Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[F:22][C:23]1[CH:35]=[CH:34][C:26]([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:25][CH:24]=1>N1C=CC=CC=1>[F:21][C:3]1[C:2]([N:31]2[CH2:30][CH2:29][N:28]([CH2:27][C:26]3[CH:34]=[CH:35][C:23]([F:22])=[CH:24][CH:25]=3)[CH2:33][CH2:32]2)=[CH:20][C:6]2=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: Fc1ccc(CN2CCNCC2)cc1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Solvent: c1ccncc1
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(Cc5ccc(F)cc5)CC4)cc3nc21
Yield: 57.8 %

Procedure:
7-Fluoro-8-[4-(4-fluorobenzyl)piperazin-1-yl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 2, but from 1.6 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 5 g of 4-(4-fluorobenzyl)piperazine in 16 cm3 of pyridine. After recrystallizing twice from 25 cm3 of dimethylformamide on each occasion, 1.4 g of 7-fluoro-8-[4-(4-fluorobenzyl)piperazin-1-yl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid were obtained in the form of a yellow solid melting at about 311° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH2:9])[CH:7]=1.[C:20]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35](O)=[O:36])=[N:33][CH:34]=2)[CH2:25][CH2:24]1)(=[O:22])[CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:20]([N:23]1[CH2:24][CH2:25][N:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([NH:9][CH2:8][C:6]3[CH:7]=[C:2]([F:1])[C:3]([C:10]4[CH:15]=[CH:14][N:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=4)=[N:4][CH:5]=3)=[O:36])=[N:33][CH:34]=2)[CH2:27][CH2:28]1)(=[O:22])[CH3:21]
Reactant: NCc1cnc(-c2ccnc(C(F)(F)F)c2)c(F)c1
Reactant: CC(=O)N1CCN(c2ccc(C(=O)O)nc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2ccc(C(=O)NCc3cnc(-c4ccnc(C(F)(F)F)c4)c(F)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (3-fluoro-2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)methanamine 84-2 (54 mg, 0.20 mmol), 5-(4-acetylpiperazin-1-yl)picolinic acid 48-2 (50 mg, 0.20 mmol) and HATU (76 mg, 0.20 mmol) in DMF (0.9 mL) was added DIEA (0.16 mL, 1.00 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 5-(4-acetylpiperazin-1-yl)-N-((3-fluoro-2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)methyl)picolinamide 84 as a white powder. MS m/z 503.20 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 9.28 (t, 1H, J=6.4 Hz), 8.92 (d, 1H, J=5.2 Hz), 8.62 (m, 1H), 8.32 (m, 2H), 8.20 (d, 1H, J=4.8 Hz), 7.88-7.82 (m, 2H), 7.43 (dd, 1H, J1=9.0 Hz, J2=3.2 Hz), 4.59 (d, 2H, J=6.4 Hz), 3.61-3.58 (m, 4H), 3.41-3.39 (m, 4H), 2.05 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH:6]([CH3:17])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11](O)=[O:12])=[O:8])=[O:4].C(OC(Cl)=O)C(C)C.C([N:28](CC)CC)C>ClCCl>[CH3:1][O:2][C:3]([CH2:5][CH:6]([CH3:17])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([NH2:28])=[O:12])=[O:8])=[O:4]
Reactant: COC(=O)CC(C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Product: COC(=O)CC(C)C(=O)N1CCC[C@H]1C(N)=O

Procedure:
1-(3-Methoxycarbonyl-2-methylpropanoyl)-L-proline (2.4 g.) is dissolved in a mixture of dichloromethane (50 ml.) and triethylamine (1.4 ml.). The solution is chilled in an ice water bath and isobutylchloroformate (1.36 g.) is added while the mixture is stirred. After 10 minutes ammonia (gas) is bubbled through the solution, still in the ice bath, for fifteen minutes. The reaction mixture is stirred for 1 hour at room temperature, diluted with methylene chloride (100 ml.) and washed with water, 0.1 N hydrochloric acid, water, and dried over magnesium sulfate. The solvent is removed in vacuo to yield 1-(3-methoxycarbonyl-2-methylpropanoyl)-L-prolineamide.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5](Br)=[CH:6][CH:7]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:15][C:14]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([C:18]2[CH:17]=[C:16]([O:19][CH2:20][CH2:21][CH3:22])[CH:15]=[CH:14][C:13]=2[F:12])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)nc1C(=O)O
Reactant: CCCOc1ccc(F)c(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: CCCOc1ccc(F)c(-c2ccc(N)c(C(=O)O)n2)c1
Yield: 75 %

Procedure:
Method 1 was followed using 3-amino-6-bromopicolinic acid (1.0 equiv.) and 2-fluoro-5-propoxyphenylboronic acid (1.5 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) to give 3-amino-6-(2-fluoro-5-propoxyphenyl)picolinic acid in 75% yield. LC/MS=291.0 (M+H), Rt=0.81 min.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][CH2:21][CH2:20][NH:19]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][C:25]1[CH:26]=[C:27]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:26]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nc([C@H]3CCCN3)oc2-c2ccccc2)cc1
Reactant: CCOC(=O)COc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(CN2CCC[C@@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 2 h
Yield: 40.6 %

Procedure:
To a solution of (2R)-2-(4,5-diphenyloxazol-2-yl)pyrrolidine (400 mg) and 3-bromomethyl-1-ethoxycarbonylmethoxybenzene (0.76 g) in N,N-dimethylformamide (10 ml) was added K2CO3 (1 g) at room temperature. The mixture was stirred for 2 hours at the same temperature and then partitioned between ethyl acetate and water. The organic layer was washed with water, sat. NaHCO3, and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give (2R)-2-(4,5-diphenyloxazol-2-yl)-1(3-ethoxycarbonylmethoxybenzyl)pyrrolidine (0.27 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14](O)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.CN1CCOCC1.ClC(OCC)=O.Cl.[CH2:38]([O:45][NH2:46])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1COCC1>[CH2:38]([O:45][NH:46][C:14](=[O:15])[CH:13]([CH2:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:10])=[O:11])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COc1ccc(S(=O)(=O)CC(Cc2ccccc2)C(=O)O)cc1
Reactant: NOCc1ccccc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)CC(Cc2ccccc2)C(=O)NOCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-[(4-methoxybenzenesulfonyl)methyl]-3-phenyl-propionic acid (1.05 g, 3.14 mmol) and 0.69 mL (6.3 mmol) of NMM in dry THF, under nitrogen, is cooled in an ice bath. Ethyl chloroformate (0.33 mL, 3.5 mmol) in 7 mL of THF is added dropwise over 5 minutes. The suspension is stirred at 0° C. for 10 minutes, after which a slurry of O-benzylhydroxylamine hydrochloride (0.64 g, 4 mmol) and NMM (0.44 mL, 4 mmol) in 7 mL of THF is introduced in several portions. The mixture is stirred for 10 minutes and stored at 10° C. overnight. The mixture is allowed to warm to room temperature for 0.5 hours, and is then partitioned between ethyl acetate and aqueous 10% HCl. The organic phase is washed with water, three portions of 1M sodium bicarbonate and brine. It is dried over anhydrous sodium sulfate, concentrated and chromatographed on silica gel, eluting with 40%-50% ethyl acetate in hexanes. This affords 1.26 g of the title compound as a colorless oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19][C:7]1=2)C.[Li+].[BH4-].O>C1COCC1>[OH:3][CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19][C:7]1=2
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCO)c3ccccc23)CC1
Temperature: -10 °C
Reaction time: 19.5 h
Yield: 99.6 %

Procedure:
tert-Butyl 6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.602 g, 1.62 mmol) was dissolved in THF (15 mL), and the resulting solution was cooled to −10° C. under N2. LiBH4 (0.0756 g, 3.47 mmol, 2.14 equiv.) was added and the reaction mixture was allowed to warm to rt. After 19.5 h, the reaction mixture was cooled to 0° C., and LiBH4 (0.0250 g, 1.15 mmol, 0.71 equiv.) was added and the reaction mixture was allowed to warm up for 3.5 h. The reaction mixture was combined with water and was extracted with EtOAc (2×). The combined organic layers was washed with brine, dried over MgSO4, filtered, and concentrated to give tert-butyl 6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.533 g) in acceptable purity and essentially quantitative yield. 1H NMR (300 MHz, CD3OD) δ 1.48-1.51, 3.00-3.11, 3.66-3.79, 3.87-3.95, 4.27, 7.12, 7.19, 7.32, 7.50; MS (ESI+) for C19H26N2O3 m/z 331.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][OH:13])=[C:6]([NH2:14])[CH:5]=1.[CH:16](O)=O>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH2:11][CH2:12][OH:13])[CH:16]=[N:14][C:6]=2[CH:5]=1)=[O:15]
Reactant: O=CO
Reactant: COC(=O)c1ccc(NCCO)c(N)c1
Product: COC(=O)c1ccc2c(c1)ncn2CCO
Temperature: 45 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
3-Amino-4-(2-hydroxy-ethylamino)-benzoic acid methyl ester (2.6 g, 12.0 mmol) was dissolved in formic acid (20 mL). The solution was heated at 45° C. for 1 h. After checking the completion of reaction by TLC, formic acid was evaporated at <40° C. under reduced pressure and the resulting solid was recrystallized from EtOAc. The above solid was dissolved in 3N HCl, stirred at ambient temperature for 1 h, basified back with saturated sodium bicarbonate solution and extracted with EtOAc. The organic layer was evaporated to give 2.1 g (78%) of 1-(2-hydroxy-ethyl)-1H-benzoimidazole-5-carboxylic acid methyl ester. MS-ESI m/z 221 (M+1): 1H NMR (300 MHz, DMSO-d6) δ 3.7 (q, 2H), 3.9 (s, 3H), 4.3 (t, 3H), 5.0 (t, 1H), 7.7 (d, 1H), 7.9 (dd, 1H), 8.25 (s, 1H), 8.35 (s, 1H)
Reaction SMILES: [H-].[Na+].[CH3:3][OH:4].F[C:6]1[C:13]([F:14])=[C:12]([I:15])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9]>CN(C=O)C>[F:14][C:13]1[C:6]([O:4][CH3:3])=[C:7]([CH:10]=[CH:11][C:12]=1[I:15])[C:8]#[N:9]
Reactant: CO
Reactant: N#Cc1ccc(I)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C#N)ccc(I)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.7 %

Procedure:
Sodium hydride (60 mg, 2.5 mmol) was slurried in DMF (15 mL) and treated with dry methanol (120 μl, 96 mg, 3.0 mmol). After stirring for 10 minutes at 25° C., the solution was cooled to −25° C. and treated with 2,3-difluoro-4-iodobenzonitrile (500 mg, 1.9 mmol). After 25 minutes, the mixture was quenched by addition of 10% citric acid solution (5 mL) and warmed to 25° C. The mixture was extracted with ethyl ether (2×15 mL), the combined ether phases washed with water (5 mL), brine, dried (sodium sulfate) and evaporated to give 3-fluoro-4-iodo-2-methoxybenzonitrile (500 mg, 1.8 mmol): LC/MS (m/z=277).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][N:13]3[C:17]4[C:18](=[O:24])[N:19]([CH3:23])[N:20]=[C:21](Cl)[C:16]=4[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:29][O-:30].[Na+].CO.O>CO>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][N:13]3[C:17]4[C:18](=[O:24])[N:19]([CH3:23])[N:20]=[C:21]([O:30][CH3:29])[C:16]=4[N:15]=[CH:14]3)=[CH:25][CH:26]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Cn1nc(Cl)c2ncn(Cc3ccc(C(=O)c4ccc(Cl)cc4)cc3)c2c1=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nn(C)c(=O)c2c1ncn2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Yield: 70 %

Procedure:
In methanol (5 ml) was dissolved 1-[4-(4-chloro-benzoyl)benzyl]-4-chloro-6-methylimidazo[4,5-d]pyridazin-7(6H)-one (72 mg) followed by addition of 28% sodium methoxide/methanol (1.0 ml), and the mixture was refluxed for 5 hours. To this reaction mixture was added a large quantity of water and the resulting crystals were rinsed with water and dried under reduced pressure to provide 50 mg (yield 70%) of the title compound. 1H-NMR (CD3OD) δ: 3.7.1(3H,s), 4.00(3H,s), 5.85(2H,s), 7.50(2H,d,J=8.6Hz), 7.52(2H,d,J=8.8Hz), 7.74(2H,d,J=8.8Hz), 7.75(2H,d,J=8.6Hz), 8.42(1H,s).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][NH2:12])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[CH2:13]=O>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[CH2:13][NH:12][CH2:11][CH2:10]2)[CH3:2]
Reactant: CCOc1cccc(CCN)c1
Reactant: C=O
Product: CCOc1ccc2c(c1)CCNC2
Temperature: 110 °C

Procedure:
A stirred mixture of 2-(3-ethoxy-phenyl)-ethylamine (7.0 g, 42 mmol) and 37% aqueous formaldehyde solution (3.5 mL) was heated at 110° C. for 30 minutes. The stirring was stopped and the upper water layer was removed by pipette. To the resulting mixture water (5.25 mL) and concentrated HCl (10.5 mL) were added followed by heating 100° C. for 30 minutes. After allowing to cool to room temperature the mixture was evaporated to dryness and recrystallised from acetone yielding the subtitled compound as a cream solid (2.73 g). MH+ 178. 1H NMR δ (DMSO) 1.27-1.35 (3H, t), 2.88-3.03 (2H, t), 3.18-3.40 (2H, br, t), 3.95-4.08 (2H, q), 4.10-4.22 (2H, m), 6.74-6.85 (2H, m), 7.05-7.15 (1H, m), 9.33-9.55 (2H, br.s).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:20][O-].[Na+]>>[CH3:20][O:8][C:6]1[N:7]=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=1
Reactant: C[O-]
Reactant: Cc1cccc(=O)[nH]1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc(C)n1

Procedure:
Successive treatment of 6-methyl-2-pyridone with a mixture of phosphoryl chloride and phosphorus pentachloride, and sodium methoxide gives 6-methoxy-2-methylpyridine which may be converted into 2-bromomethyl-6-methoxypyridine with N-bromosuccinimide. Substitution of 2-bromomethyl-6-methoxypyridine for 2-chloromethyl-3-methoxypyridine in the general procedure of Example 1(iii)-(v) leads to the preparation of N-cyano-N'-methyl-N"-[2-((6-methoxy-2-pyridyl)methylthio)ethyl]guanidine.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:17][CH2:16][CH2:15][NH:14][C:4]1[N:5]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:7]([C:8]#[N:9])=[C:2]([N:29]2[CH2:28][CH2:27][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][CH3:18])[CH2:31][CH2:30]2)[N:3]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1N1CCN(c2nc(NCCO)nc(NCCO)c2C#N)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-(2-methoxy-phenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 60° C. to yield the 2,4-bis-(2-hydroxy-ethylamino)-6-[4-(2-methoxy-phenyl)-piperazin-1-yl]-pyrimidine-5-carbonitrile as a yellowish lyophilisate; MS: [M+H]+=414.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=4)[N:18]=3)[CH2:9]2)[N:5]=[C:4]([NH2:27])[N:3]=1.[F:28][C:29]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[CH:33][C:30]=1[C:31]#[N:32].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[NH2:27][C:4]1[N:3]=[C:2]([C:35]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29]([F:28])[CH:36]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=4)[N:18]=3)[CH2:9]2)[N:5]=1
Reactant: COc1cccc(-c2c[nH]c(C3CN(c4cc(Cl)nc(N)n4)CCO3)n2)c1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2c[nH]c(C3CN(c4cc(-c5ccc(C#N)c(F)c5)nc(N)n4)CCO3)n2)c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 10.7 %

Procedure:
A mixture of 4-chloro-6-(2-{4-[3-(methyloxy)phenyl]-1H-imidazol-2-yl}-4-morpholinyl)-2-pyrimidinamine (770 mg, 1.991 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (590 mg, 2.389 mmol), Na2CO3 (464 mg, 4.38 mmol) and Pd(PPh3)4 (138 mg, 0.119 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was heated at 140° C. under microwave condition with stirring for 1 hour. The mixture was filtered, washing with EtOAc (100 mL), and concentrated to afford the crude title compounde (1.0 g) as a grey oil. This material was combined with another sample of the title compound (100 mg). The combined material was purified by silica gel chromatography, eluting with EtOAc in PE from 50% to 80% to afford the title compound (760 mg) as a brown solid. LC-MS (ES) m/z=472 [M+H]+.
Reaction SMILES: C(OC([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[CH:13]=[C:12]1[CH2:24][CH2:25][CH3:26])=O)C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[CH2:24]([C:12]1[NH:11][C:19]2[C:14]([CH:13]=1)=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[CH2:25][CH3:26]
Reactant: CCCc1cc2ccc(C(=O)OC)cc2n1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1cc2ccc(C(=O)OC)cc2[nH]1
Reaction time: 0.33 h
Yield: 90.6 %

Procedure:
To a solution of methyl 1-benzyloxycarbonyl-2-propylindole-6-carboxylate (200 mg) in a mixture of methanol and ethyl acetate (1:1, 8 ml) was added 10% palladium on carbon (30 mg), and the mixture was stirred under hydrogen atmosphere for 20 minutes. The catalyst was removed by filtration through celite and washed with methanol. The filtrate was evaporated in vacuo to give methyl 2-propylindole-6-carboxylate (112 mg) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[S:16][C:15]([CH3:17])=[N:14][C:13]=1[CH3:18]>C(O)C>[CH3:17][C:15]1[S:16][C:12]([C:4]2[CH:5]=[CH:6][C:7]([NH2:9])=[CH:8][C:3]=2[O:2][CH3:1])=[C:13]([CH3:18])[N:14]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-c1sc(C)nc1C
Solvent: CCO
Product: COc1cc(N)ccc1-c1sc(C)nc1C
Yield: 75 %

Procedure:
A suspension of 5-(2-methoxy-4-nitro-phenyl)-2,4-dimethyl-thiazole (415 mg, 1.57 mmol) and anhydrous stannous chloride (1.52 g, 7.85 mmol) in ethanol (25 mL) was stirred at reflux for 3 hours. The yellow solution was evaporated and the residue dissolved in ethyl acetate. This solution was washed with 1N aqueous sodium hydroxide solution, twice with water, with brine, dried with magnesium sulfate and the solvent was evaporated to dryness. Column chromatography (50 g silica, heptane/ethyl acetate 30-60% v/v) afforded the title compound (276 mg, 75%) as a pale yellow solid. MS ISP (m/e): 235.2 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.04 (d, 1H), 6.31 (m, 2H), 3.80 (s broad, 2H), 3.78 (s, 3H), 2.66 (s, 3H), 2.29 (s, 3H). Mp 112-115° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]([NH2:12])=[S:11])=[N:6][CH:7]=1.[O-]CC.[Na+].[C:17]([CH2:19][C:20](OCC)=[O:21])#[N:18].Cl>>[NH2:18][C:17]1[N:9]([CH2:8][C:5]2[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=2)[C:10](=[S:11])[NH:12][C:20](=[O:21])[CH:19]=1
Reactant: CCOC(=O)CC#N
Reactant: Cc1cnc(CNC(N)=S)cn1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1cnc(Cn2c(N)cc(=O)[nH]c2=S)cn1
Yield: 84.7 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 12(b) by using 1-[(5-methylpyrazin-2-yl)methyl)thiourea (1.30 g, 7.10 mmol, obtained from Example 14(a)), sodium ethoxide (21% w/w, 28.4 ml, 28.4 mmol) and ethyl cyanoacetate (3.00 ml, 28.4 mmol) with the exception that the pH was adjusted by using 2N HCl until the mixture became cloudy. The mixture was then concentrated in vacuo until precipitation occurred. The solid was collected by filtration, washed with water and dried in vacuo to give the title compound (1.50 g, 81% yield) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>C(Cl)Cl>[O:17]=[C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:18])[N:8]1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N+:6]=1[O-:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(N2C(=O)c3ccccc3C2=O)nc1
Solvent: ClCCl
Product: Cc1ccc(N2C(=O)c3ccccc3C2=O)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(5-methylpyridin-2-yl)isoindoline-1,3-dione (1.62 g, 6.8 mmol) in DCM (32 ml) is added mCPBA (4.1 g, 18.2 mmol) in small portions at room temperature, and the solution is then stirred at room temperature overnight. The solution is diluted with dichloromethane, washed with aqueous Na2CO3 solution, dried over Na2SO4 and concentrated to afford 2-(1,3-dioxoisoindolin-2-yl)-5-methylpyridine 1-oxide as a brown solid. It is used without further purification in the next step. LC-MS m/z: 254.1 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].Cl[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=1.CCN(C(C)C)C(C)C>C(#N)C>[F:16][C:15]([F:18])([F:17])[C:12]1[CH:13]=[CH:14][C:9]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[N:10][CH:11]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=C1CNCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(c2ccc(C(F)(F)F)cn2)CCN1
Yield: 13 %

Procedure:
Piperazinone (1.16 g, 11.6 mmol), 2-chloro-5-(trifluoromethyl)pyridine (2.10 g, 11.6 mmol) and i-Pr2NEt (4.6 g, 6.4 mL, 36 mmol) were heated at reflux for 40 h in acetonitrile (60 mL). The mixture was concentrated, and the residue was purified by column chromatography (40 g ISCO column eluting with methylene chloride and a 10:1 methanol/ammonium hydroxide mixture; gradient 100% methylene chloride to 90% methylene chloride) to provide the title compound (370 mg, 13%) as a yellow powder: ESI MS m/z 246 [M+H]+.