17][CH:16]=1.Cl.C(=O)(O)[O-].[Na+]>ClCCl.CO.O>[Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3ccc4c(nnn4CC4CC4)c3Cl)cc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Clc1c(-c2ccc(CN3CCNCC3)cc2)ccc2c1nnn2CC1CC1
Temperature: 0 °C

Procedure:
tert-Butyl 4-{4-[4-chloro-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl]benzyl}piperazine-1-carboxylate (Example 52, 430 mg, 0.89 mmol) was dissolved in a dichloromethane (8.9 mL) and methanol (8.9 mL), cooled to 0° C. and treated with a hydrochloric acid (2.2 mL, 4 M in dioxane, 8.9 mmol). The mixture was warmed to ambient temperature and treated with hydrochloric acid (200 μL, 12 N aqueous). The mixture was stirred at ambient temperatures until complete, at which time the mixture was treated with aqueous saturated sodium bicarbonate, diluted with water and extracted with ethyl acetate (3×40 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (100:0 to 90:5; dichloromethane:methanol) to afford the product as a clear oil: 1H-NMR (400 MHz, CDCl3) δ 7.51 (1H, d, J=1.9 Hz); 7.48-7.42 (5H, m); 4.56 (2H, d, J=7.0 Hz); 3.57 (2H, s); 2.93 (5H, t, J=4.8 Hz); 2.81 (3H, t, J=4.8 Hz); 1.49-1.38 (1H, m); 0.73-0.65 (2H, m); 0.57-0.48 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 382.1796 [(M+H)+; calculated for C21H25ClN5: 382.1793].
Reaction SMILES: N[C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.N1C=CC=CC=1C=[O:23]>>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][C:2](=[O:23])[C:13]([OH:15])=[O:14])=[CH:5]1
Reactant: O=Cc1ccccn1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: O=C(O)C(=O)Cc1c[nH]c2ccccc12
Yield: 64 %

Procedure:
In a chemical method for producing 3-indole-pyruvic acid disclosed by Giovanna De Luca et al., 3-indole-pyruvic acid was produced with a yield of 50 to 62% by reacting tryptophan as a starting material with pyridine aldehyde in the presence of a base for dehydrating a proton acceptor (see JP Sho-62-501912 [Patent Document 1], International Publication 87/00169 Pamphlet [Patent Document 2]). In this method, the required base and pyridine aldehyde are expensive and the yield is low. As a result, production cost are very high. Politi Vincenzo et al. produced 3-indole-pyruvic acid with the yield of 64% by a condensation reaction using indole and ethyl-3-bromopyruvate ester oxime as raw materials followed by acid hydrolysis (see Europe Patent Application Publication No. 421946 [Patent Document 3]). This method, however, requires a purification step using silica gel, the yield is low, the raw materials are expensive and the industrial production cost is very high.
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11].C([Li])CCC.CN(C)CCN(C)C.C(N([P:30](N(CC)CC)[Cl:31])CC)C.[ClH:37]>CCCCCC.C(OCC)C.C1COCC1>[Cl:37][P:30]([Cl:31])[C-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C-:6]1([P:30]([Cl:31])[Cl:37])[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11]
Reactant: c1cc[cH-]c1
Reactant: Cl
Reactant: CCN(CC)P(Cl)N(CC)CC
Agent: [Fe+2]
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: ClP(Cl)[c-]1cccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
At room temperature, 40.69 g (0.2186 mol) of ferrocene in 400 ml of abs. hexane is charged in a vessel. A mixture of 342 ml (0.547 mol) of 1.60 M n-butyllithium solution in hexane and 82.0 ml (63.6 g, 0.547 mol) of abs. N,N,N′,N′-tetramethylethylenediamine is added dropwise at room temperature within 6 h. The mixture is allowed to stir at room temperature for 18 h. The supernatant is filtered off through an immersion frit, and the orange filtration residue is suspended in 400 ml of abs. THF. At −78° C., a solution of 95.0 ml (94.6g, 0.481 mol) of bis(diethylamino)chlorophosphine in 200 ml of abs. THF is added dropwise within 4 h. The mixture is allowed to thaw to room temperature and stirred for another 15 h. The solution, which has now a red-brown color, is cooled down to −78° C., and 390 ml of 5.6 M HCl in diethyl ether is added dropwise within 5 h. After warming up to room temperature, the solvent is distilled off completely, and the residue is taken up in 2 l of diethyl ether, and the solution filtrated from insolubles through a P4 frit with Celite 545® as a filtering aid. The clear filtrate is again completely freed from solvent. The red-brown solid is finally recrystallized from 200 ml of toluene/pentane at −20° C.. After drying in an oil pump vacuum, 52.82 g of a coarse-crystalline solid (0.136 mol, 62%) is obtained. Analytical results: appropriate (see Example 2).
Reaction SMILES: [C:1]1([C:7]2[C:11]3[C:12](=O)[CH2:13][CH2:14][CH2:15][C:10]=3[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCl.[N-:20]=[N+]=[N-].[Na+].Cl>OS(O)(=O)=O>[N:8]1[O:9][C:10]2[CH2:15][CH2:14][CH2:13][C:12]3[C:11]=2[C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:20]=3
Reactant: O=C1CCCc2onc(-c3ccccc3)c21
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc2c(c1)nc1c3c(onc32)CCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 31.3 %

Procedure:
3-Phenyl-4-oxo-4,5,6,7-tetrahydrobenz[1,2-d]isoxazole (6.0 g) was dissolved in 40 ml conc. H2SO4 and then dichloromethane (60 ml) was added. NaN3 (2.0 g) was added portionwise at such a rate that foaming could be controlled. After 90 minutes, the reaction mixture was poured into ice/water and conc. HCl was added until the precipitated amine sulfate dissolved. The dichloromethane layer was separated and the aqueous phase was washed with additional dichloromethane. The aqueous phase was made basic with 50% NaOH and ice (up to pH 1-4) and then with NaHCO3 (up to pH 8). The product was extracted into dichloromethane and then flushed over a short alumina column before concentration under reduced pressure. Recrystallization from EtOAc/hexane gave 1.85 g of product, m.p. 149°-150° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[C:20]4[O:25][CH2:24][O:23][C:21]4=[CH:22][C:17]=3[CH2:16][C:15]([CH3:26])=[N:14][N:13]=2)=[CH:8][CH:7]=1)=[O:4].[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>>[CH2:27]([N:29]([CH2:30][CH3:31])[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[C:20]4[O:25][CH2:24][O:23][C:21]4=[CH:22][C:17]=3[CH2:16][C:15]([CH3:26])=[N:14][N:13]=2)=[CH:8][CH:7]=1)=[O:4])[CH3:28]
Reactant: CCNCC
Reactant: CC1=NN=C(c2ccc(NC(=O)CCl)cc2)c2cc3c(cc2C1)OCO3
Product: CCN(CC)CC(=O)Nc1ccc(C2=NN=C(C)Cc3cc4c(cc32)OCO4)cc1

Procedure:
It was prepared from 1-(4-chloroacetylaminophenyl)-4-methy1-7,8-methylenedioxy-5H-2,3-benzodiazepine by using the process of Example 102, except that diethylamine was used instead of pyrrolidine, m.p.: 157°-158° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]1([C:48]([F:51])([F:50])[F:49])[CH2:19][CH2:18][CH:17]([N:20]2[C:25](=[O:26])[C:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:30][CH:29]=3)=[C:23]([CH2:42][CH2:43][CH3:44])[N:22]3[N:45]=[CH:46][N:47]=[C:21]23)[CH2:16][CH2:15]1>C(OCC)(=O)C>[OH:13][C:14]1([C:48]([F:50])([F:51])[F:49])[CH2:19][CH2:18][CH:17]([N:20]2[C:25](=[O:26])[C:24]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]4[NH:3][C:4](=[O:7])[O:5][N:41]=4)=[CH:32][CH:33]=3)=[C:23]([CH2:42][CH2:43][CH3:44])[N:22]3[N:45]=[CH:46][N:47]=[C:21]23)[CH2:16][CH2:15]1
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(O)(C(F)(F)F)CC2)c2ncnn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(O)(C(F)(F)F)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
A mixture of hydroxylammonium chloride (0.54 g), sodium hydrogen carbonate (0.88 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({4-[4-hydroxy-4-(trifluoromethyl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.28 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.1 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.086 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution 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 colorless crystals (0.16 g, 51%).
Reaction SMILES: [CH:1]([N:4]1[C:8](=[O:9])[C:7]([NH:10][C:11](=[O:27])[O:12][CH2:13][CH:14]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[C:6]([CH3:28])[NH:5]1)([CH3:3])[CH3:2].[CH3:29]I>CN(C=O)C>[CH:1]([N:4]1[C:8](=[O:9])[C:7]([NH:10][C:11](=[O:27])[O:12][CH2:13][CH:14]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[C:6]([CH3:28])[N:5]1[CH3:29])([CH3:3])[CH3:2]
Reactant: CI
Reactant: Cc1[nH]n(C(C)C)c(=O)c1NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Product: Cc1c(NC(=O)OCC2c3ccccc3-c3ccccc32)c(=O)n(C(C)C)n1C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of (9H-fluoren-9-yl)methyl (2-isopropyl-5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)carbamate (2.109 g, 5.59 mmol) in DMF (30 mL) was added methyl iodide (2.80 mL, 44.7 mmol). The reaction mixture was stirred at 90° C. overnight. The resulting mixture was quenched with IPA and water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and the solvent removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography using a gradient of 0-10% MeOH in EtOAc afforded the title compound;
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6](/[CH:8]=[CH:9]/[CH2:10]P(OCC)(OCC)=O)=[O:7].[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24][O:25][C:26]1[C:33]([CH3:34])=[CH:32][C:29]([CH:30]=O)=[CH:28][C:27]=1[CH3:35]>O1CCCC1>[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24][O:25][C:26]1[C:33]([CH3:34])=[CH:32][C:29](/[CH:30]=[CH:10]/[CH:9]=[CH:8]/[C:6]([O:5][CH2:4][CH3:3])=[O:7])=[CH:28][C:27]=1[CH3:35]
Reactant: COCCOCOc1c(C)cc(C=O)cc1C
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C=C/c1cc(C)c(OCOCCOC)c(C)c1
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
To a stirred suspension of 60% sodium hydride (1.01 g) in dry tetrahydrofuran (60 ml), 80% triethyl 4-phosphonocrotonate (6.57 g) was added dropwise below 10° C. under an inert atmosphere. After being stirred for 30 minutes, a solution of 4-[(2-methoxyethoxy)methoxy]-3,5-dimethylbenzaldehyde (5.0 g) in dry tetrahydrofuran (50 ml) was added thereto below 10° C. After stirring for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 ml), washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel (130 g) and eluted with a mixture of n-hexane and ethyl acetate (7:3 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure to give a syrup of ethyl 5-[4-{(2-methoxyethoxy)methoxy}-3,5-dimethylphenyl]-(2E,4E)-2,4-pentadienoate (5.28 g).
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:5][CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:11]([CH2:21][CH2:22][CH2:23][CH3:24])=[N:10][CH:9]=1.[OH-].[K+].O.C(O)C>CCOCC>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:12]1[C:8]([CH2:7][CH2:6][NH:5][C@H:4]([C:3]([OH:32])=[O:2])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:9][N:10]=[C:11]1[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCc1ncc(CCN[C@@H](Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CCCCc1ncc(CCN[C@@H](Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl

Procedure:
The procedure of Example 2 (ii) was followed using 0.9 g (1.99 mmol) of N-[2-{1-[(2-chlorophenyl)methyl]-2-n-butyl-1H-imidazol -5-yl}ethyl]phenylalanine methyl ester, 0.33 g of potassium hydroxide, 15 ml of water and 25 ml of ethanol to afford after workup 0.54 q of product. Trituration with ether provided the title compound; mp 78°-80° C. (free base) and mp 232°-233° C. (for the dihydrochloride salt).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][NH:19][CH:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].Cl[C:30]([O:32][CH3:33])=[O:31]>CN(C)C=O.O>[CH3:33][O:32][C:30]([N:19]1[CH:20]=[C:6]2[C:7]([CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]3[CH:3]=[C:2]([Cl:1])[CH:22]=[CH:21][C:5]=32)=[CH:18]1)=[O:31]
Reactant: COC(=O)Cl
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1c[nH]cc1-2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)n1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reaction time: 0.25 h

Procedure:
In one portion 6.0 g (18.3 mmol) of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was added to a solution of 3.0 g (26.5 mmol) of potassium t-butoxide in 50 ml of dimethylformamide which was cooled to 0°. When solution was complete 1.8 ml (2.3 g; 24.5 mmol) of methyl chloroformate was added and the resulting mixture was stirred for 15 min. The mixture was diluted with 150 ml of water and the resulting precipitate was collected by filtration. The precipitate was dissolved in methylene chloride and washed with water. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue crystallized from ether to give an off-white solid. Recrystallization from a mixture of methylene chloride and ether gave off-white fine needles, mp 185°-186° (dec.).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]([NH2:12])=[O:11].Cl[CH2:14][C:15]1[CH:16]=[CH:17][C:18]2[S:22][CH:21]=[CH:20][C:19]=2[CH:23]=1.S1C2C=CC(CO)=CC=2C=C1.S(Cl)(Cl)=O>>[S:22]1[C:18]2[CH:17]=[CH:16][C:15]([CH2:14][O:8][C:7]3[C:2]([F:1])=[C:3]([C:10]([NH2:12])=[O:11])[C:4]([F:9])=[CH:5][CH:6]=3)=[CH:23][C:19]=2[CH:20]=[CH:21]1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Reactant: ClCc1ccc2sccc2c1
Agent: OCc1ccc2sccc2c1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1c(F)ccc(OCc2ccc3sccc3c2)c1F
Yield: 10 %

Procedure:
Synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide according to Method B, scheme 2. The required building block, 5-(chloromethyl)-1-benzothiophene, was synthesised by chlorination of commercially available 1-benzothiophen-5-ylmethanol with thionyl chloride. Yield 10%, mp 146-148° C., HPLC-MS (method 1): m/z 320 [M+H]+, Rt=3.95 min.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]#[C:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(O)[O-].[Na+].[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH2:37]>CO>[NH3:7].[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]#[C:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]4[NH:37][C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=5[N:30]=4)=[CH:19][CH:18]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccccc1N
Reactant: O=Cc1ccc(C#CCCN2CCN(c3ccccc3)CC2)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CO
Product: C(#Cc1ccc(-c2nc3ccccc3[nH]2)cc1)CCN1CCN(c2ccccc2)CC1
Product: N
Yield: 85.7 %

Procedure:
A mixture of 4-[4-(4-phenylpiperazin-1-yl)but-1-ynyl]benzaldehyde (Example B) (1.28 g), sodium bisulfite (0.4 g) and 1,2-diaminobenzene (0.43 g) is stirred in methanol (50 mL) at reflux for 18 hours. The mixture is filtered and the solvent evaporated. The residue is purified by chromatography on silica gel eluting with 200:8:1 dichloromethane:ethanol:0.880 aqueous ammonia to give 0.70 g of the title compound as a tan solid; mp 247°-248° C.
Reaction SMILES: C[O:2][C:3]1[N:4]([CH2:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[C:10]([N:11]=1)=[C:9]([NH2:12])[N:8]=[C:7]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:6]=2.Cl.[OH-].[Na+]>CO.O1CCOCC1.O>[NH2:12][C:9]1[N:8]=[C:7]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:6]=[C:5]2[C:10]=1[NH:11][C:3](=[O:2])[N:4]2[CH2:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: COCCOc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: COCCOc1nc(N)c2[nH]c(=O)n(CC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.4 %

Procedure:
8-(Methoxy)-2-{[2-(methoxy)ethyl]oxy}-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (0.1434 g) was dissolved in methanol (5 mL) and treated with 4N hydrogen chloride in 1,4-dioxane (2 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was evaporated under reduced pressure to give a solid, which was suspended in water (1 mL) and methanol (2-3 mL) before 2N sodium hydroxide was added to neutralise (to pH 7). After evaporating the suspension to near dryness under reduced pressure, the solid was suspended in water (3 mL) and filtered under suction and then washed with a few drops of methanol. This solid was dried to constant weight under vacuo at 50° C. after being initially air-dried under suction. This gave the title compound as a white solid (94 mg).