Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([OH:9])=O)[CH2:5][N:4]([C:10]2[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][N:11]=2)[C:3]1=[O:18].C(N1CCOCC1)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:50][C:51]1[CH:56]=[C:55]([Cl:57])[CH:54]=[CH:53][C:52]=1[CH2:58][NH2:59]>ClCCl.C(=O)([O-])O.[Na+]>[Cl:50][C:51]1[CH:56]=[C:55]([Cl:57])[CH:54]=[CH:53][C:52]=1[CH2:58][NH:59][C:7]([CH:6]1[CH2:5][N:4]([C:10]2[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][N:11]=2)[C:3](=[O:18])[N:2]1[CH3:1])=[O:9]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: COc1ccnc(N2CC(C(=O)O)N(C)C2=O)n1
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccnc(N2CC(C(=O)NCc3ccc(Cl)cc3Cl)N(C)C2=O)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 48.8 %

Procedure:
3-Methyl-1-[4-(methyloxy)-2-pyrimidinyl]-2-oxo-4-imidazolidinecarboxylic acid (76 mg, 0.3 mmol) (˜0.3 mmol) in dichloromethane (4 ml) was treated with the 4A molecular sieves (200 mg, 0.300 mmol), and the mixture stirred at RT for 5 minutes. N-Ethylmorpholine (0.190 ml, 1.500 mmol), 1-hydroxybenzotriazole hydrate (55.1 mg, 0.360 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (82 mg, 0.360 mmol) were then added and the reaction stirred at RT under argon for 10 minutes. [(2,4-Dichlorophenyl)methyl]amine (58.1 mg, 0.330 mmol) was added and the reaction left to stir at RT under argon for 4 hours. The reaction mixture was diluted with dichloromethane (15 ml) and saturated sodium hydrogen carbonate solution (20 ml), and the product was extracted into dichloromethane (×2). The combined organic extracts were washed with water (20 ml), brine (20 ml) and then dried over magnesium sulphate. The solvent was evaporated in vacuo to give a yellow solid, which was purified by mass-directed automated HPLC. Fractions containing product were combined and solvent evaporated in vacuo, co-evaporated with diethyl ether to give N-[(2,4-dichlorophenyl)methyl]-3-methyl-1-[4-(methyloxy)-2-pyrimidinyl]-2-oxo-4-imidazolidinecarboxamide as a white solid (60 mg, 46.3% yield). LC/MS [M+H]+=410, retention time 1.73=minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:24])=[C:6]([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[C:22]#[N:23])=[N:9]S(C(C)C)=O)[CH:7]=1.Br[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:24])=[C:6]([C:8]2([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:15]3[C:16](=[C:17]([F:21])[CH:18]=[CH:19][CH:20]=3)[C:22]([NH2:23])=[N:9]2)[CH:7]=1
Reactant: CC(C)S(=O)N=C(c1cc(Br)ccc1F)c1cccc(F)c1C#N
Reactant: FC(F)(F)c1cc(Br)ccn1
Product: NC1=NC(c2ccnc(C(F)(F)F)c2)(c2cc(Br)ccc2F)c2cccc(F)c21
Yield: 90 %

Procedure:
The title compound was synthesized as described for example 11i in 90% yield starting from N-((5-bromo-2-fluorophenyl)(2-cyano-3-fluorophenyl)methylene)propane-2-sulfinamide (0.980 g, 2.38 mmol) and 4-bromo-2-(trifluoromethyl)pyridine (0.646 g, 2.86 mmol). Purification was achieved by flash chromatography using a gradient of 100% CH2Cl2 to 30% 0.1M NH3 in MeOH in CH2Cl2.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])=[CH:4][CH:3]=1.O.[NH2:17][NH2:18]>N1C=CC=CC=1>[NH:17]([C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])=[CH:4][CH:3]=1)[NH2:18]
Reactant: NN
Reactant: N#Cc1cccc(-c2ccc(Cl)nn2)c1
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1cccc(-c2ccc(NN)nn2)c1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A solution of 3-(6-chloro-pyridazin-3-yl)-benzonitrile (75.6 g, 350 mmol) in 900 mL of dried pyridine was cooled in an ice bath and 119.2 mL of hydrazine hydrate was added. The cooling was continued so as to keep the temperature below 30° C. at which time yellow needle separated. The mixture was then heated to 65° C. and stirred overnight. Then the mixture was concentrated and the residue was washed with water and Methanol to return the title compound (60 g, 81%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 8.38˜8.39 (m, 1H), 8.32˜8.35 (m, 1H), 8.24 (s, 1H), 7.97˜8.00 (d, 1H), 7.82˜7.85 (m, 1H), 7.64˜7.69 (m, 1H), 7.09˜7.12 (d, 1H), 4.39 (s, 2H); MS (m/z) 212.1 [M++1].
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].Br[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[F:22]>CN(C=O)C>[F:22][C:14]1[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=1[CH:4]([C:3]([O:10][CH3:11])=[O:9])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=[N+]([O-])c1ccc(Br)c(F)c1
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Temperature: 70 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
To a suspension of sodium hydride (NaH, 60%, 0.40 g, 10.0 mmol) in dry DMF (10 mL) under ice cooling was added dimethyl malonate (1.04 mL, 9.1 mmol) dropwise followed by a solution of 1-bromo-2-fluoro-4-nitrobenzene (1.00 g, 4.55 mmol) in dry DMF (3 mL) under an argon atmosphere. The resulting mixture was stirred at 70° C. overnight and then allowed to cool to 21° C. The reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate (2×50 mL). The organic layer was dried over MgSO4, concentrated and the residue was purified with silica gel column chromatography (hexane:ethyl acetate, 2:1) to give Dimethyl 2-(2-fluoro-4-nitrophenyl)malonate (86) (0.90 g, 73%) as a light yellowish solid: 1H NMR δ 8.07 (dd, 1H, J=8.6, 2.2 Hz), 7.98 (dd, 1H, J=9.3, 2.2 Hz), 7.74 (dd, 1H, J=8.6, 7.1 Hz), 5.08 (s, 1H), 3.81 (s, 6H).
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)[C:3](=[O:5])[CH3:4].C(N(CC)CC)C.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1>C(O)C>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[C:3](=[O:5])[CH3:4])=[CH:27][CH:26]=1
Reactant: CC(=O)C(Cl)=NNc1cccc([N+](=O)[O-])c1
Reactant: Sc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)C(=NNc1cccc([N+](=O)[O-])c1)Sc1ccc(Cl)cc1

Procedure:
1-chloro-1-[(3-nitrophenyl)hydrazono]-2-propanone is reacted with 4-chlorothiophenol triethyl amine in ethanol as Example 11 to yield 1-[(4-chlorophenyl)thio]-1-[(3-nitrophenyl)hydrazono]-2-propanone.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([C@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.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>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)[N:14]=1)[N:11]([C@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2[C@@H](C)c2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2[C@@H](C)c2ccccc2)c1O
Temperature: 120 °C
Yield: 39.3 %

Procedure:
A mixture of (S)-8-bromo-5-hydroxy-2-oxo-3-phenyl-1-(1-phenyl-ethyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (78 mg, 0.16 mmol), 3-tributylstannanyl-pyridine (0.078 mL, 0.24 mmol) and PdCl2(PPh3)2 (23 mg, 0.033 mmol) in 4 mL of DMF was heated at 120° C. for 3 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified by silica gel chromatography (5-90% EtOAc/hexanes+1% AcOH) to give 30 mg of the title compound. MS: (+) m/z 478.39 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11]2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Br[CH2:27][CH2:28][CH2:29][N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>CC#N>[CH3:9][O:8][C:7]1[C:2]([O:1][CH2:27][CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:3][C:4]([N+:16]([O-:18])=[O:17])=[C:5]([C:10]2([C:14]#[N:15])[CH2:11][CH2:12][CH2:13]2)[CH:6]=1
Reactant: COc1cc(C2(C#N)CCC2)c([N+](=O)[O-])cc1O
Reactant: BrCCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C2(C#N)CCC2)c([N+](=O)[O-])cc1OCCCN1CCCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 59.8 %

Procedure:
To a solution of 1-(4-(hydroxyl)-5-methoxy-2-nitrophenyl)cyclobutanecarbonitrile (0.73 g, 2.93 mmol), from Step 3, in MeCN (20 mL) was added potassium carbonate (1.215 g, 8.79 mmol) and 1-(3-bromopropyl)pyrrolidine hydrochloride (1 g, 4.4 mmol) and stirred at 100° C. for 3 hours. The reaction mixture was concentrated, and extracted with dichloromethane. The combined organic extracts were washed with brine. The organic layer was dried (MgSO4), filtered and concentrated. Purification by flash chromatography (silica gel, 5-20% methanol/dichloromethane) afforded 0.63 g (59%) of 1-(5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)phenyl)cyclobutanecarbonitrile. 1H NMR (400 MHz, METHANOL-D4) δ 7.65 (s, 1H), 6.94 (s, 1H), 4.14 (t, J=6.1 Hz, 2H), 3.97 (s, 3H), 2.87 (ddd, J=8.6, 5.3, 2.5 Hz, 2H), 2.77-2.67 (m, 2H), 2.68-2.52 (m, 6H), 2.42 (dd, J=14.6, 6.3 Hz, 1H), 2.13-2.01 (m, 2H), 2.01-1.89 (m, 1H), 1.84 (dt, J=6.6, 3.2 Hz, 4H). MS (ESI) m/z 360 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[NH:17][C@@H:18]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:19](=[O:31])[NH:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[NH:30])[CH3:29])[CH2:24][CH2:23]1)C1C=CC=CC=1.C(O)(=O)C>CO.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:17][C@@H:18]([CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)[C:19]([NH:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[NH:30])[CH3:29])[CH2:24][CH2:23]1)=[O:31]
Reactant: CC(=N)N1CCC(CNC(=O)[C@@H](NC(=O)OCc2ccccc2)C2CCCCC2)CC1
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CC(=N)N1CCC(CNC(=O)[C@@H](N)C2CCCCC2)CC1
Yield: 113.3 %

Procedure:
(S)-(Cyclohexyl-{[1-(1-imino-ethyl)-piperidin-4-ylmethyl]-carbamoyl}-methyl)-carbamic acid benzyl ester trifluoroacetic acid salt (340 mg, 0.62 mmol) was hydrogenated in methanol (50 ml) and acetic acid (3 ml) using palladium/charcoal (10%) as a catalyst. The solvent was evaporated and the residue solved in water and lyophilized to give 287 mg of the desired product (88%). MS m/z: 295.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1([S:15]([C:18]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[CH:19]OCC)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[C:9]1([S:15]([C:18]([S:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)(=[O:25])=[O:24])=[CH:19][NH:1][C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)(=[O:16])=[O:17])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC=C(S(=O)(=O)c1ccccc1)S(=O)(=O)c1ccccc1
Reactant: Nc1ccc(Br)cn1
Solvent: Cc1ccccc1
Product: O=S(=O)(C(=CNc1ccc(Br)cn1)S(=O)(=O)c1ccccc1)c1ccccc1
Yield: 84 %

Procedure:
A mixture of 2-amino-5-bromopyridine (38 g) and 1,1-bis(phenylsulphonyl)-2-ethoxyethene [70 g; prepared as described by Stetter et al, Monatshefte fur Chemie, 103, 1262-1270 (1972)] in toluene (1 liter) was slowly distilled during a period of 2 hours, maintaining the volume approximately constant by the gradual addition of further toluene to replace the liquid removed by the distillation. The mixture was then concentrated under vacuum and the residue was recrystallised twice from a mixture of chloroform and ethanol, to give 1,1-bis(phenylsulphonyl)-2-(5-bromopyrid-2-ylamino)ethene (80 g) m.p. 177°-179° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](Br)=[CH:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2].[NH2:14][C:15]1[N:19]([CH3:20])[N:18]=[C:17]([CH3:21])[CH:16]=1>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([CH3:21])[CH:16]=2)=[CH:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: Cc1cc(N)n(C)n1
Reactant: CCOC(=O)c1nc(C)ccc1Br
Agent: [Pd]
Product: CCOC(=O)c1nc(C)ccc1Nc1cc(C)nn1C

Procedure:
The Pd catalyzed coupling of 3-Bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester and 5-Amino-1,3-dimethylpyrazole was performed in accordance with the general method of Example 78, step 3 to yield the title compound as a yellow-cristalline solid, MS (ISP): m/e=275.4 (M+H+).
Reaction SMILES: Cl[C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:8][C:6]1[N:7]=[C:2]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([CH3:12])[CH:14]=2)[C:3]([C:9]([NH2:11])=[O:10])=[N:4][CH:5]=1
Reactant: NC(=O)c1ncc(Cl)nc1Cl
Reactant: Cc1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccc(Nc2nc(Cl)cnc2C(N)=O)c1

Procedure:
To an acetonitrile solution of 3,5-dichloropyrazine-2-carboxamide were added 3-methylaniline and N,N-diisopropylethylamine, followed by heating to reflux for 17 hours. Thereafter, purification in the usual way afforded 5-chloro-3-(3-methylanilino)pyrazine-2-carboxamide (yellow solid).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3=[CH:17][S:18][C:19]([C:20]([OH:22])=O)=[C:15]3[N:14]=[C:13]2[C:23](=[O:34])[NH:24][CH:25]2[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]2)=[O:10])=[N:6][CH:7]=1.[CH2:35]1[CH2:41][O:40][CH2:39][CH2:38][NH:37][CH2:36]1.Cl>>[CH:31]([N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:23]([C:13]2[N:12]([CH2:11][C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[C:16]3[C:15](=[C:19]([C:20]([N:37]4[CH2:36][CH2:35][CH2:41][O:40][CH2:39][CH2:38]4)=[O:22])[S:18][CH:17]=3)[N:14]=2)=[O:34])[CH2:26][CH2:27]1)([CH3:32])[CH3:33]
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)scc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Reactant: C1CNCCOC1
Agent: Cl
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)N4CCCOCC4)scc3n2CC(=O)Nc2ccc(Cl)cn2)CC1

Procedure:
3-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-6-([1,4]oxazepane-4-carbonyl)-3H-thieno[3,4-d]imidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 80 mg (0.158 mmol) 3-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid and 21.8 mg (0.158 mmol) homomorpholine-hydrochloride. The title compound was obtained as its formiate in form of a white amorphous solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[CH:12][C:13]=1[F:14].[CH3:16][O:17][C:18](=[O:27])/[CH:19]=[C:20](\[NH:22][C:23](=[O:26])[CH2:24]Br)/[CH3:21]>CC(C)=O>[F:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[F:14])[O:15][CH2:24][C:23]([NH:22]/[C:20](/[CH3:21])=[CH:19]\[C:18]([O:17][CH3:16])=[O:27])=[O:26]
Reactant: Oc1ccc(F)c(F)c1
Reactant: COC(=O)/C=C(/C)NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)/C=C(/C)NC(=O)COc1ccc(F)c(F)c1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
To a suspension of K2CO3 (1.38 g, 10.0 mmol) in acetone (50 mL) were added 3,4-difluorophenol (0.78 g, 6.00 mmol) and (Z)-methyl-3-(2-bromoacetamido)but-2-enoate (1.18 g, 5.00 mmol) and the mixture was refluxed for 5 h. The mixture was cooled to rt and filtered and the filtrate was concentrated in vacuo. To the residue was added DCM (100 mL) and the mixture was washed with water (100 mL×2) and brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=5:1) to give the title compound as a white solid (0.85 g, 59%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[N:15]=[C:14]3[C:17](=[O:26])[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=4[CH2:20][CH2:21][C:13]3=[C:12](Br)[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CN>>[CH2:1]([N:8]1[C:16]2[N:15]=[C:14]3[C:17](=[O:26])[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=4[CH2:20][CH2:21][C:13]3=[C:12]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2CCc2c1nc1c(cnn1Cc1ccccc1)c2Br
Reactant: C1COCCN1
Agent: CN
Product: O=C1c2ccccc2CCc2c1nc1c(cnn1Cc1ccccc1)c2N1CCOCC1

Procedure:
By substituting the product of Example 11 in the procedure of Example 5 and substituting morpholine for the methylamine, 1-benzyl-4-(morpholino)-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)one is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[NH:21][C:16]2=[N:17][CH:18]=[CH:19][N:20]=[C:15]2[CH:14]=1.C([Li])CCC.C1(C)C=CC(S([Cl:36])(=O)=O)=CC=1>COC(OC)(O)C>[Cl:36][C:7]1[N:8]([CH3:12])[C:9]2[C:5]([C:6]=1[C:13]1[NH:21][C:16]3=[N:17][CH:18]=[CH:19][N:20]=[C:15]3[CH:14]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c(c1)c(-c1cc3nccnc3[nH]1)cn2C
Agent: COC(C)(O)OC
Agent: [Li]CCCC
Product: COc1ccc2c(c1)c(-c1cc3nccnc3[nH]1)c(Cl)n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
A solution of 6-(5-methoxy-1-methyl-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine [100 mg, Example 1(a)] in dimethoxy ethanol (25 mL), cooled to −78° C., was treated with a solution of n-butyllithium in hexanes (172 μl, 2.5M). After stirring for 30 minutes the mixture was treated with 4-toluenesulfonyl chloride (82 mg) then allowed to warm slowly to ambient temperature and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (19:1, v/v) to give the title compound (45 mg) as a black solid. MS: 313 (MH+). 1H NMR [(CD3)2SO]: δ 12.20 (1H, s); 8.39 (1H, d, J=3 Hz); 8.21 (1H, d, J=3 Hz); 7.54 (1H, d, J=9 Hz); 7.30 (1H, d, J=2 Hz); 6.96 (1H, dd, J=9 and 2 Hz); 6.84 (1H, d, J=2 Hz); 3.82 (3H, s); 3.81 (3H, s).
Reaction SMILES: C(O[C:9](=O)[N:10]([CH:12]([C:14](=[O:51])[NH:15][CH:16]([CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)[C:17]([N:19]1[CH2:23][CH2:22][CH:21]2[N:24]([C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[CH2:25][CH:26]([C:27](=[O:39])[NH:28][CH:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:32][CH2:31][CH2:30]3)[CH:20]12)=[O:18])[CH3:13])C)C1C=CC=CC=1>CO.[Pd]>[CH:29]1([NH:28][C:27]([CH:26]2[CH2:25][N:24]([C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[CH:21]3[CH2:22][CH2:23][N:19]([C:17](=[O:18])[CH:16]([CH:45]4[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]4)[NH:15][C:14](=[O:51])[CH:12]([NH:10][CH3:9])[CH3:13])[CH:20]23)=[O:39])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1
Reactant: CC(C(=O)NC(C(=O)N1CCC2C1C(C(=O)NC1CCCc3ccccc31)CN2C(=O)C1CC1)C1CCCCC1)N(C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNC(C)C(=O)NC(C(=O)N1CCC2C1C(C(=O)NC1CCCc3ccccc31)CN2C(=O)C1CC1)C1CCCCC1
Reaction time: 1.5 h
Yield: 33.8 %

Procedure:
A mixture of 48 (450 mg, 0.63 mmol) and 10% palladium-on-carbon (wet, 90 mg) in MeOH (15 mL) was shaken at 50 psi under a H2 atmosphere. After 1.5 h, the mixture was filtered through a 0.45 μM filtering disc, washed with MeOH and concentrated. Purification by reverse-phase HPLC (2″ Dynamax® C18, 10-70% ACN in H2O with 0.1% HOAc over 30 min) afforded 49 (123 mg) as a white flocculent solid following lyophilization of the purified fractions.
Reaction SMILES: [CH2:1]([CH:8]([O:25][C:26](=[O:28])[CH3:27])[CH:9]([NH:11][C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[NH:11][CH:9]([CH3:10])[CH:8]([O:25][C:26](=[O:28])[CH3:27])[CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:18][CH:19]=3)=[CH:39][CH:38]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CC(=O)OC(Cc1ccccc1)C(C)Nc1c(C)noc1-c1ccc(Br)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)C(Cc4ccccc4)OC(C)=O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using acetic acid 1-benzyl-2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamino]-propyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:33][CH2:32][NH:31][CH2:30][C@H:29]4[OH:34])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:33][CH2:32][N:31]([C:39](=[O:38])[CH2:40][OH:41])[CH2:30][C@H:29]4[OH:34])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)CO)C[C@H]4O)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f27) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Na].Cl[C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1.[CH2:14]([OH:16])[CH3:15]>>[CH2:14]([O:16][C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1)[CH3:15]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CCO
Agent: [Na]
Product: CCOc1nsnc1-c1cccnc1
Temperature: 40 °C
Reaction time: 10 h
Yield: 76 %

Procedure:
To a solution of sodium (440 mg, 17 mmol) in ethanol (10 ml) was added 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (540 mg, 3.3 mmol). The mixturewas stirred at 40° C. for 10 h and evaporated. The residue was dissolved in water and extracted with methylene chloride. The combined organic phases were dried and evaporated to yield 520 mg (76%) of the title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([C@H:12]([NH2:14])[CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[C:6]1([C@H:12]([NH:14][S:2]([CH:1]=[CH:13][C:12]2[C:6]3[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=3[N:14]([CH2:12][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:14]=2)(=[O:4])=[O:3])[CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: C[C@@H](NS(=O)(=O)C=Cc1nn(Cc2ccccc2)c2c1CCCC2)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanesulfonyl chloride Compound 11f1 (2.0 g, 17 mMol) and TEA (2.43 mL, 17.46 mMol) were added to a solution of (1R)-1-phenyl-ethylamine Compound 11f2 (1.75 g, 17.5 mMol) in CH2Cl2 (50 mL) at 0° C. under a N2 atmosphere. The mixture was stirred for 3 hrs while warming to r.t., then the reaction was quenched with water (5 mL). The organic layer was diluted with CH2Cl2 (100 mL) and then washed with water and brine. The organic layer was separated, dried with anhydrous sodium sulfate, then filtered and concentrated in vacuo to afford the corresponding N-(1-phenyl-ethyl)-methanesulfonamide Compound 11f3 as an oil.