Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([F:19])=[C:12](F)[C:11]=3[F:21])[CH:5]=2)[CH2:3][CH2:2]1.[NH2:22][C@H:23]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[CH2:24][OH:25].CCN(C(C)C)C(C)C>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]([F:21])=[C:12]([NH:22][C@H:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[CH2:24][OH:25])[C:13]([F:19])=[CH:14][C:15]=3[N+:16]([O-:18])=[O:17])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: N[C@@H](CO)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1Nc1cc(C2CC2)[nH]n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(F)c(N[C@@H](CO)c2ccc(F)cc2)c(F)c1Nc1cc(C2CC2)[nH]n1
Reaction time: 8 h
Yield: 57.1 %

Procedure:
A mixture of 5-cyclopropyl-N-(2,3,4-trifluoro-6-nitrophenyl)-1H-pyrazol-3-amine (Method 103, 0.300 g, 1.01 mmol), (R)-2-amino-2-(4-fluorophenyl)ethanol (0.172 g, 1.11 mmol) and DIEA (0.263 ml, 1.51 mmol) in n-BuOH (2 ml) was heated in a sealed tube placed in an oil bath set at 135° C. for 8 hours. The solvent was removed under reduced pressure and the residue was purified by chromatography (hexane-EtOAc=1:1) to give the title compound as an orange solid (0.25 g, 57%). 1H NMR (400 MHz) 11.88 (s, 1H), 8.57 (s, 1H), 7.70 (d, J=13.2 Hz, 1H), 7.34 (m, 2H), 7.15 (t, J=8.8 Hz, 2H), 6.61 (b, 1H), 5.38 (s, 1H), 5.07 (t, J=5.6 Hz, 1H), 4.88 (m, 1H), 3.62-3.71 (m, 2H), 1.80 (m, 1H), 0.90 (m, 2H), 0.61 (m, 2H). MS: Calcd.: 433; Found: [M+H]+ 434.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:6]=1[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](Cl)=[O:12]>C(OCC)(=O)C>[CH2:1]([NH:3][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([O:7][C:6]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:5]=2[Cl:4])[CH:9]=1)[CH3:2]
Reactant: O=C(Cl)c1cccc(Oc2cc(Cl)ccc2Cl)c1
Reactant: CCN
Solvent: CCOC(C)=O
Product: CCNC(=O)c1cccc(Oc2cc(Cl)ccc2Cl)c1
Yield: 90.7 %

Procedure:
Ethyl acetate (50 ml) was added to 1.4 g of an aqueous ethylamine solution (70 %), and an ethyl acetate solution containing 3.0 g of 3-(2,5-dichlorophenoxy)benzoic acid chloride was dropwise added thereto with stirring, during which the reaction mixture was cooled in an ice bath. After the addition was finished, the mixture was stirred for 1 hour at room temperature. The reaction mixture was washed with 1 N hydrochloric acid, water, 1% aqueous sodium hydroxide solution and water saturated with sodium chloride in this order and dried over anhydrous sodium sulfate. Thereafter, the solvent was removed by evaporation to obtain 3.1 g of crude crystals. On recrystallizing the crude crystals from a benzene-hexane mixed solvent, 2.8 g of N-ethyl-3-(2,5-dichlorophenoxy)benzamide were obtained. Melting point, 74.5°-75.5° C. Elementary analysis: Calcd. for C15H13Cl2NO2 : C, 58.08%; H, 4.22%; N, 4.52%; Cl, 22.86%. Found: C, 58.16%; H, 4.25%; N, 4.49%; Cl, 22.97%. NMR: δCCl 4: 1.15 (t 3H), 3.34 (quintet 2H), 6.65-7.61 (8H).
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[O:24][C:25](=[O:31])[C@H:26]([CH:28]([CH3:30])[CH3:29])[NH2:27]>CN(C=O)C>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:27][C@H:26]([C:25]([OH:31])=[O:24])[CH:28]([CH3:30])[CH3:29])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O

Procedure:
Z-Phe-OAt is reacted with valine methyl ester in DMF in accordance with the procedure described in Example 33 to form Z-Phe-Val.
Reaction SMILES: Cl.[C:2]1([S:8]([N:11]2[C:23]3[CH2:22][N:21]([CH2:24][CH:25]([CH:34]4[CH2:39][CH2:38][C:37]([N:47]([CH3:49])[CH3:48])([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=5)[CH2:36][CH2:35]4)[O:26][Si](C(C)(C)C)(C)C)[CH2:20][CH2:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1>[C:2]1([S:8]([N:11]2[C:23]3[CH2:22][N:21]([CH2:24][CH:25]([CH:34]4[CH2:35][CH2:36][C:37]([N:47]([CH3:49])[CH3:48])([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=5)[CH2:38][CH2:39]4)[OH:26])[CH2:20][CH2:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)(=[O:9])=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C1(c2cccc(F)c2)CCC(C(CN2CCc3c(n(S(=O)(=O)c4ccccc4)c4ccccc34)C2)O[Si](C)(C)C(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)C1(c2cccc(F)c2)CCC(C(O)CN2CCc3c(n(S(=O)(=O)c4ccccc4)c4ccccc34)C2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2 M hydrochloric acid (20 ml) was added to a solution of the product from stage 8 (176 mg, 0.255 mmol) in tetrahydrofuran (20 ml) and the mixture was stirred at room temperature for 1 d. The reaction mixture was then stirred at 50° C. for 15 h and then at room temperature for a further 16 h. The mixture was then rendered alkaline with 2 M sodium hydroxide solution (30 ml) and the phases were separated. The aqueous phase was extracted with diethyl ether (3×10 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude product 151 mg) was purified by flash chromatography with methylene chloride/methanol (97:3).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:28](OCCC)[CH2:27][C@@:26]2([CH3:33])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:34])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:21])[CH2:13][S:14]([CH2:17][CH2:18][CH2:19][OH:20])(=[O:16])=[O:15])[CH2:3]1.[CH3:35][CH2:36]CCCC.CC(C)=O>>[C:35]([C@@:2]1([OH:1])[CH2:28][CH2:27][C@@:26]2([CH3:33])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:34])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:21])[CH2:13][S:14]([CH2:17][CH2:18][CH2:19][OH:20])(=[O:16])=[O:15])[CH2:3]1)#[CH:36]
Reactant: CCCCCC
Reactant: CCCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(=O)CS(=O)(=O)CCCO)CC[C@@H]32)C[C@@H]1O
Solvent: CC(C)=O
Product: C#C[C@@]1(O)CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(=O)CS(=O)(=O)CCCO)CC[C@@H]32)C1

Procedure:
Similarly prepared was 3α-hydroxy-21-(3'-hydroxypropylsulfonyl)-2β-propoxy-5α-pregnan-20-one; TLC Rf (hexane:acetone 2:1)=0.26.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[NH2:5].C([O-])([O-])=O.[Na+].[Na+].[CH2:17]([O:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1>[CH3:1][O:2][C:3](=[O:10])[C@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[NH:5][C:25]([O:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:26]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.9 %

Procedure:
To a stirring solution of L-leucine methyl ester (2.0 g, 11.0 mmol) in 1,4-dioxane (20 mL) was added aqueous Na2CO3 solution (12.1 mL, 2M in H2O) followed by benzylchloroformate (1.96 g, 11.5 mmol). The mixture stirred at room temperature for 4 h then partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried (MgSO4), filtered and concentrated to yield the title compound as a colorless oil (3.1 g, 100%). 1HNMR (400 MHz, CDCl3) δ 7.34 (m, 5H), 5.27 (d, 1H), 5.12 (s, 2H), 4.41 (s, 2H), 3.75 (s, 3H), 1.65 (m, 3H), 0.96 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21]([OH:23])=O)=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:24][C:25]1([CH2:28][OH:29])[CH2:27][CH2:26]1.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>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21]([NH:24][C:25]5([CH2:28][OH:29])[CH2:27][CH2:26]5)=[O:23])=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Reactant: NC1(CO)CC1
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: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(CO)CC4)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 4.7 %

Procedure:
A mixture of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (70 mg, 0.225 mmol), (1-aminocyclopropyl)methanol (30 mg, 0.337 mmol), HATU (171 mg, 0.45 mmol) and DIEA (58 mg, 0.45 mmol) in DMF (3 mL) was stirred at 25° C. for 16 hours. Then the mixture was filtered and the cake was washed with MeOH. The crude product 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: 55% acetonitrile/45% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 80% acetonitrile/20% water (0.1% trifluoroacetic acid, v/v) in a linear fashion after 9 min.) to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-(1-(hydroxymethyl)cyclopropyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (4 mg, 5%). MS: (M+H)+=381; 1H NMR (300 MHz, DMSO): δ 12.88 (s, 1H), 9.12 (s, 1H), 8.71 (s, 1H), 8.60-8.55 (m, 1H), 8.46 (s, 1H), 7.72 (dd, 1H, J=9.6, 2.1 Hz), 7.28-7.21 (m, 1H), 4.17 (s, 3H), 3.60 (s, 2H), 0.96-0.85 (m, 4H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][C:11]3([C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15][CH2:14]3)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:26]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:24][C:25]1[CH:30]=[C:29]([O:31][CH2:2][C:3]2[CH:23]=[CH:22][C:6]([CH2:7][N:8]3[CH2:13][CH2:12][C:11]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH2:15][CH2:14]4)[CH2:10][CH2:9]3)=[CH:5][CH:4]=2)[CH:28]=[CH:27][C:26]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: BrCc1ccc(CN2CCC3(CCc4ccccc43)CC2)cc1
Reactant: CCOC(=O)CCc1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1ccc(OCc2ccc(CN3CCC4(CCc5ccccc54)CC3)cc2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
A mixture of 1′-[4-(bromomethyl)benzyl]-2,3-dihydrospiro[indene-1,4′-piperidine] (0.35 g, 0.94 mmol), ethyl 3-(2-fluoro-4-hydroxyphenyl)propanoate (0.2 g, 0.94 mmol) and K2CO3 (0.32 g, 2.3 mmol) in DMF (15 mL) is stirred overnight at room temperature. The reaction mixture is diluted with cold water and extracted with DCM (3×50 mL). The combined organic layer is washed with brine solution, dried over Na2SO4, and concentrated under vacuum. The crude material is purified by silica gel chromatography (gradient DCM/MeOH 8/2) to give the title compound as an off-white solid (0.22 g, crude). ESI/MS 502 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].O.[NH:11]1[C:15](=[O:16])[CH2:14][CH:13]2[CH2:17][C:18]3[C:23]([CH:12]12)=[CH:22][CH:21]=[CH:20][CH:19]=3>[N+](C)([O-])=O>[N+:6]([C:21]1[CH:22]=[C:23]2[C:18]([CH2:17][CH:13]3[CH2:14][C:15](=[O:16])[NH:11][CH:12]32)=[CH:19][CH:20]=1)([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: O=C1CC2Cc3ccccc3C2N1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C[N+](=O)[O-]
Product: O=C1CC2Cc3ccc([N+](=O)[O-])cc3C2N1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
Sulphuric acid (72 mL) was added to a cooled mixture of nitric acid (63.5 mmol, 4.4 mL) and water (11.3 mL), and the mixture was added dropwise to a cold (2-8° C.) suspension of 3,3a,4,8b-tetrahydro-1H-indeno[1,2-b]pyrrol-2-one (10 g, 57.7 mmol) in nitromethane (100 mL). The mixture was stirred 1.5 h at 2-8° C. after end of addition, and poured onto a mixture of ice and water (1 L). The white suspension was stirred for one hour, filtered and washed with water. The white solid was suspended in 1 L of ethyl acetate, dried and concentrated under vacuum. 7-nitro-3,3a,4,8b-tetrahydro-1H-indeno[1,2-b]pyrrol-2-one (9.2 g, 73%) was obtained. 1H NMR (400 MHz, CD3OD) δ 8.16-8.08 (2H, m), 7.39 (1H, d), 6.89 (1H, brs), 5.09 (1H, d), 3.49-3.37 (2H, m), 2.93 (1H, d), 2.78 (1H, dd), 2.26 (1H, dd) ppm.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH:6]([CH3:17])[CH2:7][NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16].O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:2][CH:6]([CH3:17])[CH2:7][NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16]
Reactant: BrP(Br)Br
Reactant: Cc1cccc(C)c1NCC(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cccc(C)c1NCC(C)Br
Reaction time: 6 h
Yield: 87.5 %

Procedure:
A mixture of 250 ml (712 g, 2.63 moles) of phosphorous tribromide and 250 ml of dry chloroform is added dropwise to a solution of 100 g (0.558 moles) of N-(β-hydroxypropyl)-2,6-dimethyl-aniline in 500 ml of dry chloroform. During the addition the temperature of the mixture is maintained below +25° C. by cooling with icy water. The resulting mixture is boiled for 6 hours, thereafter it is cooled on salted ice, and 100 ml of water are added dropwise. The pH of the resulting mixture is adjusted to 9 with 10 n aqueous sodium hydroxide solutions. The phases are separated from each other, and the aqueous phase is extracted thrice with 300 ml of chloroform each. The organic solutions are combined, washed four times with 500 ml of water each, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. 118.2 g (87.5%) of N-(β-bromopropyl)-2,6-dimethyl-aniline are obtained as a colourless oily residue. This product is sufficiently pure to be applied directly in the next step. When distilling the oil at 0.3 mm Hg it boils at 102°-106° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[CH:13]=O.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1.N1CCCC1>CO>[CH3:1][O:2][C:3](=[O:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1/[CH:13]=[C:21]1\[C:22](=[O:26])[NH:23][C:24]2[C:20]\1=[CH:19][CH:18]=[C:17]([Cl:16])[CH:25]=2
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: COC(=O)COc1ccc(Cl)cc1C=O
Solvent: CO
Solvent: C1CCNC1
Product: COC(=O)COc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Yield: 74.6 %

Procedure:
In a manner similar to the method described in Example 227b, (4-chloro-2-formyl-phenoxy)-acetic acid methyl ester (34 g, 149 mmol) was reacted with 6-chlorooxindole (20.7 g, 124 mmol) and pyrrolidine (10.58 g, 149 mmol) in methanol to give title compound as a yellow solid (35 g).
Reaction SMILES: [C:1]([S:4][CH:5]1[NH:8][C:7](=[O:9])[CH2:6]1)(=[O:3])[CH3:2].O.[C:11]([O:15][CH2:16][CH:17]=[CH2:18])(=[O:14])[CH:12]=[O:13]>C1C=CC=CC=1>[CH2:16]([O:15][C:11]([CH:12]([OH:13])[N:8]1[CH:5]([S:4][C:1](=[O:3])[CH3:2])[CH2:6][C:7]1=[O:9])=[O:14])[CH:17]=[CH2:18]
Reactant: C=CCOC(=O)C=O
Reactant: CC(=O)SC1CC(=O)N1
Solvent: c1ccccc1
Solvent: O
Product: C=CCOC(=O)C(O)N1C(=O)CC1SC(C)=O

Procedure:
4-Acetylthioazetidin-2-one (Annalen, 1974, p. 553) (1.4 g) and allyl glyoxylate hydrate (1.5 g) are refluxed for 2 hours in benzene to afford a solution of 1-(allyloxycarbonylhydroxymethyl)-4-acetylthioazetidin-2-one which is cooled and used directly in the next step.
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[NH:6][C:5]=1Br)(=[O:3])[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[NH:6][C:5]=1[C:21]1[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(Br)[nH]c(-c2ccncc2)c1C
Reactant: OB(O)c1ccc(F)cc1
Product: CC(=O)c1c(-c2ccc(F)cc2)[nH]c(-c2ccncc2)c1C

Procedure:
The title compound was prepared from 3-acetyl-2-bromo-4-methyl-5-(4-pyridyl)-1H-pyrrole according to the procedure of Example 46 using 4-fluorophenylboronic acid instead of 4-pyridylboronic acid in step 3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].I[CH3:18]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][CH3:18])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Reactant: CI
Solvent: CN(C)C=O
Product: CNc1cc(-c2ccccc2)sc1C(=O)OC
Temperature: 60 °C
Reaction time: 18 h
Yield: 32.2 %

Procedure:
To a mixture of methyl-3-amino-5-phenylthiophene-2-carboxylate (200 mg, 0.855 mmol) in anhydrous N,N-dimethylformamide (4.6 ml) were added 4.2 ml (8.55 mmol) of 2M iodomethane solution in t-buthylmethylether. The mixture was stirred at 60° C. for 18 hours, concentrated and purified using biotage technics (silica gel, hexane to hexane:ethyl acetate; 95:5 containing few drops of triethylamine) to give 68 mg (32% yield) of 3-methylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester. 1H NMR (CDCl3, 400 MHz) 7.65-7.62 (m, 2H), 7.42-7.36 (m, 3H), 6.86 (broad s, 1H), 3.83 (s, 3H), 3.04 (d, 3H)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:22])=[C:5]2[C:10]=1[C:9]([CH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=O)=[N:8][NH:7][C:6]2=[O:21].[CH2:23]([O:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:24].C(N(CC)CC)C>CN(C=O)C>[CH2:23]([O:25][CH:26]1[CH2:31][CH2:30][N:29]([C:15]([C:14]2[CH:13]=[C:12]([CH:20]=[CH:19][CH:18]=2)[CH2:11][C:9]2[C:10]3[C:5](=[C:4]([CH3:22])[NH:3][C:2]=3[CH3:1])[C:6](=[O:21])[NH:7][N:8]=2)=[O:17])[CH2:28][CH2:27]1)[CH3:24]
Reactant: CCOC1CCNCC1
Reactant: Cc1[nH]c(C)c2c(=O)[nH]nc(Cc3cccc(C(=O)O)c3)c12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC1CCN(C(=O)c2cccc(Cc3n[nH]c(=O)c4c(C)[nH]c(C)c34)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.1 %

Procedure:
2-(1H-Benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.163 g, 0.43 mmol) was added to 3-((5,7-dimethyl-1-oxo-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-4-yl)methyl)benzoic acid (51) (0.091 g, 0.31 mmol), 4-ethoxypiperidine (0.044 g, 0.34 mmol) and triethylamine (0.107 mL, 0.77 mmol) in DMF (2 mL). The resulting solution was stirred at room temperature for 16 hours. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material (0.028 g, 22.5% yield). 1H NMR (400.132 MHz, DMSO) δ 1.11 (3H, t), 1.16-1.95 (4H, m), 2.24 (3H, s), 2.51 (3H, s), 2.99-3.26 (2H, m), 3.33-3.54 (4H, m), 3.85-4.01 (1H, m), 4.09 (2H, s), 7.14 (1H, s), 7.20 (1H, d), 7.27 (1H, d), 7.35 (1H, t), 11.08 (1H, s), 11.92 (1H, s); m/z (LC-MS, ESI+), RT=1.53 min (M+H=409.13).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([N:29]3[CH2:34][CH2:33][CH:32]([CH:35]([C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=4[F:44])[F:36])[CH2:31][CH2:30]3)=[C:20]([NH:25][CH:26]([CH3:28])[CH3:27])[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:44][C:38]1[CH:39]=[C:40]([F:43])[CH:41]=[CH:42][C:37]=1[CH:35]([F:36])[CH:32]1[CH2:33][CH2:34][N:29]([C:19]2[N:18]=[C:17]3[CH2:16][NH:15][CH2:24][CH2:23][C:22]3=[N:21][C:20]=2[NH:25][CH:26]([CH3:27])[CH3:28])[CH2:30][CH2:31]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(F)c3ccc(F)cc3F)CC1)CN(Cc1ccccc1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)Nc1nc2c(nc1N1CCC(C(F)c3ccc(F)cc3F)CC1)CNCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-benzyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (108.3 mg, 0.174 mmol) and Pd(OH)2 on carbon, (20 wt %, 11 mg, 0.016 mmol) in THF (1.7 mL) was stirred under an atmosphere of hydrogen gas (balloon) at rt. After 2 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (67.5 mg, 72.9%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.24 (dd, J=6.6, 2.3 Hz, 6H), 1.41-1.48 (br m, 1H), 1.52-1.74 (m, 2H), 1.97-2.14 (m, 2H), 2.61-2.73 (m, 2H), 2.99 (t, J=6.3 Hz, 2H), 3.38-3.49 (m, 2H), 3.50-3.55 (m, 2H), 4.14 (s, 2H), 4.14-4.21 (m, 1H), 5.53 (dd, J=46.5, 7.3 Hz, 1H), 6.95-7.10 (m, 2H), 7.46-7.55 (m, 1H); ESI-MS m/z [M+H]+ 420.3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[OH-].[Na+].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>O>[C:10]([NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCNC(=O)c1ccccc1
Reaction time: 6 h
Yield: 74.7 %

Procedure:
6.4 g of gamma-aminobutyric acid and 4.5 g of sodium hydroxide were dissolved in 100 mL of purified water, and 7.9 g of benzoyl chloride was dropwise added thereto under ice-cooling. After stirring the mixture for 6 hours, hydrochloric acid was added to adjust the pH to 2 or less. The precipitated crude product was filtered, and then recrystallized with ethanol solution to give 8.7 g of the desired product.
Reaction SMILES: [CH2:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([Sn](CCCC)(CCCC)CCCC)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH2:2][CH3:3].Br[C:27]1[N:28]=[C:29]([N:37]2[CH2:42][CH2:41][N:40]([CH:43]=[O:44])[CH2:39][CH2:38]2)[C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.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>[CH:43]([N:40]1[CH2:39][CH2:38][N:37]([C:29]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:36]=[C:27]([C:10]3[CH:9]=[CH:8][C:7]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:5])=[O:6])=[CH:12][CH:11]=3)[N:28]=2)[CH2:42][CH2:41]1)=[O:44]
Reactant: O=CN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(S(=O)(=O)CCC)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)c1ccc(-c2cc3ccccc3c(N3CCN(C=O)CC3)n2)cc1
Yield: 61.8 %

Procedure:
Propyl-(4-tributylstannylphenyl)sulfone (1.59 g) and 3-bromo-1-(4-formylpiperazin-1-yl)isoquinoline (0.93 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.13 g) in xylene in nitrogen atmosphere overnight. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 5N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate. Then, it was adjusted to pH 10 by a 8N aqueous solution of sodium hydroxide, extracted with ethyl-acetate, washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (toluene/acetone system), to give 1-(4-formylpiperazin-1-yl)-3-[4-(propylsulfonyl)phenyl]isoquinoline (0.76 g).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]#[N:14])[CH:10]=2)[NH:5]1.Cl[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:27][CH2:26][C@H:25]3[CH2:28][N:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][C@@H:24]23)=[CH:18][N+:17]=1[O-:36]>>[C:13]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4]([OH:3])=[C:12]2[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:27][CH2:26][C@H:25]3[CH2:28][N:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][C@@H:24]23)=[CH:18][N+:17]=1[O-:36])#[N:14]
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: CCOC(=O)N1C[C@@H]2CCN(Cc3ccc(Cl)[n+]([O-])c3)[C@@H]2C1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)N1C[C@@H]2CCN(Cc3ccc(-c4c(O)[nH]c5ccc(C#N)cc45)[n+]([O-])c3)[C@@H]2C1

Procedure:
The titled compound was prepared in analogy to example 4.1 using sodium hydride on mineral oil (101 mg, 2.53 mmol), 2-oxoindoline-5-carbonitrile (300 mg, 1.897 mmol), and 2-chloro-5-(((3aS,6aS)-5-(ethoxycarbonyl)hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)methyl)pyridine 1-oxide (412, 1.265 mmol).