Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[C:23]([Br:24])=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=[CH:11][CH:12]=1.[I:25]I.S(=O)(O)[O-].[Na+]>CCCCCC.C1COCC1.O>[I:25][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][Br:24])[CH:10]=[CH:11][CH:12]=1
Reactant: II
Reactant: Brc1cccc(CCCCOc2ccccc2Br)c1
Agent: O=S([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: BrCCCCCCOCCCCc1cccc(I)c1
Temperature: 0 °C
Yield: 70.8 %

Procedure:
A solution of n-butyl lithium in hexane (1.6 M; 50 ml) was added to a stirred solution of 6-bromophenyl 4-(3-bromophenyl)butyl ether (21 g) in dry THF (150 ml) at −85° C. under nitrogen. After 15 min a solution of iodine (19.8 g) in THF (100 ml) was added dropwise over 20 min. The solution was then allowed to warm up to 0° C. and aqueous sodium bisulphite was added. The mixture was poured into water and extracted into ether. The combined extracts were dried (Na2SO4) and evaporated. The residue was purified by flash silica gel column chromatography (1 kg) eluting with cyclohexane-ether (9:1). The appropriate fractions were evaporated to give the title compound (17 g). LCMS RT=4.41 min.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2=[N:9][C:10]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:11][C:12](=[O:13])[N:7]2[CH2:6][CH2:5][O:4][CH2:3]1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](O)=[O:27].C(OC(N1CCC2C(=CC(C(O)=O)=CC=2)C1)=O)(C)(C)C>>[O:13]=[C:12]1[N:7]2[C:8]([CH:2]([NH:1][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)=[O:27])[CH2:3][O:4][CH2:5][CH2:6]2)=[N:9][C:10]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:11]1
Reactant: O=C(O)c1ccccn1
Reactant: NC1COCCn2c1nc(-c1ccncc1)cc2=O
Agent: CC(C)(C)OC(=O)N1CCc2ccc(C(=O)O)cc2C1
Product: O=C(NC1COCCn2c1nc(-c1ccncc1)cc2=O)c1ccccn1

Procedure:
By analogy with the method described in example 1 (step 1.4), using (+/−) 9-amino-2-pyridin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-one and 2-pyridine carboxylic acid in place of (+/−)-9-amino-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-one and 3,4-dihydro-1H-isoquinoline-2,7-dicarboxylic acid 2-tert-butyl ester, the compound, 0.035 g (57%), was obtained as a white powder.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]#[N:9])=[CH:5][N:6]=1.N1C=CC=CC=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(Cl)Cl>[C:16]([NH:1][C:2]1[S:3][C:4]([S:7][C:8]#[N:9])=[CH:5][N:6]=1)(=[O:18])[CH3:17]
Reactant: N#CSc1cnc(N)s1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ncc(SC#N)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.3 %

Procedure:
To a mixture of 2-amino-5-thiocyanatothiazole (15.7 g, 0.1 mol) and pyridine (12 g, 0.15 mol) in methylene chloride (100 mL) was added acetic anhydride (1.2 g, 0.12 mol) at rt. The mixture was stirred at rt for 6 h. The mixture was concentrated to dryness and to the residue MeOH (50 mL) was added. The precipitates were collected and washed with water. The solid was dried and recrystallized from MeOH to afford 2-acetylamino-5-thiocyanatothiazole (15.2 g, 76%) as a solid, mp 212° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N+:14]([O-])=[C:13]([Cl:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]([O:23]C(=O)C)(=[O:22])[CH3:21]>C(Cl)Cl>[C:20]([O:23][CH:16]1[C:15]2[N:14]=[C:13]([Cl:19])[CH:12]=[CH:11][C:10]=2[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:17]1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCc2c(ccc(Cl)[n+]2[O-])C1
Solvent: ClCCl
Product: CC(=O)OC1CN(C(=O)OC(C)(C)C)Cc2ccc(Cl)nc21
Temperature: 70 °C
Yield: 66.4 %

Procedure:
A solution of 6-(tert-Butoxycarbonyl)-2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine 1-oxide (150 mg, 0.53 mmol) in acetic anhydride (2.5 mL, 26.3 mmol), was stirred and heated at 70° C. overnight under nitrogen atmosphere. DCM (20 mL) was added to the reaction mixture, and the resulting solution was washed sequentially with water, saturated aqueous NaHCO3 solution and brine, dried over anhydrous MgSO4, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with 0% to 30% EtOAc in hexane to give the title compound (115 mg, 66.8% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.51 (9H, s), 2.13 (3H, s), 3.30-3.49 (1H, d, J=12.0 Hz), 4.25-4.40 (1H, m), 4.45-4.55 (1H, d, J=12.0 Hz), 5.20-5.00 (1H, m), 5.73 (1H, br. s), 7.34 (1H, d, J=8.22 Hz), 7.51 (1H, d, J=8.41 Hz) ppm; LC/MS m/z: 327 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:20])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1.[C:21](=O)([O-])[O-].[K+].[K+].CI>CO>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH3:21])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:20])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccc(F)cc1
Agent: [K+]
Solvent: CI
Solvent: CO
Product: CSc1nc(N)c2nc(O)n(Cc3ccc(F)cc3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
6-amino-9-(4-fluorobenzyl)-8-hydroxy-2-mercaptopurine (200 mg, 0.687 mmol) was suspended in methanol (20 ml). To the suspension were added potassium carbonate (190 mg, 1.37 mmol) and methyl iodide (975 mg, 6.87 mmol) in order. The mixture was stirred at room temperature for 30 minutes. The reaction mixture were evaporated in vacuo to dryness and extracted with chloroform. The organic layer was dried on sodium sulfate. After removal of the solvent in vacuo, the residue was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (63 mg, yield 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](CC2C=CC=CC=2)=[C:7]1[C:22]([O:24]CC)=S.OO[S:33]([O-:35])=O.[K+].[OH-:37].[Na+]>ClCCl.C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([S:33]([CH2:5][C:4]2[CH:27]=[CH:28][CH:29]=[CH:2][CH:3]=2)=[O:35])=[C:7]1[C:22]([OH:24])=[O:37]
Reactant: O=S([O-])OO
Reactant: CCOC(=S)c1c(Cc2ccccc2)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: [OH-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1c(S(=O)Cc2ccccc2)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 5 h
Yield: 7 %

Procedure:
A solution of ethyl N-(3,4-dichlorobenzyl)-3-benzylthioindole-2-carboxylate (0.50 g) in dichloromethane (2 ml) was added to a slurry of wet alumina (1 g) and Oxone® (0.615 g) in dichloromethane (10 ml). The mixture was then heated at reflux for two hours, and allowed to cool. The product was washed away from the alumina using methylene chloride (200 ml). The solution was then dried (MgSO4) and evaporated to afford the crude sulphoxide ester (103 mg). The crude ester was dissolved in THF (2 ml) and methanol (1 ml), and sodium hydroxide (2M, 3 ml) was added. The solution was stirred for five hours, then concentrated in vacuo. The residue was dissolved in water (10 ml) and the product precipitated by dropwise addition of aqueous HCl (2M, 10 ml). The resulting solid was collected by filtration and washed with cold water, then dried in vacuo to afford the product as a pale yellow solid (36 mg, 7%. 2 steps), NMR d (CD3SOCD3) 4.37 (d, 2H), 5.83 (d, 2H), 6.96 (dd, 1H), 7.10 (m, 3H), 7.20 (m, 3H), 7.30 (t, 1H), 7.38 (d, 1H), 7.59 (s, 1H), 7.62 (s, 1H), 8.05 (d, 1H); M/z (−) 456 (M−H+), 412, 365, 323, 321, 320.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]3[C:14](=[O:15])[O:13][C:11](=[O:12])[C:9]=3[CH:10]=[C:5]2[CH:4]=[N:3]1.[Cl:16][C:17]1[C:18]([CH2:26][CH3:27])=[C:19]([C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=1)[NH2:20]>O1CCCC1>[Cl:16][C:17]1[C:18]([CH2:26][CH3:27])=[C:19]([NH:20][C:14]([C:8]2[N:7]=[C:6]3[N:2]([CH3:1])[N:3]=[CH:4][C:5]3=[CH:10][C:9]=2[C:11]([OH:13])=[O:12])=[O:15])[C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=1
Reactant: Cn1ncc2cc3c(nc21)C(=O)OC3=O
Reactant: CCc1ccc(Cl)c(CC)c1N
Solvent: C1CCOC1
Product: CCc1ccc(Cl)c(CC)c1NC(=O)c1nc2c(cnn2C)cc1C(=O)O
Reaction time: 12 h

Procedure:
In 100 ml of tetrahydrofuran was dissolved 8.0 g (39.4 mmol) of 1-methyl-pyrazolo[5,4-b]pyridine-5,6-dicarboxylic acid anhydride. After adding 7.23 g (39.4 mmol) of 3-chloro-2,6-diethylaniline to the solution obtained above, a reaction was carried out at ambient temperature for 12 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([NH:12][N+:13]([O-:15])=[O:14])=[NH:11])=[CH:4][N:3]=1.Cl[CH2:17][N:18]([CH2:20]Cl)[CH3:19].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:19][N:18]([CH3:20])[CH2:17][NH:11][C:10]2=[N:12][N+:13]([O-:15])=[O:14])=[CH:4][N:3]=1
Reactant: CN(CCl)CCl
Reactant: N=C(NCc1ccc(Cl)nc1)N[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CNC(=N[N+](=O)[O-])N(Cc2ccc(Cl)nc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 104.9 %

Procedure:
0.6 g of 1-(2-chloro-5-pyridylmethyl)-3-nitroguanidine and 0.4 g of bis(chloromethyl)methylamine were suspended in dried THF. To the suspension, a solution of 0.52 g of triethylamine in THF was added dropwise with cooling. The reaction mixture was stirred for 1 hour, and then poured into ice water. The mixture was extracted with dichloromethane. After the extract was dried over anhydrous magnesium sulfate, dichloromethane was distilled off. The residue was recrystallized from methanol to obtain 0.78 g of the title compound. This compound is No. 1 in Table 1. m.p.: 150-154° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C:6]2[C:8]([O:13][CH3:14])=[CH:9][CH:10]=[C:11]([F:12])[C:5]=2[O:4][CH2:3]1.[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH:15]1([NH:1][C@@H:2]2[CH2:7][C:6]3[C:8]([O:13][CH3:14])=[CH:9][CH:10]=[C:11]([F:12])[C:5]=3[O:4][CH2:3]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1ccc(F)c2c1C[C@@H](N)CO2
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(F)c2c1C[C@@H](NC1CCCCC1)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-amino-8fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyran (0.45 g, 2.2 mmol), cyclohexanone (0.7 g, 7.2 mmol) and HOAc (0.14 g, 2.3 mmol) in methanol (25 mL) was NaCNBH3 (0.5 g, 8 mmol) added in portions at room temperature. The solution was stirred at room temperature overnight to give a quantitative yield of the title compound. GC/MS (70 eV) M=279 (30%).
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[H][H].[NH3:8]>[Ni]>[CH:1](=[N:8][CH2:1][CH:2]([CH3:4])[CH3:3])[CH:2]([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: N
Reactant: CC(C)C=O
Agent: [Ni]
Product: CC(C)C=NCC(C)C
Temperature: -15 °C

Procedure:
1000g isobutyraldehyde and about 100 g of a commercially available nickel containing carrier catalyst (containing about 52 to 53% by weight nickel, and employing chromium (3)-oxide as activator) are introduced into a 2 l three-necked flask, equipped with a gas inlet tube, a stirrer and a reflux condensor, and cooled to -15° C. Hydrogen and ammonia are introduced into the resulting suspension in a volume ratio of 1 : 1 and at a temperature of 90° C. 160 l of gas are introduced per hour. Altogether, 240 l hydrogen and 240 l gaseous ammonia are introduced. After termination of the reaction, the catalyst is separated by filtration. 889 g isobutylidene -- isobutylamine are obtained.
Reaction SMILES: [C:1]([C:4]1[C:5]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[C:6]=2[O:7][C:8]=1[CH3:9])(=[O:3])[CH3:2].[CH3:18][Mg]Br.[Cl-].[NH4+].O>O1CCCC1.C(OCC)C>[C:15]([NH:14][C:10]1[C:6]2[O:7][C:8]([CH3:9])=[C:4]([C:1]([OH:3])([CH3:18])[CH3:2])[C:5]=2[CH:13]=[CH:12][CH:11]=1)(=[O:17])[CH3:16]
Reactant: C[Mg]Br
Reactant: CC(=O)Nc1cccc2c(C(C)=O)c(C)oc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc2c(C(C)(C)O)c(C)oc12
Reaction time: 5 h

Procedure:
To a solution of 3-acetyl-7-acetylamino-2-methylbenzo[b]furan (2.92 g) in tetrahydrofuran (60 ml) was added a 3M solution of methylmagnesium bromide in diethyl ether (12.7 ml) dropwise with ice cooling. The solution was stirred at ambient temperat ure for 5 hours and to the solution was added aqueous saturated ammonium chloride. Then, the mixture was poured into water and the separated oil was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from methanol to give 7-acetylamino-3-(1-hydroxy-1-methylethyl)-2-methylbenzo[b]furan (1.82 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][NH2:48])=[CH:42][CH:41]=1>C(#N)C.C(N(CC)C(C)C)(C)C>[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][NH:48][C:9]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:14])=[CH:13][CH:12]=2)=[O:11])=[CH:42][CH:41]=1
Reactant: COC(=O)Cc1ccc(C(=O)O)cc1
Reactant: NCCc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1ccc(C(=O)NCCc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(2-methoxy-2-oxoethyl)benzoic acid (1.00 g) in acetonitrile (50 ml), N,N-diisopropyl ethyl amine (2.63 ml), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (2.94 g) and 2-(4-chlorophenyl)ethylamine (790 ml) were added, and the mixed solution was stirred at room temperature for 16 hours. The solvent was removed by evaporation under reduced pressure, and the resulting crude product was purified by column chromatography (neutral OH type silica gel, ethyl acetate/n-hexane=30 to 50%) to give methyl (4-{[2-(4-chlorophenyl)ethyl]carbamoyl}phenyl)acetate (2.02 g).
Reaction SMILES: C(O)C.[NH2:4][C:5]1[C:6]([N+:33]([O-])=O)=[CH:7][C:8]([O:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[C:9]([CH:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH:10]=1.[H][H].[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH:44]=O>[Ni].O.CO>[F:18][C:17]([F:20])([F:19])[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][CH:11]1[C:9]1[C:8]([O:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:7][C:6]2[N:33]=[C:44]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][N:38]=3)[NH:4][C:5]=2[CH:10]=1)=[O:21]
Reactant: O=Cc1ccccn1
Reactant: [H][H]
Reactant: CS(=O)(=O)c1ccc(Oc2cc([N+](=O)[O-])c(N)cc2C2CCCN2C(=O)C(F)(F)F)cc1
Agent: [Ni]
Solvent: CCO
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2C(=O)C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
100 mg of developed Raney nickel catalyst was added to an ethanol (10 ml) solution of 521 mg of 1-(2-(5-amino-2-(4-methanesulfonyl-phenoxy)-4-nitro-phenyl)-pyrrolidin-1-yl)-2,2,2-trifluoro-ethanone, and the reaction liquid was stirred overnight in a hydrogen atmosphere. The catalyst was removed through filtration through Celite, and the solvent was evaporated away under reduced pressure to obtain a crude product. 226 mg of pyridine-2-carboxaldehyde was added to a methanol (10 ml) solution of 448 mg of the resulting crude product, and the reaction liquid was stirred overnight at 50° C. Water was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol=20/1) to obtain the entitled compound as a pale yellow solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(N(CC)CC)C.[S:15]1[CH:19]=[CH:18][C:17]2[C:20]([N:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][O:33][C:34]4[N:38]([CH3:39])[N:37]=[C:36]([NH2:40])[CH:35]=4)[CH2:26][CH2:25]3)=[CH:21][CH:22]=[CH:23][C:16]1=2.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[S:15]1[CH:19]=[CH:18][C:17]2[C:20]([N:24]3[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][CH2:32][O:33][C:34]4[N:38]([CH3:39])[N:37]=[C:36]([NH:40][C:1](=[O:3])[CH3:2])[CH:35]=4)[CH2:28][CH2:29]3)=[CH:21][CH:22]=[CH:23][C:16]1=2
Reactant: CC(=O)OC(C)=O
Reactant: Cn1nc(N)cc1OCCCN1CCN(c2cccc3sccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(OCCCN2CCN(c3cccc4sccc34)CC2)n(C)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
Acetic anhydride (1 ml) and triethylamine (0.09 ml, 0.65 mmol) were added to a dichloromethane solution (4 ml) of 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazol-3-yl-amine (0.20 g, 0.54 mmol) and the mixture was stirred at room temperature for 6 hours. An aqueous potassium carbonate solution was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and thereafter concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=2:1→0:1). The purified product was concentrated under reduced pressure and the residue was recrystallized from a solvent mixture of ethyl acetate-diisopropylether to obtain N-{5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazol-3-yl}acetamide (0.19 g, 89% yield) as white powder.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.CCN(C(C)C)C(C)C.[C:27](Cl)(=[O:30])[CH2:28][CH3:29]>C1COCC1.C(OCC)(=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH:17][C:27](=[O:30])[CH2:28][CH3:29])[CH:14]=[CH:15][CH:16]=1
Reactant: CCC(=O)Cl
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.8 %

Procedure:
To a solution of (3-quinoxalin-2-ylphenyl)amine (200 mg, 0.904 mmol) and DIEA (180 μL, 1.09 mmol) in THF (5 mL), propionyl chloride (87 μL, 1.0 mmol) was added and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate (20 mL), the organic phase was washed with water (10 mL), brine (10 mL), dried over MgSO4, and the solvent evaporated in vacuo. The resulting solid was triturated with diethyl ether and dried to afford 170 mg (67%) N-[3-(quinoxalin-2-yl)phenyl]propionamide. LCMS calculated for C17H15N3O (M+H): 278.12. found 276.00. 1H-NMR (CDCl3, 400 Mhz) δH: 9.44 (1H, br. s), 8.32 (1H, s), 8.14 (m, 2H), 7.41 (1H, d, J=7.5 Hz), 7.88-7.55 (4H, m), 7.52 (m, 1H), 7.40 (1H, br. S), 2.45 (2H, q, J=7 Hz), 1.28 (3H, t, J=7 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([C:8]1(O)[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)([CH3:7])[CH3:6])[CH3:2].CN(C)C=O.S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:22])[C:5]([C:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)C1(O)CCN(Cc2ccccc2)CC1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C)(C)C1=CCN(Cc2ccccc2)CC1
Yield: 38.4 %

Procedure:
2-(1-benzyl-4-hydroxy-piperidin-4-yl)-2-methyl-propionic acid ethyl ester (3.24 g, 10.6 mmol) from above was dissolved in chloroform (13 mL) containing N,N-dimethylformamide (34 μL). To this solution was added thionyl chloride (1.56 mL). The mixture was refluxed overnight. Solvents were evaporated and the residue was extracted with ethyl acetate and sodium hydroxide (1N) solution. The organic layer was washed with brine and dried over sodium sulfate. After evaporation of solvents, the residue was purified using flash chromatography (eluting with ethyl acetate and hexanes) to give 2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propionic acid ethyl ester (1.17 g) as an oily material. The NMR spectrum obtained on the sample is compatible with its structure. LC-MS calcd for C18H25NO2 (m/e) 287.4, obsd 288.2 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:26][C:25]3[CH:24]=[N:23][N:22]([CH3:27])[C:21]=3[NH:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[O:16])=[C:11]([F:32])[CH:10]=1)(C)(C)C.[ClH:34].O1CCOCC1>>[ClH:34].[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:26][C:25]3[CH:24]=[N:23][N:22]([CH3:27])[C:21]=3[NH:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[O:16])=[C:11]([F:32])[CH:10]=1
Reactant: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1F)C2
Agent: Cl
Solvent: C1COCCO1
Product: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(CN)cc1F)C2
Yield: 97 %

Procedure:
[3-Fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-carbamic acid tert-butyl ester from Example E90.1 (1.25 g, 2.8 mmol) was re-acted with 4N HCl/dioxan using an analogous procedure to that described for Example E4.2 to yield the title compound (11.0 g, 97%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([CH3:27])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15](Br)=[C:14]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:13]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].B([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([OH:37])=[O:36])(O)O.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CO>[CH3:2][C:1]([O:5][C:6]([NH:7][CH:8]([CH3:27])[C:9]([NH:11][C:12]1[N:13]=[C:14]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]([C:32]2[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=2)[C:35]([OH:37])=[O:36])=[CH:16][CH:17]=1)=[O:10])=[O:28])([CH3:4])[CH3:3]
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Br)c(C#Cc2ccccc2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1ccc(-c2cccc(C(=O)O)c2)c(C#Cc2ccccc2)n1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of tert-butyl-N-[1-[[5-bromo-6-(2-phenylethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]carbamate C2d (40 mg, 0.09 mmol), 3-boronobenzoic acid (18 mg, 0.11 mmol), Dichlorobis(triphenylphosphine)palladium(II) (6.3 mg, 0.01 mmol), Na2CO3 (19 mg, 0.18 mmol), dioxane (0.9 ml), MeOH (0.2 ml) and water (0.1 ml) is stirred under argon atmosphere for 4 h at 70° C. The reaction mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 16 mg (37%). HPLC-MS: M+H=486; tR=1.49 min (*Method—5).