Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:5]2[CH:13]=[C:14]([Cl:20])[C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:4]=2[N:3]=1.[CH2:21]([O:23][C:24]([C:26]1[CH:27]=[N:28][NH:29][CH:30]=1)=[O:25])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:21]([O:23][C:24]([C:26]1[CH:27]=[N:28][N:29]([C:2]2[N:6]([CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:5]3[CH:13]=[C:14]([Cl:20])[C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:4]=3[N:3]=2)[CH:30]=1)=[O:25])[CH3:22]
Reactant: COCCOCn1c(Cl)nc2cc([N+](=O)[O-])c(Cl)cc21
Reactant: CCOC(=O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2nc3cc([N+](=O)[O-])c(Cl)cc3n2COCCOC)c1
Temperature: 60 °C
Yield: 99.4 %

Procedure:
To a solution of 2,6-dichloro-1-(2-methoxy-ethoxymethyl)-5-nitro-1H-benzoimidazole (6.15 g, 19.2 mmol), 1H-pyrazole-4-carboxylic acid ethyl ester (2.96 g, 21.1 mmol) and DMF (40 mL) was added cesium carbonate (12.5 g, 38.4 mmol) in a sealable pressure vessel. The vessel was purged with nitrogen, sealed, and heated at 60° C. for 2 h. The reaction mixture was poured into a 1:1 mixture of brine/water (80 mL), and was extracted with EtOAc (3×125 mL). The combined organic layers were washed with brine (3×125 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (5-45% EtOAc/hexanes) to yield the titled compound (8.09 g, 98%) as a mixture of regioisomers. MS (ESI/CI): mass calcd. for C17H18ClN5O6, 423.1; m/z found, 424.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.93 (d, J=0.6 Hz, 1H), 8.28 (s, 1H), 8.22 (d, J=0.6 Hz, 1H), 7.83 (s, 1H), 6.26 (s, 2H), 4.37 (q, J=7.1 Hz, 2H), 3.73-3.67 (m, 2H), 3.49-3.44 (m, 2H), 3.29 (s, 3H), 1.39 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C@@H:11]([CH3:12])[CH2:10][N:9]([C:13]3[S:14][C:15]([C:19]([O:21]CC)=[O:20])=[C:16]([CH3:18])[N:17]=3)[C:8]2=[O:24])=[CH:4][CH:3]=1.[OH-].[Li+].Cl>O1CCCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C@@H:11]([CH3:12])[CH2:10][N:9]([C:13]3[S:14][C:15]([C:19]([OH:21])=[O:20])=[C:16]([CH3:18])[N:17]=3)[C:8]2=[O:24])=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1sc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Yield: 69.4 %

Procedure:
To a solution of (S)-ethyl 2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate (0.50 g, 1.32 mmol) in tetrahydrofuran (20.0 mL) was added a solution of lithium hydroxide (0.16 g, 6.62 mmol) in water (15 mL). The reaction mixture was refluxed for 16 h and followed by the addition of 1 N aqueous hydrochloric acid solution to adjust pH to 2. The mixture was extracted with ethyl acetate (3×40 mL). The organic layer was washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated in vacuo and the residue was purified by crystallized in ethyl acetate to afford the title compound as a colorless solid (0.32 g, 69%): mp 208-210° C. (ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.31-7.26 (m, 2H), 7.04 (dd, J=8.6, 8.6 Hz, 2H), 4.83 (d, J=15.3 Hz, 1H), 4.29-4.14 (m, 2H), 3.78-3.65 (m, 2H), 2.65 (s, 3H), 1.31 (d, J=5.9 Hz, 3H); MS (ES−) m/z 347.9 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11](=O)[NH2:12])[CH2:7][CH2:6]1)=[O:4].O=C(Cl)OC(Cl)(Cl)Cl>P(OC)(OC)(OC)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]#[N:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCC(C(N)=O)CC1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: COP(=O)(OC)OC
Product: COC(=O)C1CCC(C#N)CC1
Temperature: 25 °C
Yield: 35.4 %

Procedure:
To a mixture of 4-carbamoyl-cyclohexanecarboxylic acid methyl ester (2.14 g, 11.6 mmol) in trimethyl phosphate (14 mL) cooled in an ice bath was dripped in diphosgene (2.24 g 11.6 mmol) and the reaction was allowed to warm to room temperature over 2 hr. The material was diluted with ethyl acetate (200 mL) and washed with an aqueous sodium bicarbonate (saturated, 200 mL) and brine (200 mL), dried over sodium sulfate, and concentrated as a clear oil. The oil was triturated with hexanes to give 4-cyano-cyclohexanecarboxylic acid methyl ester (687 mg 36%) as a clear oil. LCMS calcd for C9H13NO2 (m/e) 167, obsd 168 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:4]=1.[CH3:19][NH2:20]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:20][CH3:19])(=[O:11])=[O:10])=[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)c(N2CCOCC2)c1
Reactant: CN
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(OC)cc1N1CCOCC1
Reaction time: 15 h

Procedure:
To a stirred solution of 4-methoxy-2-morpholin-4-yl-benzenesulfonyl chloride (37 mg; 0. 13 mmol) in dry CH2Cl2 (1 mL) was added methylamine (0.16 mL of 2.0 M solution in tetrahydrofuran; 0.32 mmol) via syringe at room temperature under a nitrogen atmosphere. After stirring for 15 hours, the reaction was diluted with CH2Cl2 (25 mL), washed with water, saturated aqueous NaHCO3 and brine, then dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified via HPLC (Biotage with 2:1 hexanes/EtOAc) to provide the sulfonamide as a white solid (12.5 mg; 34%).
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12](C(OC(C)(C)C)=O)[NH:13]C(OC(C)(C)C)=O)[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].C(O[C:31](=[O:36])[CH2:32][C:33](=O)[CH3:34])C.Cl>C(O)C.O>[CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[C:31](=[O:36])[CH2:32][C:33]([CH3:34])=[N:13]3)[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1CCc2ccc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc21
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCC1CCc2ccc(N3N=C(C)CC3=O)cc21
Yield: 32.3 %

Procedure:
Di-tert-butyl 1-(3-ethyl-2,3-dihydro-1H-inden-5-yl)hydrazine-1,2-dicarboxylate 41c (3.43 g, 9.1 mmol) was dissolved in 50 mL of a solvent mixture of ethanol/water (V:V=3:2) followed by addition of 3-oxo-butanoic acid ethyl ester (1.18 g, 9.1 mmol) and 4.55 mL of hydrochloric acid (6 N). Upon completion of the addition, the reaction mixture was heated to reflux and reacted for 1 hour. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure to remove ethanol and then extracted with dichloromethane (15 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2-(3-ethyl-indan-5-yl)-5-methyl-2,4-dihydro-pyrazol-3-one 41d (0.712 g, 39.8%) as a yellow oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5](OC)=[O:6].[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[C:21](=O)[O:20][C:19](=O)[N:18](C)[C:17]=2[CH:25]=1.O>CN(C=O)C>[Br:12][C:13]1[CH:25]=[C:17]2[C:16]([C:21]([OH:20])=[C:4]([C:3]([O:10][CH3:11])=[O:9])[C:5](=[O:6])[N:18]2[CH3:19])=[CH:15][CH:14]=1
Reactant: COC(=O)CC(=O)OC
Reactant: Cn1c(=O)oc(=O)c2ccc(Br)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(O)c2ccc(Br)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
To a 50 mL RBF was added sodium hydride (0.15 g, 3.7 mmol) and N,N-dimethylformamide (50 mL, 3.1 mmol) under nitrogen. The mixture was cooled with an ice-water bath for 10 min, and then dimethyl malonate (6.4 mL, 56 mmol) was added over 3 min. A mixture of 7-bromo-1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (0.80 g, 3.1 mmol) in DMF (5.0 mL) was added, and then the reaction was placed in oil bath at 120° C. for 3 hours. The reaction was cooled to room temperature, and water (25 mL) was added to the mixture. A white solid was collected by filtration and washed with water (100 mL), followed by ether (100 mL). The white solid was placed in vacuum oven at 50° C. for 6 h to afford the desired product as a white solid (0.65 g, 67%).
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11]C)=[C:5]([CH3:13])[C:4]=1[CH2:14]/[CH:15]=[C:16](\[CH3:25])/[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:24])[CH3:23]>C(C#N)(C)=O.C(Cl)Cl.O>[CH3:25]/[C:16](=[CH:15]\[CH2:14][C:4]1[C:3](=[O:2])[C:8]([CH3:9])=[C:7]([CH3:10])[C:6](=[O:11])[C:5]=1[CH3:13])/[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:24])[CH3:23]
Reactant: COc1c(C)c(C)c(OC)c(C/C=C(\C)CCCCNC(C)=O)c1C
Agent: CC(=O)C#N
Solvent: O
Solvent: ClCCl
Product: CC(=O)NCCCC/C(C)=C/CC1=C(C)C(=O)C(C)=C(C)C1=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Ceric ammonium nitrate (90.1 mg, 0.164 mmol) was dissolved into H2O (0.5 mL) and AcCN (0.5 mL) and cooled to 0° C. A solution containing 25.2 mg N-((E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-enyl)acetamide (0.0725 mmol) in AcCN (1 mL) and CH2Cl2 (0.25 mL) was added over 0.5 min. The reaction was stirred for 0.75 h at 0° C. then diluted with H2O (2 mL). The layers were separated and the organic phase diluted with EtOAc (5 mL) and washed with H2O (3×2 mL). The combined aqueous phase was back extracted using EtOAc (3×4 mL) and discarded. The combined organics were washed with brine (2×3 mL), dried over Na2SO4, concentrated in vacuo and subjected to flash chromatography (SiO2) gave N-((5E)-5-methyl-7-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)hept-5-enyl)acetamide as a bright yellow liquid. 1H NMR (400 MHz, CDCl3) d 5.61 (br s, 1H), 3.20 (m, 4H), 2.01 (m, 14H), 1.72 (s, 3H), 1.41 (m, 2H). 1C NMR (100 MHz, CDCl3) d 187.9, 187.1, 170.0, 143.1, 140.43 140.37, 136.7, 119.9, 60.1, 39.5, 39.2, 29.1, 25.6, 25.0, 23.3, 16.1, 12.4, 12.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[N-:9]=[N+:10]=[N-:11].[Na+].[NH4+].[Cl-]>CN(C=O)C>[N:9]([C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1)=[N+:10]=[N-:11]
Reactant: Nc1ccnc(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1cc(N)ccn1
Temperature: 110 °C
Yield: 71.2 %

Procedure:
To a solution of 2-chloropyridin-4-amine (2.0 g, 15.6 mmol) in DMF (20 mL) under nitrogen was added NaN3 (2.0 g, 31.2 mmol) and NH4Cl (1.7 g, 31.2 mmol). The mixture was heated to 110° C. for 10 hours and then quenched with saturated Na2CO3. The reaction was filtered and then the filtrate was extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with water (50 mL), dried over Na2SO4, and concentrated under reduced pressure to afford 2-azidopyridin-4-amine (1.5 g, yield: 83%). LCMS (ESI) m/z: 136.2 [M+H+].
Reaction SMILES: [Br:1][C:2]1[C:6]2=[CH:7][C:8]([Cl:30])=[C:9]3[C:14]([C:13](=[O:15])[O:12][C:11]([C:16]4[N:17]([C:23]5[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=5)[N:18]=[C:19]([O:21][CH3:22])[CH:20]=4)=[N:10]3)=[C:5]2[NH:4][N:3]=1.Cl.[C:32]1([NH2:38])([CH:35]2[CH2:37][CH2:36]2)[CH2:34][CH2:33]1.C(N(CC)CC)C>CN(C)C=O>[C:32]1([NH:38][C:13]([C:14]2[C:9]([NH:10][C:11]([C:16]3[N:17]([C:23]4[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=4)[N:18]=[C:19]([O:21][CH3:22])[CH:20]=3)=[O:12])=[C:8]([Cl:30])[CH:7]=[C:6]3[C:5]=2[NH:4][N:3]=[C:2]3[Br:1])=[O:15])([CH:35]2[CH2:37][CH2:36]2)[CH2:34][CH2:33]1
Reactant: NC1(C2CC2)CC1
Reactant: COc1cc(-c2nc3c(Cl)cc4c(Br)n[nH]c4c3c(=O)o2)n(-c2ncccc2Cl)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)Nc2c(Cl)cc3c(Br)n[nH]c3c2C(=O)NC2(C3CC3)CC2)n(-c2ncccc2Cl)n1
Temperature: 50 °C
Reaction time: 24 h
Yield: 55.1 %

Procedure:
To a solution of 120 mg (0.24 mmol) of the above 3-bromo-5-chloro-7-[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazol-3-yl]-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 2.4 mL of N,N-dimethylformamide is added 95 mg (0.71 mmol) of bicyclopropyl-1-ylamine hydrochloride and 99 μL (0.71 mmol) of triethylamine. The reaction is stirred at 50° C. for 24 hours and then concentrated in vacuo. The residue is taken-up with acetone and after filtration the filtrate is evaporated. Purification of the residue by flash chromatography (SiO2, hexanes/ethyl acetate 1:1) affords 80 mg (56%) of a solid; LC/MS:606/608 (M+H)+, m.p.: 190-194° C.
Reaction SMILES: [ClH:1].[C:2]1([S:8]([C:11]2[CH:12]=[CH:13][C:14]3[CH:23]4[CH:19]([NH:20][CH2:21][CH2:22]4)[CH2:18][O:17][C:15]=3[CH:16]=2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][C:25](=O)[CH3:26].C([BH3-])#N.[Na+].C1COCC1>ClCCCl.CO.C(O)(=O)C>[ClH:1].[C:2]1([S:8]([C:11]2[CH:12]=[CH:13][C:14]3[CH:23]4[CH:19]([N:20]([CH:25]([CH3:26])[CH3:24])[CH2:21][CH2:22]4)[CH2:18][O:17][C:15]=3[CH:16]=2)(=[O:10])=[O:9])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)OCC1NCCC21
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)N1CCC2c3ccc(S(=O)(=O)c4ccccc4)cc3OCC21
Reaction time: 0.17 h

Procedure:
7-(Phenylsulfonyl)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-b]pyrrole hydrochloride (enantiomer 1, Example 55, 20 mg, 0.08 mmol) was dissolved in 500 μL DCE:MeOH (9:1). After 10 min stirring, propan-2-one (7 μL, 1.5 eq), a 1 M solution of sodium cyanoborohydride in THF (0.16 mL, 0.16 mmol) and acetic acid (50 μL) were added sequentially. After stirring for 16 h, the reaction mixture was passed through a plug of silica gel and the solvent was evaporated. The residue was purified by preparative LC/MS using the standard procedure. The resulting material was dissolved in a small amount of DCM, treated with 1.0 N HCl in diethyl ether and the solvent evaporated to provide 7-(phenylsulfonyl)-3-(propan-2-yl)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-b]pyrrole hydrochloride. MS m/z 358.1 [M+H]+. 1H-NMR (400 MHz, DMSO-d6): δ 1.30 (d, J=1.6 Hz, 3H), 1.35 (d, J=1.6 Hz, 3H), 1.83-1.88 (m, 1H), 2.62-2.66 (m, 1H), 3.21-3.24 (m, 1H), 3.37 (bs, 1H), 3.66-3.72 (m, 2H), 4.10-4.24 (m, 3H), 4.23-4.41 (m, 1H), 7.45 (s, 1H), 7.52-7.77 (m, 5H), 7.97 (d, J=2 Hz 1H), 10.4 (bs, 1H).
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:10][SH:11])[C:6](OC)=[O:7])(=[O:3])[CH3:2].[OH-].[NH4+:13]>C1(C)C=CC=CC=1.ClCCl.CO>[C:1]([NH:4][C@@H:5]([CH2:10][SH:11])[C:6]([NH2:13])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H](CS)NC(C)=O
Reactant: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N[C@@H](CS)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
45a (53.4 g, 0.30 mol) was diluted with 250 mL of toluene and 200 mL of ammonium hydroxide. The mixture was stirred at room temperature overnight then concentrated. The resulting residue was suspended in 250 mL of acetonitrile/H2O (9.3:1) and stirred at room temperature until the insoluble material formed a viscous paste. The solvent was decanted then concentrated to give a viscous liquid. The crude product was taken up in dichloromethane/methanol (8.5:1) and passed through a silica gel column eluting with dichloromethane/methanol (8.5:1). Fractions containing the least polar UV-active component were combined and concentrated to give 25 g (52%) of (R)-2-acetamido-3-mercaptopropanamide as white solid. 1HNMR (DMSO-d6) δ 8.0 (d, 1H), 7.41 (s, 1H), 7.13 (s, 1H), 4.33 (m, 1H), 2.76 (m, 1H), 2.65 (m, 1H), 2.22 (m, 1H), 1.88 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:30]1[CH:31]=[N:32][CH:33]=[N:34][CH:35]=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:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:30]1[CH:31]=[N:32][CH:33]=[N:34][CH:35]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncnc1
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ncc2c(cc(-c3cncnc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 71.1 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (80 mg, 0.21 mmol), 5-tributylstannanyl-pyrimidine (0.1 mL, 0.31 mmol), and PdCl2(PPh3)2 (29 mg, 0.041 mmol) in DMF (5 mL) was heated at 120° C. under nitrogen atmosphere for 2 h. After the mixture was cooled to r.t., brine and EtOAc were added. 1 M HCl was added until pH was about 4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent, the crude product was purified by silica gel chromatography (90% EtOAc/hexanes+1% AcOH) to give 58 mg of the title compound. MS: (+) m/z 389.27 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:31])[CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[C:44](=[O:45])[C:43]([C:46](O)=[O:47])=[CH:42][CH:41]=[N:40]2)=[CH:35][CH:34]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:46]([C:43]2[C:44](=[O:45])[N:39]([C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)[N:40]=[CH:41][CH:42]=2)=[O:47])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:18][CH:17]=3)[S:15][C:8]=12
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c3s2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61 %

Procedure:
A round-bottomed flask was charged with tert-butyl 4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (30.0 mg, 0.068 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (Example 104, Step C, 31.8 mg, 0.136 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (39.1 mg, 0.204 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (27.5 mg, 0.204 mmol), N-ethyl-N-isopropylpropan-2-amine (0.061 ml, 0.340 mmol) and DMF (5 mL). The reaction mixture was stirred at room temperature for 48 hours. Then the reaction was partitioned between EtOAc (50 mL) and H2O (50 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (27.3 mg, 61.1%). LRMS (APCI pos) m/e 658 (M+1). 1H NMR (400 MHz, CDCl3) δ 11.82 (s, 1H), 8.42 (m, 2H), 8.24 (d, 1H), 7.98 (dd, 1H), 7.21-7.66 (m, 7H), 6.58 (s, 1H), 6.30 (m, 1H), 4.18 (m, 2H), 3.68 (m, 2H), 2.62 (m, 2H), 1.52 (s, 9H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6]1.N1C(C)=CC=CC=1C.[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[C:26](Cl)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[C:26]([NH:10][C:7]2[CH:8]=[CH:9][N:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]=2)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COCCn1ccc(N)n1
Reactant: O=C(Cl)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
In a round bottom flask was placed 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared in Example 72, 51 mg, 0.36 mmol), 2,6-lutidine (57 μL, 0.49 mmol) and methylene chloride (5 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl chloride in methylene chloride (prepared as in Example 102, ˜0.16 M solution, 2 mL, 0.33 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was diluted with methylene chloride (5 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 25% ethyl acetate/hexanes to 45% ethyl acetate/hexanes) afforded (R)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-propionamide (85 mg, 63%) as a white foam: [α]30589=−24.0° (c=0.10, methylene chloride); ES-HRMS m/e calcd for C20H25N3O2Cl2 (M+H)+ 410.1397, observed 410.1396; 1H NMR (300 MHz, DMSO-d6) δ 1.09 (m, 2H, CH2), 1.38-1.79 (m, 8H, 4×CH2), 2.05 (m, 1H, CH), 3.19 (s, 3H, OCH3), 3.61 (t, J=5.4 Hz, 2H, OCH2), 3.79 (m, 1H, ArCHCO), 4.12 (t, J=5.4 Hz, 2H, NCH2), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.34 (dd, Jm=2.1 Hz, Jo=8.4 Hz, 1H, Ar), 7.54 (d, J=2.2 Hz, 1H, Ar), 7.59 (d, Jo=8.4 Hz, 1H, Ar), 7.59 (d, Jm=2.1 Hz, 1H, Ar), 10.72 (s, 1H, NH).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH2:31]([O:33][C:34]1[CH:35]=[C:36]([CH:41]=[CH:42][C:43]=1[O:44][CH2:45][CH3:46])/[C:37](=[N:39]/O)/[NH2:38])[CH3:32].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:31]([O:33][C:34]1[CH:35]=[C:36]([C:37]2[N:39]=[C:1]([C:2]3[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=3)[O:9][N:38]=2)[CH:41]=[CH:42][C:43]=1[O:44][CH2:45][CH3:46])[CH3:32]
Reactant: CCOc1ccc(/C(N)=N/O)cc1OCC
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2noc(-c3ccncc3)n2)cc1OCC
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 26 %

Procedure:
In a microwave vial, a stirring solution of isonicotinic acid (200 mg, 1.62 mmol) in DMF was treated with HOBt (319 mg, 2.43 mmol) and EDCI (467 mg, 2.43 mmol) at room temperature. The reaction was stirred for 20 min followed by addition, in a single portion, of (Z)-3,4-diethoxy-N′-hydroxybenzimidamide (436 mg, 1.94 mmol). The reaction was stirred for additional 30 min at room temperature and then heated to 130° C. for 35 min in the initiator. The reaction was diluted using a saturated solution of NaHCO3 and extracted with EtOAc (80 ml×3). The organic phase was dried over Na2SO4 anhydrous and concentrated under reduced pressure. The product was purified by column chromatography using CH2Cl2:MeOH (95:5) to offer the product in 26% yield (131 mg) as pale brown solid. 1H NMR (300 MHz, CDCl3): δ 8.85 (d, J=5.4 Hz, 2H), 8.02 (d, J=6.0 Hz, 2H), 7.71 (dd, J1=1.8 Hz, J2=8.1 Hz, 1H), 7.62 (d, J=2.1 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 4.19 (q, J=6.9 Hz, 2H), 4.14 (q, J=6.9 Hz, 2H), 1.50 (t, J=3.0 Hz, 3H), 1.46 (t, J=3.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 173.54, 16928, 151.64, 151.07, 148.91, 131.37, 121.48, 121.15, 118.75, 112.74, 111.82, 64.78, 64.59, 14.87, 14.81. MS (EI) m/z: 312 (M+), HRMS (EI) for C17H17N3O3 (M+): calcd 312.1343. found 312.1348.