Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[OH:11])[CH:2]=[CH2:3].[C:12](OC(=O)C)(=[O:14])[CH3:13].N1C=CC=CC=1>O.CCOCC>[CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[O:11][C:12](=[O:14])[CH3:13])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(F)ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Solvent: CCOCC
Product: C=CCc1cc(F)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To crude (4p), acetic anhydride (36.5 mL, 386.4 mmol) and pyridine (37.5 mL, 463.7 mmol) were added. The resulting mixture was stirred at room temperature for 18 hours, checked by HPLC the next day (reaction appeared mostly complete). The mixture was then poured onto cold H2O/Et2O, the aqueous layer was extracted with Et2O (2×), the combined organic layers were washed sequentially with 10% HCl (3×), saturated NaHCO3 (2×), H2O (2×) and brine, and then dried over anhydrous Na2SO4. After concentration, crude product purity was checked by thin-layer chromatography (hexane/ethyl acetate, 7:3) and HPLC. No mass ion was observed. The crude product (5p) was carried on to next step directly without subsequent purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[N:10]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)[C:11]2[C:16]([C:17]=1[C:18]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:19])=[CH:15][CH:14]=[CH:13][CH:12]=2>>[CH3:33][O:32][C:28]1[CH:27]=[C:26]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[C:9]2[N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:31]=[CH:30][CH:29]=1
Reactant: COc1cccc(-n2c(Cl)c(C(=O)N3CCOCC3)c3ccccc32)c1
Reactant: CN1CCNCC1
Product: COc1cccc(-n2c(N3CCN(C)CC3)c(C(=O)N3CCOCC3)c3ccccc32)c1

Procedure:
This compound was prepared from 2-chloro-1(3-methoxyphenyl)-indole-3-carboxylic acid chloride and morpholine to yield 2-chloro-1-(3-methoxyphenyl)-indole 3-carboxylic acid morpholide which was reacted with N-methyl-piperazine according to Example 42. The yield of amorphous product was 85% of the theoretical yield; the amorpheus hydrochloride had a decomposition point above 160° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:8][CH2:7][NH:6][CH2:5]1.C(N(CC)CC)C.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[NH:24][C:25]1[N:34]=[C:33](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:32]([F:48])=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28].C(Cl)(Cl)Cl.[CH2:53]([O:55]CC)[CH3:54]>O>[C:53]([NH:3][CH:4]1[CH2:8][CH2:7][N:6]([C:33]2[C:32]([F:48])=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([NH:24][C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[F:16])[N:34]=2)[CH2:5]1)(=[O:55])[CH3:54]
Reactant: NC1CCNC1
Reactant: CCOCC
Reactant: COC(=O)c1cc(F)c(OS(=O)(=O)c2c(C)cc(C)cc2C)nc1Nc1ccc(F)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)c1cc(F)c(N2CCC(NC(C)=O)C2)nc1Nc1ccc(F)cc1F
Yield: 82.4 %

Procedure:
In 3 ml of N,N-diemthylformamide was suspended 120 mg of 3-aminopyrrolidine dihydrochloride, and 250 mg of triethylamine was added to the resulting suspension, after which the resulting mixture was subjected to reaction at room temperature for 5 minutes. Thereafter, 300 mg of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-(2,4,6-trimethylbenzenesulfonyloxy)nicotinate was added to the reaction mixture, and the resulting mixture was subjected to reaction at room temperature for 1.5 hours. To the reaction mixture were added 10 ml of chloroform and 10 ml of water, and the organic layer was separated, washed successively with 10 ml of water and 10 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Subsequently, 100 mg of acetic anhydride was added to the organic layer, and the resulting mixture was subjected to reaction at room temperature for 10 minutes, after which the solvent was removed by distllation under reduced pressure. To the crystalline material thus obtained was added 5 ml of diethyl ether, and crystals were collected by filtration to obtain 210 mg (yield 82.4%) of methyl 6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinate. The physical properties of this compound were identical with those of the compound obtained in Example 9.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[C@H:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:4]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:14][S:15]([O:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[C@H:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:4]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C[C@@H]1C[C@@H](CO)NC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)C[C@@H]1C[C@@H](COS(C)(=O)=O)NC1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 8.0 g of (3S,5S)-5-hydroxymethyl-3-[(methoxycarbonyl)methyl]-2-pyrrolidinone and 4.95 ml of methanesulphonic acid chloride in 100 ml of methylene chloride, a solution of 9.0 ml of triethylamine in 15 ml of methylene chloride is added dropwise at 0° C. within 15 minutes. The mixture is stirred for one hour at 0° C. and for a further hour at ambient temperature. After the addition of 20 ml of water the organic phase is separated off and washed twice with water. The organic phase is dried over magnesium sulphate and evaporated under reduced pressure in vacuo. The crude product is chromatographed with ethyl acetate/methanol (15:1) over silica gel and the solid obtained is recrystallised from methyl tert.butylether/acetone.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>C(#N)C>[CH2:2]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: C1CCNC1
Reactant: CCCCCCCCCCCCCCBr
Solvent: CC#N
Product: CCCCCCCCCCCCCCN1CCCC1
Temperature: 25 °C
Yield: 74.8 %

Procedure:
In a 250-mL round bottom flask, equipped with a magnetic stirrer, a heating mantle and reflux condenser, were placed 1-bromotetradecane (10 g, 36 mmol), acetonitrile (100 mL) and pyrrolidine (5.1 g, 72 mmol). The reaction mixture was refluxed for 3 hrs. The reaction mixture was cooled to room temperature and was concentrated on a rotary evaporator to a residue. Water and ethyl acetate were added. The organic phase was separated and washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated to dryness affording 7.2 g (75% yield) of 1-tetradecylpyrrolidine, as a light yellow semi-solid. This intermediate was subjected to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].[CH:20]([P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[CH2:21].Cl>CS(C)=O>[O:11]=[C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]([CH2:21][CH2:20][P:22]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:29])([O:2][CH3:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(C(=O)c1ccccc1)c1ccccc1
Reactant: C=CP(=O)(OCC)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOP(=O)(CCC(OC)(C(=O)c1ccccc1)c1ccccc1)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
16.4 g. (0.1 mole) of benzoin methyl ether are dissolved in 100 ml of dimethyl sulphoxide. While passing in nitrogen, 3 ml of 4 normal sodium hydroxide solution are added dropwise. Then 18 g (0.11 mole) of diethyl vinylphosphonate are added dropwise in the course of 10 minutes. The reaction mixture is stirred for 16 hours at room temperature under nitrogen and subsequently neutralised with 2 normal hydrochloric acid. After the reaction mixture has been completely concentrated under reduced pressure, the oily residue is taken up in toluene, washed twice with water and again completely concentrated by rotary evaporation to yield 1-oxo-2-(2-diethylphosphonoethyl)-2-methoxy-1,2-diphenylethane as a slightly viscous yellowish oil which crystallises on standing; m.p. 60°-62° C. (initiator 1).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[CH2:35]([C@@H:37]1[O:39][CH2:38]1)Cl>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:35][CH:37]2[CH2:38][O:39]2)=[CH:9][CH:10]=1
Reactant: ClC[C@H]1CO1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC2CO2)cc1

Procedure:
Analogously to Method D, 5.60 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 2.05 ml of (R)-(−)-epichlorohydrin are reacted. The title compound is obtained as a colourless oil. Rf=0.12 (1:3 EtOAc-heptane); Rt=5.55.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([NH:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3c2)cc1
Reactant: NC1CCCCC1
Product: Fc1ccc(-c2ccc3ncnc(NC4CCCCC4)c3c2)cc1
Yield: 78 %

Procedure:
This compound was synthesized from 4-chloro-6-(4-fluorophenyl)-quinazoline and cyclohexylamine in 78% yield, using the procedure described for example 37. The product was characterized by its mass spectrum as follows: MS (m/z): 322 ([M+H]+, 100).
Reaction SMILES: C([O:8][C:9](=[O:34])[CH:10]([NH:15][CH:16]([C:30]([O:32]C)=[O:31])[CH2:17][C:18]1[CH:22]=[CH:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:19]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1.[OH-].[Na+]>CO>[CH2:23]([N:20]1[CH:21]=[CH:22][C:18]([CH2:17][C@H:16]([NH:15][C@@H:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:9]([OH:34])=[O:8])[C:30]([OH:32])=[O:31])=[N:19]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1.[CH2:23]([N:20]1[CH:21]=[CH:22][C:18]([CH2:17][C@@H:16]([NH:15][C@@H:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:9]([OH:34])=[O:8])[C:30]([OH:32])=[O:31])=[N:19]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)C(Cc1ccn(Cc2ccccc2)n1)NC(CC(C)C)C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C[C@H](N[C@@H](Cc1ccn(Cc2ccccc2)n1)C(=O)O)C(=O)O
Product: CC(C)C[C@H](N[C@H](Cc1ccn(Cc2ccccc2)n1)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2-[2-(1-Benzylpyrazol-3-yl)-1-methoxycarbonyl-ethylamino]-4-methylpentanoic acid benzyl ester (150 mg, 0.324 mmol) was dissolved in 3 mL of MeOH and a 1.0 M solution of NaOH (3.24 mL, 3.24 mmol) was added. The reaction mixture was stirred for 14 h at room temperature and then concentrated to give a white solid. Purification by reverse-phase HPLC chromatography provided (S,S)-2-[2-(1-benzyl-1H-pyrazol-3-yl)-1-carboxy-ethylamino]-4-methyl pentanoic acid (less polar fractions, 52-6a, R=CH2Ph) and (S,R)-2-[2-(1-benzyl-1H-pyrazol-3-yl)-1-carboxy-ethylamino]-4-methyl pentanoic acid (more polar fractions, 52-6b, R=CH2Ph) as white powders.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]2)([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C.C(OCC)(=O)C.O.C([O-])(O)=O.[Na+]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]2
Reactant: CCOC(=O)C(C)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(C)c1cc2cc(N)ccc2[nH]1
Temperature: 120 °C
Yield: 99.7 %

Procedure:
To a solution of ethyl 2-(5-nitro-1H-indol-2-yl)propanoate (0.10 g, 0.38 mmol) in ethanol (4 mL) was added tin chloride dihydrate (0.431 g, 1.91 mmol). The mixture was heated in the microwave at 120° C. for 1 h. The mixture was diluted with ethyl acetate before water and saturated aqueous NaHCO3 were added. The reaction mixture was filtered through a plug of celite using ethyl acetate. The organic layer was separated from the aqueous layer. The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to give ethyl 2-(5-amino-1H-indol-2-yl)propanoate (0.088 g, 99%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOC(C)=O.[BH4-].[Na+]>CCO.CCCCCCC>[CH2:1]([O:8][C:9](=[O:23])[NH:10][C:11]1[CH:12]=[CH:13][C:14]([C@H:17]2[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]2)=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC[C@H](c2ccc(NC(=O)OCc3ccccc3)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C(Nc1ccc([C@H]2CCC(O)C2)cc1)OCc1ccccc1
Yield: 99.6 %

Procedure:
[4-((S)-3-Oxo-cyclopentyl)-phenyl]-carbamic acid benzyl ester (150 mg, 0.5 mmol) was dissolved in EtOH (1 mL) and EtOAc (0.1 mL) to form a clear solution. To this solution was added powder NaBH4 (50 mg) with stirring. The reaction was judged to be complete by TLC (30% EtOAc in heptane). The reaction was quenched by EtOAc (2 mL) and NaHCO3 aq. solution (2 mL). The two layers were separated and the aqueous layer was extracted with EtOAc (2×2 mL). The combined extracts were washed with NaHCO3 aq. (2 mL), brine (2 mL), and dried (K2CO3). The solution was filtered through a silica gel pad, eluted with EtOAc. The filtrate was concentrated to dryness to afford 155 mg (100%) of the title compound as a very white crystalline material. mp 99.0-100.6° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[C:10]([NH:23]C=O)[CH:9]=2)=[O:5])[CH3:2].Cl>CC(C)=O.O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[C:10]([NH2:23])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)c(NC=O)cc2[nH]1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1cc2cc(OCc3ccccc3)c(N)cc2[nH]1

Procedure:
5-Benzyloxy-6-formylamino-1H-indole-2-carboxylic acid ethyl ester (0.2 g, 0.591 mmol) is suspended in a 9:1 mixture of acetone/water (10 mL). The suspension is treated with 1N HCl (1.8 mL) and brought to reflux for 1 h. The separated solid is filtered, washed with saturated aqueous sodium bicarbonate and water, and air dried for 2 h to afford 6-amino-5-benzyloxy-1H-indole-2-carboxylic acid ethyl ester as a grey solid: (M−H)−=311.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30]C)=[O:29])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C1COCC1.CO>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][CH:27]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:17])[F:18])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(C(=O)O)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A solution of 25 mg (0.0577 mmole) of 5-n-butyl-2,4-dihydro-4-[4-(methoxycarbonyl)benzyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 26) in 0.25 mL of THF was treated with 0.25 mL of 1N sodium hydroxide in methanol, and the resulting solution was stirred overnight at 60° C. Volatiles were removed by evaporation, and the residue was taken up in 1 mL of methanol and acidified to pH 1.5 by addition of 1N HCl in methanol. The mixture was concentrated to dryness. The residue was leached with chloroform. The CHCl3 solution was dried over anhydrous sodium sulfate, filtered through Celite, and concentrated in vacuo to give 23 mg (96%) of the title compound as a colorless, glassy solid; homogeneous by TLC in 9:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 420 (M+1)+.
Reaction SMILES: [Na].[Cl-].[NH2:3][C:4]([NH2:6])=[NH2+:5].[CH:7]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH:16]([CH2:20][C:21](OCC)=[O:22])[N:15]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:14]2=[O:30])([CH3:9])[CH3:8]>C(O)C>[CH2:26]([N:15]1[C:14](=[O:30])[C:13]2[C:17](=[CH:18][CH:19]=[C:11]([O:10][CH:7]([CH3:8])[CH3:9])[CH:12]=2)[CH:16]1[CH2:20][C:21]([NH:5][C:4]([NH2:6])=[NH:3])=[O:22])[CH:27]([CH3:29])[CH3:28]
Reactant: CCOC(=O)CC1c2ccc(OC(C)C)cc2C(=O)N1CC(C)C
Reactant: NC(N)=[NH2+]
Agent: [Cl-]
Agent: [Na]
Solvent: CCO
Product: CC(C)CN1C(=O)c2cc(OC(C)C)ccc2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 18 h
Yield: 4 %

Procedure:
N-[2-(2-Isobutyl-5-isopropoxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-acetyl]-guanidine is prepared as described in Example 9, starting with 20 cm3 of absolute ethanol, 0.086 g of sodium, 0.36 g of guanidinium chloride and 0.42 g of ethyl (5-isopropyloxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate. The reaction mixture is stirred at a temperature in the region of 20° C. for 18 hours and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is then taken up in 50 cm3 of ethyl acetate and the organic phase is washed twice with 30 cm3 of aqueous 1N sodium hydroxide solution and then twice with 50 cm3 of aqueous 1N hydrochloric acid solution. The acidic aqueous phase is treated with aqueous 30% sodium hydroxide solution to pH 14, and then extracted with 3 times 30 cm3 of ethyl acetate. The organic extracts are combined, washed with 50 cm3 of saturated brine, dried over magnesium sulfate and concentrated under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is triturated with diethyl ether and then filtered and dried in a desiccator under reduced pressure (2 Pa) at a temperature in the region of 40° C. for 2 hours. 0.0175 g of N-[2-(2-Isobutyl-5-isopropoxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-acetyl]-guanidine is thus obtained in the form of a white powder melting at 208° C. 1H NMR (300 MHz, d6-(CD3)2SO, δ in ppm): 0.75 (d, J=6.5 Hz: 3H); 0.90 (d, J=6.5 Hz: 3H); 1.30 (mt: 6H); 2.01 (mt: 1H); 2.40 (dd, J=15 and 6.5 Hz: 1H); 2.65 (dd, J=15 and 6.5 Hz: 1H); 3.00 (dd, J=13.5 and 5.5 Hz: 1H); 3.53 (dd, J=13.5 and 10 Hz: 1H) 4.68 (mt: 1H); 4.96 (broad t, J=6.5 Hz: 1H); from 6.40 to 7.10 (broad multiplet: 2H); 6.98 (dd, J=8.5 and 2 Hz: 1H); 7.09 (d, J=2 Hz: 1H); 7.54 (d, J=8.5 Hz: 1H); from 7.60 to 8.20 (broad multiplet: 2H).
Reaction SMILES: [CH:1]1([NH:5][C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[N:13][CH:14]=3)[N:9]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[BH4-].[Na+]>CC#N>[CH:1]1([NH:5][C:6]([C:8]2[CH:17]=[CH:16][C:15]3[CH2:14][N:13]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12][CH2:11][C:10]=3[N:9]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(NC1CCC1)c1ccc2cnccc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN1CCc2nc(C(=O)NC3CCC3)ccc2C1

Procedure:
A mixture of N-cyclobutyl-1,6-naphthyridine-2-carboxamide (227 mg, 1 mmol), tert-butyl bromoacetate (234 mg, 1.2 mmol) in CH3CN (15 mL) is refluxed overnight. Solvent is removed in vacuo and the residue is dissolve in MeOH (20 mL). To the solution is added NaBH4 (181 mg, 4.8 mmol) and the mixture is refluxed for 4 hr. The solvent is removed in vacuo and the residue is partitioned between water (20 mL) and EtOAc (20 mL). The layers are separated and the aqueous layer is extracted with EtOAc (20 ml). The combined extracts are washed with brine (10 mL), dried and evaporated. The residue is purified by flash column to give the title compound as a light yellow oil. MS (M+1): 346.2.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:8]2[C:13]=1[C:12](=[O:14])[NH:11][C:10](=[O:15])[NH:9]2)([O:3][CH3:4])=[O:2].NC1C([C:28](OC)=[O:29])=C(C(OC)=O)NC=1C1C=CC=CC=1.[N-]=C=O.[Na+]>>[C:12]([C:13]1[C:8]([NH:9][C:10]([NH2:11])=[O:15])=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:6][C:5]=1[C:1]([O:3][CH3:4])=[O:2])([O:29][CH3:28])=[O:14]
Reactant: COC(=O)c1[nH]c(-c2ccccc2)c2[nH]c(=O)[nH]c(=O)c12
Reactant: COC(=O)c1[nH]c(-c2ccccc2)c(N)c1C(=O)OC
Agent: [N-]=C=O
Agent: [Na+]
Product: COC(=O)c1[nH]c(-c2ccccc2)c(NC(N)=O)c1C(=O)OC

Procedure:
5-Carbomethoxy-7-phenyl-6H-pyrrolo[3,4-d]pyrimidine-2,4(1H,3H)-dione, from 3-amino-4,5-dicarbomethoxy-2-phenyl-pyrrole and sodium isocyanate. The intermediate 4,5-dicarbomethoxy-2-phenyl-3-ureido-pyrrole is isolated. M.p. 246°-8° C (from methanol/water). Yield of the title compound 88.5%. M.p. 320°-7° C. (from methanol/water).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:12]=1>>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[C:11]([O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[N:12][C:13]([NH:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1)=[CH:14]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: COc1ccc(O)cc1
Product: COc1ccc(Oc2nc(Nc3cc(C)[nH]n3)cc3cc(OC)ccc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-methoxy-phenol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [6-methoxy-1-(4-methoxy-phenoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 377(MH+).
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][C:8]2[C:11]([C:15]([OH:17])=[O:16])=[CH:12][CH:13]=[CH:14][C:7]1=2.[Br:18][C:19]1[CH:20]=[N:21][C:22]([Cl:25])=[N:23][CH:24]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.Cl>C1COCC1.C(O)(=O)C>[Br:18][C:19]1[C:20]([C:10]2[S:6][C:7]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([OH:17])=[O:16])[C:8]=3[CH:9]=2)=[N:21][C:22]([Cl:25])=[N:23][CH:24]=1
Reactant: Clc1ncc(Br)cn1
Reactant: O=C(O)c1cccc2sccc12
Agent: Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(O)c1cccc2sc(-c3nc(Cl)ncc3Br)cc12
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 42 %

Procedure:
Butyllithium (2.5 M in hexane, 14.1 mL) is added dropwise to a stirred solution of benzo[b]thiophene-4-carboxylic acid (3.00 g, 16.8 mmol) in anhydrous THF (50 mL) at −78° C. under nitrogen. The resultant mixture is allowed to stir for 45 minutes at −78° C. before it is added, via cannula, to a stirred cold solution of 5-bromo-2-chloropyrimidine (3.26 g, 16.8 mmol) in anhydrous THF (50 mL) at −30° C. Upon the completion of the addition, the reaction mixture is stirred for 30 minutes at −30° C., then at ambient temperature for another 1.5 hours. Acetic acid (2.4 mL) is added to the reaction mixture, after 5 minutes, followed by the addition of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (4.01 g, 17.7 mmol) dissolved in THF (10 mL). The mixture is allowed to stir for 10 minutes before it is treated dropwise with HCl (37%, 30 mL), then the mixture is stirred for another 1 hour. THF is evaporated off and the mixture becomes a suspension. The solid is filtered off, washed with water (100 mL×2), and then dried under vacuum. The dry solid is suspended in dichloromethane (45 mL) and ethanol (5 mL) and stirred for 30 minutes. After filtration, the solid is resuspended in ether (50 mL) and the suspension is stirred for another 30 minutes. After filtration and vacuum drying, the title compound is obtained as a yellow solid. (2.64 g, 42% yield).