Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]1=[O:22].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>CN(C=O)C>[CH3:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([Cl:24])=[CH:26][CH:27]=2)[C:14]1=[O:22]
Reactant: ClCc1ccc(Cl)cc1
Reactant: COC(=O)CCCCCCCn1c(=O)[nH]c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(=O)n(Cc2ccc(Cl)cc2)c2ccccc21

Procedure:
The product is produced as described in example 1 from 0.72 g. of NaH (80% suspension in mineral oil), 7 g. of 8-(2-oxo-benzimidazolin-1-yl)-caprylic acid methyl ester, 100 cc. of DMF, 3.9 g. of 4-chlorobenzylchloride and 0.72 g. of NaJ Eluant in chromatographic purification: hexane/ethylacetate.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([CH3:13])[C:7]2=[CH:6][C:5]=1[N:14]1[CH2:19][CH2:18][C:17]([CH3:21])([OH:20])[CH2:16][CH2:15]1)[CH3:3].[NH2:22][C:23]1[N:28]=[C:27]([NH2:29])[C:26]([C:30]#[N:31])=[C:25](Cl)[N:24]=1.CCN(CC)CC>CN(C=O)C>[NH2:22][C:23]1[N:28]=[C:27]([NH2:29])[C:26]([C:30]#[N:31])=[C:25]([NH:1][CH:2]([C:4]2[N:9]=[C:8]3[CH:10]=[CH:11][N:12]([CH3:13])[C:7]3=[CH:6][C:5]=2[N:14]2[CH2:15][CH2:16][C:17]([OH:20])([CH3:21])[CH2:18][CH2:19]2)[CH3:3])[N:24]=1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Reactant: CC(N)c1nc2ccn(C)c2cc1N1CCC(C)(O)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1N1CCC(C)(O)CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a 10 mL vial were added 1-(5-(1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-4-methylpiperidin-4-ol (56 mg, 0.194 mmol), 2,4-diamino-6-chloropyrimidine-5-carbonitrile (32.9 mg, 0.194 mmol) and Et3N (0.054 mL, 0.388 mmol) in DMF (3 mL). The resulting yellow solution was heated to 90° C. and stirred overnight. The reaction mixture was purified by preparative HPLC eluting with 5-30% ACN in water (with 0.05% ammonium carbonate). The fractions containing the desired product were combined and lyophilized to give the title compound (racemate) as a white solid (40 mg, 49%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17-1.29 (m, 3 H), 1.32-1.43 (m, 3 H), 1.52-1.87 (m, 4 H), 2.57-2.72 (m, 2 H), 2.73-2.94 (m, 2 H), 3.16-3.29 (m, 1 H), 3.71-3.86 (m, 3 H), 4.24-4.32 (m, 1 H), 5.74-5.88 (m, 1 H), 6.34-6.44 (m, 2 H), 6.44-6.52 (m, 1 H), 6.53-6.65 (m, 3 H), 7.48-7.58 (m, 1 H), 7.77-7.84 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C21H27N9O, 422.2; found 422.5.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:39][C:40]([F:58])([F:57])[O:41][C:42]1[CH:47]=[CH:46][C:45]([S:48]([N:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)(=[O:50])=[O:49])=[CH:44][CH:43]=1.CCN(C(C)C)C(C)C>CN(C)C=O>[CH3:1][C:2]1[C:3]([C:12]([N:54]2[CH2:53][CH2:52][N:51]([S:48]([C:45]3[CH:46]=[CH:47][C:42]([O:41][C:40]([F:57])([F:58])[F:39])=[CH:43][CH:44]=3)(=[O:49])=[O:50])[CH2:56][CH2:55]2)=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1CCNCC1
Reactant: Cc1c(C(=O)O)ccc2cccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)CC2)ccc2cccnc12
Reaction time: 0.33 h
Yield: 49.7 %

Procedure:
To the solution of 8-methyl-7-quinolinecarboxylic acid (may be prepared as described in Intermediate 2; 90 mg, 0.483 mmol) in N,N-Dimethylformamide (DMF) (2 ml), HATU (193 mg, 0.508 mmol) was added at room temperature. The reaction was stirred for 20 min and then 1-({4-[(trifluoromethyl)oxy]phenyl}sulfonyl)piperazine (may be prepared as described in Intermediate 11; 150 mg, 0.483 mmol) was added followed by DIPEA (0.211 ml, 1.209 mmol) and the reaction mixture was stirred for 3 hours. The reaction mixture was poured into the separating funnel and partitioned between ethyl acetate (25 ml) and sodium hydroxide (15 ml). The organic phase was washed with sodium hydroxide (2×10 ml), water (2×10 ml) and brine (10 mL) before it was dried using phase separator and the solvent was removed under vacuum. The crude product was purified by MDAP to give the title compound as a white solid (115 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH2:18]OS(C1C=CC(C)=CC=1)(=O)=O)[S:4]([C:7]1[C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:13]=2[CH:14]=[CH:15][CH:16]=1)(=[O:6])=[O:5])[CH3:2].[CH2:30]([NH2:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>ClCCl>[CH2:1]([N:3]([CH2:17][CH2:18][NH:36][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[S:4]([C:7]1[C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:13]=2[CH:14]=[CH:15][CH:16]=1)(=[O:5])=[O:6])[CH3:2]
Reactant: CCCCCCN
Reactant: CCN(CCOS(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCCCNCCN(CC)S(=O)(=O)c1cccc2cnccc12
Temperature: 110 °C

Procedure:
To 3.96 g of the thus obtained N-ethyl-N-(2-p-toluenesulfonyloxyethyl)-5-isoquinolinesulfonamide were added 1.25 g of hexylamine, 1.14 g of potassium carbonate and 20 ml of dioxane. The mixture thus obtained was heated in a pressure vessel at 110° C. for 72 hours, and then the dioxane was removed under reduced pressure to obtain a crude product. Then, 60 ml of dichloromethane was added to the crude product, and the mixture thus obtained was washed with 30 ml of water and dried with anhydrous magnesium sulfate. The dichloromethane was removed under reduced pressure to obtain a residue. The residue thus obtained was subjected to purification by silica gel column chromatography (Wacogel C-200, solvent: a 5% methanol solution in chloroform) to obtain 2.50 g of N-ethyl-N-(2-hexylaminoethyl)-5-isoquinolinesulfonamide [Compound (28)]. Compound (28) was analyzed to give the following data.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][CH:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].C(Cl)Cl>O>[CH2:28]([O:27][C:25](=[O:26])[N:10]([CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)[CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CCC(NCCCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C1CCC(N(CCCc2ccccc2)C(=O)OCc2ccccc2)CC1
Reaction time: 1.5 h

Procedure:
A mixture of 4-(3-phenyl-propylamino)-cyclohexanone (1.9 g, 8.21 mmol), K2CO3 (1.15 g, 8.3 mmol), benzyl chloroformate (1.42 g, 8.3 mmol) and CH2Cl2 (20 ml) was stirred at r.t for 1.5 h. H2O (50 ml) was added, and the mixture was extracted with CH2Cl2. The organic layer was dried (Na2SO4), evaporated and the residue was purified by chromatography (SiO2, CH2Cl2—MeOH 95:5) to give (4-Oxo-cyclohexyl)-(3-phenyl-propyl)-carbamic acid benzyl ester as a yellow oil (2.7 g, 90%, MS: m/e=365(M+)).
Reaction SMILES: [N+](C1C=CC(O[C:9]([O:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])=[O:10])=CC=1)([O-])=O.[F:24][C:25]1[CH:26]=[C:27]([CH:31]2[CH:36]([CH2:37][N:38]([C@@H:46]([C:48]3[C:57]4[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=4)[CH:51]=[CH:50][CH:49]=3)[CH3:47])[C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:35][CH2:34][NH:33][CH2:32]2)[CH:28]=[CH:29][CH:30]=1.C1COCC1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[C:41]([O:40][C:39]([N:38]([CH2:37][CH:36]1[CH2:35][CH2:34][N:33]([C:9]([O:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)=[O:10])[CH2:32][CH:31]1[C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=1)[C@@H:46]([C:48]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:51]=[CH:50][CH:49]=1)[CH3:47])=[O:45])([CH3:42])([CH3:43])[CH3:44]
Reactant: COC(=O)c1cccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1cccc(F)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OC(=O)N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3cccc(F)c3)C2)c1
Reaction time: 8 h
Yield: 101.8 %

Procedure:
To a suspension of 5.000 g of methyl 3-hydroxybenzoate, 6.955 g of 4-nitrophenyl chloroformate, and 100 mL of toluene was added 4.81 mL of triethylamine at room temperature, followed by stirring overnight. The insolubles were removed by filtration, and as solvent was removed by distillation under reduced pressure to obtain 5.948 g of methyl 3-{[(4-nitrophenoxy)carbonyl]oxy}benzoate as a pale yellow solid. To a mixture of 100 mg of methyl 3-{[(4-nitrophenoxy)carbonyl]oxy}benzoate, 139 mg of tert-butyl {[3-(3-fluorophenyl)piperidin-4-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate, and 4 ml of THF was added 0.084 mL of triethylamine at room temperature, followed by stirring overnight. A saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 196 mg of 3-(methoxycarbonyl)phenyl 4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidine-1-carboxylate as a pale yellow oily compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[S:14][C:13]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:23](O)[CH3:24]>>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[S:14][C:13]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:23][CH3:24])=[O:20])=[CH:12][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCO
Reactant: O=C(O)CCCCc1ccc(CCCc2ccccc2)s1
Agent: Cl
Product: CCOC(=O)CCCCc1ccc(CCCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3 g of 5-[5-(3-phenylpropyl)-thien-2-yl]-valeric acid are dissolved in 10 ml of ethanol and the solution is saturated with HCl gas. The solution is stirred at room temperature for 24 hours and concentrated in vacuo. Purification by column chromatography (silica gel/hexane/ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:8][CH2:9][CH2:10][OH:11])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]([C:16]1[S:25][C:19]2[N:20]=[C:21](Cl)[N:22]=[CH:23][C:18]=2[C:17]=1[CH3:26])=[O:15]>>[CH3:12][O:13][C:14]([C:16]1[S:25][C:19]2[N:20]=[CH:21][N:22]=[C:23]([NH:1][C:2]3[C:3]([O:8][CH2:9][CH2:10][OH:11])=[N:4][CH:5]=[CH:6][CH:7]=3)[C:18]=2[C:17]=1[CH3:26])=[O:15]
Reactant: Nc1cccnc1OCCO
Reactant: COC(=O)c1sc2nc(Cl)ncc2c1C
Product: COC(=O)c1sc2ncnc(Nc3cccnc3OCCO)c2c1C

Procedure:
Prepared analogously to example 28.1 from 2-(3-aminopyridin-2-yloxy)ethanol (175 mg) and chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (121 mg)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:23][C:24]([CH3:36])([CH3:35])[CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[NH2:27][CH2:26][CH2:25][C:24]([NH:23][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[NH:18][CH:19]=1)=[O:22])([CH3:35])[CH3:36]
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CCNC(=O)OC(C)(C)C)c3n2)c2ccc(F)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CCN)c3n2)c2ccc(F)cc21
Reaction time: 1 h
Yield: 30.9 %

Procedure:
To a stirred solution of tert-butyl 3-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-3-methylbutylcarbamate (110 mg, 0.22 mmol) in 6 mL of dichloromethane was added trifluoroacetic acid (3 mL) in one portion at room temperature and the solution stirred for one hour. The solvent was evaporated at 40° C. under reduced pressure and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 20% acetonitrile/80% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give N-(4-amino-2-methylbutan-2-yl)-2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide 2,2,2-trifluoroacetate (35 mg, 30.9%) as a yellow solid. MS: (M+H)+=396; 1H NMR (300 MHz, DMSO): δ 12.94 (s, 1H), 9.11 (s, 1H), 8.50-8.43 (m, 2H), 7.89 (s, 1H), 7.74-7.70 (m, 3H), 7.70-7.21 (m, 1H), 4.18 (s, 3H), 2.90 (brs, 2H), 2.31-2.26 (m, 2H), 1.53 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][N:14]([CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][N:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2cn(C3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(Br)cc(Nc2cn(C3CCNCC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
A mixture of 243d (2.2 g, 4.88 mmol) and trifluoroacetic acid (20 mL) was stirred at room temperature for 1 h. It was then concentrated under reduced pressure to afford crude 243e (1.5 g, 88%), which was used in the next step without further purification. MS-ESI: [M+H]+ 352.2
Reaction SMILES: O1CCCC1.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][C@@H:16]2[NH:21][CH2:20][CH2:19][N:18]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]2=O)=[CH:7]1.[OH-].[Na+]>O>[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][C@@H:16]2[NH:21][CH2:20][CH2:19][N:18]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:17]2)=[CH:7]1
Reactant: O=C1[C@H](Cc2c[nH]c3ccccc23)NCCN1CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CCN2CCN[C@@H](Cc3c[nH]c4ccccc34)C2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Combine lithiium aluminumhydride (100 mmol) and tetrahydrofuran (75 ml). Add (S)-3-(1H-Indol-3-ylmethyl)-1-(2-phenyl-ethyl)-2-oxo-piperazine (25 mmol) portionwise. Heat to reflux. After 24 hours, cool to ambient temperature. Carefully add water (3.8 mL), 15% aqueous sodium hydroxide solution (3.8 mL), and water (10.5 mL). Stir vigourously for 1 hour. Filter, rinse the filter cake repeatedly with tetrahydrofuran. Concentrate the filtrate in vacuo to obtain a residue. Chromatograph the residue to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[CH:5]=[N+:4]([O-])[CH:3]=1.O=P(Cl)(Cl)[Cl:19].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[C:5]([Cl:19])=[N:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cc(Br)c2cc3ccccc3cc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Clc1ncc(Br)c2cc3ccccc3cc12
Temperature: 55 °C
Reaction time: 2 h

Procedure:
4-Bromo-benzo[g]isoquinoline 2-oxide (7-4) (380 mg, 1.39 mmol, 1 eq) was taken up in a ¼ v/v mixture of POCl3 and chloroform (20 ml) and the resulting solution was stirred at 55° C. for 2 hrs. The reaction mixture was then carefully poured into sat. aq. sodium bicarbonate, extracted with ethyl acetate, dried, and concentrated to give the crude desired chloride 7-5. LRMS m/z: found 294.0, 292.0, calcd. (M+H) 294.0, 292.0
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[CH2:19]([C:21]1[CH:22]=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=1)[CH3:20]>>[CH2:19]([C:21]1[CH:22]=[C:23]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)[CH:24]=[CH:25][CH:26]=1)[CH3:20]
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: CCc1cccc(N)c1
Product: CCc1cccc(Nc2nc(Nc3cc(C)[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-ethyl-phenylamine give N1-(3-ethyl-phenyl)-N3-(5-methyl-1H-pyrazol-3-yl)-isoquinoline-1,3-diamine. LC-MS m/e 344(MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]=[S:11].[CH:12]([NH:15][CH2:16][C:17](O)=[O:18])([CH3:14])[CH3:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]1[C:17](=[O:18])[CH2:16][N:15]([CH:12]([CH3:14])[CH3:13])[C:10]1=[S:11]
Reactant: CC(C)NCC(=O)O
Reactant: Cc1cccc(C)c1N=C=S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C)c1N1C(=O)CN(C(C)C)C1=S
Yield: 49.2 %

Procedure:
The title compound was prepared by the procedure described in Example 45 using 16.3 g of 2,6-dimethylphenyl-isothiocyanate, 21.2 g of N-isopropyl glycine, 21.0 g of triethyl amine, and 300 mL of chloroform. Crystallization from ethanol afforded the title compound (12.9 g) as a white solid, m.p. 135°-137° C. Anal. Calcd. for. C14H18N2O S: C, 64.09; H, 6.92; N, 10.68. Found: C, 63.99; H, 6.72; N, 10.67. Mass spectrum (+FAB, I M+H]+) m/z 263.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5]([CH2:16][CH3:17])=[N:6][NH:7][C:8]2=O.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=2)[C:5]([CH2:16][CH3:17])=[N:6][N:7]=1
Reactant: CCc1n[nH]c(=O)c2cc(OC)cc(OC)c12
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1nnc(Cl)c2cc(OC)cc(OC)c12

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 5,7-dimethoxy-4-ethyl-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)(=[O:10])=[O:9])=[C:4]([F:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24](B(O)O)[CH:25]=1>>[F:17][C:13]1[CH:12]=[C:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:22]3[CH:21]=[C:20]([F:19])[CH:25]=[CH:24][C:23]=3[O:29][CH3:30])=[CH:3][C:4]=2[F:18])(=[O:10])=[O:9])[CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(c1cccc(F)c1)c1ccc(Br)cc1F
Reactant: COc1ccc(F)cc1B(O)O
Product: COc1ccc(F)cc1-c1ccc(S(=O)(=O)c2cccc(F)c2)c(F)c1

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of step (ii) and 5-fluoro-2-methoxybenzene boronic acid.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].Cl.[CH:13]([N:16]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:18][CH2:19]Cl)([CH3:15])[CH3:14]>>[CH:13]([N:16]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:18][CH2:19][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])([CH3:15])[CH3:14]
Reactant: CC(C)N(CCCCl)C(C)C
Reactant: O=C1Nc2ccccc2C1=O
Agent: Cl
Product: CC(C)N(CCCN1C(=O)C(=O)c2ccccc21)C(C)C
Yield: 72.9 %

Procedure:
By using isatin and 3-diisopropylaminopropyl chloride hydrochloride, a method analogous to that described in Reference Example 1 was carried out, and the reaction product was purified with silica gel column chromatography (eluent: chloroform/methanol=50/1) and then recrystallized from hexane to obtain 1-(3-diisopropylaminopropyl)isatin having a melting point of 49°-50° C. (yield: 72.9%).
Reaction SMILES: [C:1]([C:3]1[C:4]2[S:13][C:12]([CH3:14])=[CH:11][C:5]=2[NH:6][C:7]=1C(O)=O)#[N:2].O>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[C:1]([C:3]1[C:4]2[S:13][C:12]([CH3:14])=[CH:11][C:5]=2[NH:6][CH:7]=1)#[N:2]
Reactant: Cc1cc2[nH]c(C(=O)O)c(C#N)c2s1
Agent: [Cu]
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: Cc1cc2[nH]cc(C#N)c2s1
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a solution of 6-cyano-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (0.54 g) in quinoline (10 mL) was added Copper powder (33 mg), and the mixture was stirred at 200° C. for 30 minutes using microwave reactor. To the reaction solution was added water, and a precipitated insoluble matter was filtered through a Celite pad (registered trademark). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with 1 mol/L hydrochloric acid, water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=76/24−53/47) to give the title compound (0.37 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(C)(C)C.[C:20]1([CH:26]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH2:29][CH2:28]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(N(CC)CC)C>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH:37][CH2:36][CH2:35][CH2:34][CH2:33][N:30]2[CH2:31][CH2:32][N:27]([CH:26]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:28][CH2:29]2)=[O:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=CC(=O)O)cn1
Reactant: NCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C=CC(=O)NCCCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)cn1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
To a suspension of 2.71 g of 3-(6-methyl-3-pyridyl)acrylic acid in 70 ml of dry tetrahydrofuran, a solution of 1.68 g of triethylamine in 5 ml of dry tetrahydrofuran is added at room temperature. The resulting solution is cooled to -5° C., and a solution of 2.0 g of pivaloyl chloride in 5 ml of dry tetrahydrofuran is added slowly. The mixture is stirred at the same temperature for 0.5 hour and cooled to -10° C., and a solution of 6.43 g of 4-(4-diphenylmethyl-1-piperazinyl)butylamine in 5 ml of dry tetrahydrofuran is added slowly. The mixture is stirred for 0.5 hour at between -10° C. and -5° C. and then at room temperature overnight. To the reaction mixture is added 50 ml of 10% aqueous potassium carbonate, and the resulting mixture is extracted with three 100-ml portions of ethyl acetate. The combined extracts are washed with water and dried over magnesium sulfate, and the solvent is distilled off. The residue is recrystallized from acetonitrile to give 5.63 g of the title compound, m.p. 129°-131° C.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH2:6][CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])C.O.[OH-].[Li+]>C1COCC1.O>[C:12]([O:11][C:9]([NH:8][CH2:7][CH2:6][CH:5]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:4]([OH:23])=[O:3])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CCOC(=O)C(CCNC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCC(C(=O)O)c1ccc(Cl)cc1

Procedure:
The 4-tert-butoxycarbonylamino-2-(4-chlorophenyl)-butyric acid ethyl ester (5.61 g, 16.4 mmol) was dissolved in 40 mL of THF and 10 mL of water, then cooled to 0° C. The mixture was treated with lithium hydroxide mono-hydrate (1.38 g, 32.8 mmol) to afford a yellow solution. The ice-bath was removed, and the mixture was allowed to stir overnight to room temperature. The reaction mixture was concentrated to approximately 15 mL and diluted with water. The aqueous was washed with ethyl acetate (discarded) then treated with 3M HCl solution until acidic (pH=2-3). The resulting white precipitate was extracted with ethyl acetate, and the organics were combined. The organic was washed with brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to afford the 4-tert-butoxycarbonylamino-2-(4-chlorophenyl)-butyric acid as a colorless oil. The material was re-dissolved in a minimal amount of warm (60° C.) hexanes and re-concentrated to afford the pure desired product as a white foam. 1H NMR (CDCl3, 400 MHz) δ 12.05-9.51 (brs, 1H), 7.31-7.25 (m, 4H), 4.59 (brs, 1H), 3.61 (d, J=7.6 Hz, 1H), 3.14 (brs, 2H), 2.28 (m, 1H), 1.92 (m, 1H), 1.43 (s, 9H).