Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=[C:4]2[NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:13][C:3]=12.Cl.[CH3:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[NH2:29].C(N(CC)C(C)C)(C)C.CN1CCN(C)C1=O>CCOC(C)=O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[NH:11][C:4]3=[N:5][CH:6]=[C:7]([C:8]([NH2:10])=[O:9])[C:2]([NH:29][C@H:24]4[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]4[CH3:22])=[C:3]3[CH:13]=2)=[CH:15][CH:16]=1
Reactant: C[C@@H]1CCCC[C@@H]1N
Reactant: NC(=O)c1cnc2[nH]c(-c3ccc(F)cc3)cc2c1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCN(C)C1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCCC[C@@H]1Nc1c(C(N)=O)cnc2[nH]c(-c3ccc(F)cc3)cc12
Temperature: 25 °C
Yield: 15.5 %

Procedure:
4-Chloro-2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (70 mg),(1S,2R)-2-methylcyclohexanamine hydrochloride (108.5 mg),N,N-diisopropylethylamine (0.126 ml) and 1,3-dimethyl-2-imidazolidinone (0.35 ml) were combined and irradiated microwave at 16° C. for 1 hour. After cooled to ambient temperature, the mixture was diluted in EtOAc. The organic solution was washed with saturated aqueous sodium hydrogencarbonate, dried over MgSO4 and evaporated in vacuo. The residue was purified by preparative NH2 silica gel column chromatography with 5% methanol in chloroform to give 2-(4-fluorophenyl)-4-{[(1S,2R)-2-methylcyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (13.7 mg) as an off-white solid.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[C:16]([C:20]1[CH:21]=[C:22]([CH2:27][CH:28]([NH2:34])[C:29]2[S:30][CH:31]=[CH:32][N:33]=2)[CH:23]=[CH:24][C:25]=1[OH:26])([CH3:19])([CH3:18])[CH3:17].O>C1COCC1>[C:16]([C:20]1[CH:21]=[C:22]([CH2:27][CH:28]([NH:34][C:6](=[O:8])[CH:2]([NH:1][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:3]([CH3:4])[CH3:5])[C:29]2[S:30][CH:31]=[CH:32][N:33]=2)[CH:23]=[CH:24][C:25]=1[OH:26])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1cc(CC(N)c2nccs2)ccc1O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106 %

Procedure:
To a solution of Boc-Val-OH (890 mg, 4.09 mmol), 2-(3-tert-butyl-4-hydroxyphenyl)-1-(thiazol-2-yl)ethylamine (1.03 g, 3.73 mmol) and CMPI (653 mg, 1.05 mmol) in THF (10 ml), TEA (1 ml) was added under cooling with ice and stirred at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:1), giving the titled compound (1.88 g, 99%).
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].Cl[C:8]1[C:13](=[O:14])[N:12]([CH3:15])[CH:11]=[C:10]2[CH2:16][N:17]([CH2:20][CH2:21][C:22]3[N:23]=[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]4[CH:30]=3)[C:18](=[O:19])[C:9]=12.[N:31]1[CH:36]=CC=[C:33](B(O)O)[CH:32]=1.O>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl>[N:23]1[C:22]([CH2:21][CH2:20][N:17]2[C:18](=[O:19])[C:9]3[C:10](=[CH:11][N:12]([CH3:15])[C:13](=[O:14])[C:8]=3[N:31]3[CH2:36][CH2:1][O:4][CH2:33][CH2:32]3)[CH2:16]2)=[CH:30][N:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=12
Reactant: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1cn3ccccc3n1)C2
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc2c(c(N3CCOCC3)c1=O)C(=O)N(CCc1cn3ccccc3n1)C2
Temperature: 120 °C
Yield: 35.6 %

Procedure:
K2CO3 (121 mg, 0.875 mmol) and bis(triphenylphosphine) palladium(II) dichloride (20.48 mg, 0.029 mmol) were each rapidly added in sequence to a suspension of 7-chloro-2-(2-imidazo[1,2-a]pyridin-2-yl-ethyl)-5-methyl-3,5-dihydro-2H-pyrrolo[3,4-c]pyridine-1,6-dione (100 mg, 0.292 mmol, see Example c5)) and pyridin-3-ylboronic acid (53.8 mg, 0.438 mmol) in DMF (1 ml)/water (0.200 ml). The reaction mixture was heated in a microwave at about 120° C. for about 20 min. The reaction was cooled to r.t. DCM (15 ml) and DMF (1 ml) were added, the resulting mixture was filtered and the filtrate was concentrated by evaporating DCM. The concentrate was cooled to r.t., the crystallized solid was filtered and dried to afford the title compound (40 mg, 0.104 mmol, 35.6% yield).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.[CH:10](N(C(C)C)CC)([CH3:12])[CH3:11].C(O)=[O:20].C1(C)C=CC=CC=1>C(OCCCC)(=O)C=C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.O>[F:9][C:5]1[CH:6]=[C:7]2[C:2]([CH2:11][CH2:10][C:12](=[O:20])[NH:8]2)=[N:3][CH:4]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=CO
Reactant: Nc1cc(F)cnc1Cl
Agent: C=CC(=O)OCCCC
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCc2ncc(F)cc2N1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
To a suspension of 25.0 g of 2-chloro-5-fluoropyridin-3-amine, 3.8 g of bis(tricyclohexyl phosphine)palladium (II) chloride and 1.5 g of 2-(di-tert-butylphosphino)biphenyl in 75 mL of butyl acrylate, 44.1 g of diisopropylethylamine was added, 15.7 g of formic acid was added dropwise thereto at room temperature, and the mixture was refluxed for 3 hours. To the reaction mixture, 32.1 g of diisopropylethylamine and 11.5 g of formic acid were added at 100° C., and the mixture was refluxed for 5 hours. The reaction mixture was cooled to 80° C., 50 mL of toluene and 75 mL of water were added thereto and the resultant mixture was cooled to room temperature. The solid product was obtained by filtration, and washed using in the order of toluene and water to give 18.0 g of 7-fluoro-3,4-dihydro-1,5-naphthyridin-2(1H)-one as a white solid.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10](F)=[CH:9][C:8]=1[F:17])[CH3:4]>C1COCC1>[F:17][C:8]1[CH:9]=[C:10]([NH:2][CH3:1])[C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:7]=1[C:6]([O:5][CH2:3][CH3:4])=[O:18]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Reactant: CN
Solvent: C1CCOC1
Product: CCOC(=O)c1cc([N+](=O)[O-])c(NC)cc1F
Reaction time: 0.25 h

Procedure:
A 2N solution of methylamine in THF (11.5 ml, 23.0 mmol) was added at −5° C. to ethyl-2,4-difluoro-5-nitro-benzoate (2.50 g, 10.8 mmol) in 20 ml THF and the cooling bath was removed. After 15 min at room temperature, the mixture was concentrated i.vac., 50 ml DCM were added, the organic phase was washed with water and dried with MgSO4. After concentration i.vac. the crude product was triturated with ethanol to give the cristalline product.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[N:13]=[C:12]([N:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:11]=2[N:10]=[C:9]1[CH2:36][CH2:37][CH2:38][CH3:39])(=O)=O.[C:40]1([SH:46])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:36]([C:9]1[N:8]([CH2:7][CH2:6][S:46][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:20]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[N:13]=[C:12]([N:21]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[C:11]=2[N:10]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCc1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3c(c2n1CCOS(C)(=O)=O)CCCC3
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCc1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3c(c2n1CCSc1ccccc1)CCCC3
Temperature: 80 °C
Yield: 86.1 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, 2-{4-[bis(tert-butoxycarbonyl)amino]-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl }ethyl methanesulfonate (0.61 g, 1.08 mmol), benzenethiol (0.21 g, 1.88 mmol), triethylamine (0.25 g, 2.43 mmol) and anhydrous dimethyl formamide (11 mL) under a nitrogen atmosphere. The reaction mixture was heated to 80° C. to give a dark yellow, homogeneous solution that was maintained at 80° C. for 2.5 hours at which time the reaction was judged to be complete. The solution was cooled and then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a yellow oil. The material was purified by chromatography over silica gel (95/5 dichloromethane/methanol) to provide di(tert-butyl) 2-butyl-1-[2-(phenylthio)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-ylimidodicarbonate (0.54 g, 0.93 mmol) as a light yellow oil. MS (CI) for C32H44N4O4S m/z 581 (MH+), 481, 381, 245.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>ClCCl>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:14](=[O:16])[CH3:15])[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
Tert-Butyl piperazine-1-carboxylate (4.00 g, 21.4 mmol) is dissolved in dichloromethane (40 mL), cooled to 0° C. and treated with acetic anhydride (2.23 mL, 23.6 mmol) over a period of 2 min. The reaction mixture is stirred at 0° C. for 30 min, LCMS analysis used to indicate completion of the reaction and the volatiles evacuated in vacuo. The residue is treated carefully with NaHCO3 (sat. aq., 50 mL), stirred vigorously for 30 min and the resulting mixture extracted with diethyl ether (4×20 mL). The combined organic extracts are dried (MgSO4), filtered and concentrated in vacuo to afford tert-Butyl-4-acetylpiperazine-1-carboxylate as a white solid (4.53 g, 93%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.39 (s, 9H), 1.99 (s, 3H), 3.22-3.29 (m, 2H), 3.30-3.34 (m, 2H), 3.36-3.41 (m, 4H); ESI-MS: m/z 229.3 (M+H)+.
Reaction SMILES: ClC1C=C(C=CC=1[NH:11][C:12](=[O:38])[CH:13]([N:20]1[C:24]2[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=2[N:22]=C1C1C=NC(Cl)=CC=1)[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)C(O)=O.[CH:39]1([CH:45]=O)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.[CH3:47][O:48][C:49]1[N:57]=[C:56]([O:58][CH3:59])[CH:55]=[CH:54][C:50]=1[C:51](O)=O.[N+](CC1C=CC=CC=1)#[C-].Cl>CO.O1CCOCC1>[CH2:45]([NH:11][C:12](=[O:38])[CH:13]([CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[N:20]1[C:24]2[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=2[N:22]=[C:51]1[C:50]1[C:49]([O:48][CH3:47])=[N:57][C:56]([O:58][CH3:59])=[CH:55][CH:54]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=CC1CCCCC1
Reactant: COc1ccc(C(=O)O)c(OC)n1
Reactant: O=C(O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)nc3)nc3cc(F)c(F)cc32)c(Cl)c1
Agent: Cl
Agent: [C-]#[N+]Cc1ccccc1
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)NCc2ccccc2)C2CCCCC2)c(OC)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester (2.50 g, 10.24 mmol, 1.0 equiv; example 1, intermediate b) in methanol (30 mL) was added cyclohexanecarbaldehyde (1.15 g, 1.23 mL, 10.24 mmol, 1.0 equiv; [2043-61-0]) and the mixture stirred at rt. After 30 min, 2,6-dimethoxy-nicotinic acid (1.88 g, 10.24 mmol, 1.0 equiv; [CAS RN 16727-43-8]) and isocyanomethyl-benzene (1.20 g, 1.25 mL, 10.24 mmol, 1.0 equiv; [931-53-3]) were added and stirring continued at rt for 2 h. A solution of 4 M HCl in dioxane (20 mL) was added and the reaction mixture stirred at rt overnight. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 and the aqueous layer extracted with dichloromethane. The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure. The crude material was purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate to give 3.57 g (60%) of the title compound. MS (ES+): 522 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[N:11]=[C:10]([C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]2[CH:22]=[CH:21][N:20]3[N:23]=[CH:24][C:25]([C:26](O)=[O:27])=[C:19]3[N:18]=2)[CH:9]=[CH:8][CH:7]=1.CN(C=O)C.C(Cl)Cl.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CCOC(C)=O>[C:17]12[CH:22]=[CH:21][N:20]3[C:19]([N:18]=1)=[C:25]([CH:24]=[N:23]3)[C:26](=[O:27])[NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[N:11]=[C:10]([CH:9]=[CH:8][CH:7]=1)[C@@H:12]1[N:13]2[CH2:14][CH2:15][CH2:16]1
Reactant: NCCCOc1cccc([C@H]2CCCN2c2ccn3ncc(C(=O)O)c3n2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1NCCCOc2cccc(n2)[C@H]2CCCN2c2ccn3ncc1c3n2
Reaction time: 0.17 h
Yield: 45.7 %

Procedure:
To a solution of (R)-5-(2-(6-(3-aminopropoxy)pyridin-2-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (70 mg, 0.18 mmol) in 1:2 DMF/DCM (9 mL) was added EDCI (110 mg, 0.55 mmol) followed by HOBT (74 mg, 0.55 mmol) at ambient temperature. After stirring for 10 minutes, TEA (0.077 mL, 0.55 mmol) was added to the reaction mixture and stirred for 6 hours. The reaction mixture was diluted with EtOAc, washed with saturated NH4Cl, saturated NaHCO3, and brine, then dried (MgSO4), filtered, and concentrated. The crude material was purified by silica column chromatography, eluting with 2% MeOH/DCM to yield the title product (30 mg, 45% yield). MS (apci) m/z=365.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[CH3:12][O:13][C:14](=[O:26])[CH:15]=[CH:16][C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[CH:22][NH:23]2)=[CH:19][CH:18]=1>O>[CH3:12][O:13][C:14](=[O:26])[CH2:15][CH:16]([C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[CH:22][NH:23]2)=[CH:19][CH:18]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COC(=O)C=Cc1ccc2cc[nH]c2c1
Solvent: O
Product: COC(=O)CC(c1cccc(OC)c1)c1ccc2cc[nH]c2c1
Temperature: 90 °C
Reaction time: 6 h
Yield: 61.4 %

Procedure:
To a mixture of 3-methoxyphenylboronic acid (0.23 g, 1.5 mmol) and [RhCl(cod)]2 (49 mg, 0.1 mmol) in degassed water (3 ml) was added 3-(1H-indol-6-yl)-acrylic acid methyl ester XXX (200 mg, 1.0 mmol). The mixture was stirred at 90° C. for 6 hours, cooled to room temperature, and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) to provide 3-(1H-indol-6-yl)-3-(3-methoxy-phenyl)-propionic acid methyl ester XXXI (190 mg, 61% yield) as a yellow film.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH:11]2[CH2:15][CH:14]([CH2:16][S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:13][C:12]2=[O:24])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1(C2C=CC=CC=2)C=CC(S(NC(CC2OC2)C(OC)=O)(=O)=[O:38])=CC=1.CCN(CC)CC.C1(S)C=CC=CC=1>C1C=CC=CC=1.O>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH:11]([CH2:15][CH:14]([OH:38])[CH2:16][S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]([OH:13])=[O:24])(=[O:8])=[O:9])=[CH:3][CH:2]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Reactant: O=C1OC(CSc2ccccc2)CC1NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Agent: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O
Product: O=C(O)C(CC(O)CSc1ccccc1)NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 3 h

Procedure:
3-[[(1,1′-Biphenyl)-4-yl]sulfonyl]amino-2-oxo-5-[(phenylthio)methyl]-tetrahydrofuran: To a solution of methyl 2-[[(1,1′-biphenyl)-4-yl]sulfonyl]amino-4,5-epoxypentanoate 16b (0.36 g, 1.47 mmol) in benzene (5 mL) and Et3N (0.27 g, 1.91 mmol) at room temperature is added slowly benzenethiol (0.38 mL, 3.67 mmol). The reaction mixture is stirred for 3 hrs. The resulting mixture is diluted with water, and then the mixture is extracted three times with EtOAc. The combined EtOAc layer is washed with water, brine, dried over MgSO4 and concentrated to an oil which is purified by column chromatography eluting with EtOAc/hexane (1:4 to 3:7) to give the desired product as a mixture of two isomers (ratio: ˜2:1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[C:9]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH2:21])[N:15]=2)[CH:11]=[CH:12][CH:13]=1.[C:37]1(B(O)O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O.O1CCOCC1.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>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:28][C:9]2[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH2:21])[N:15]=3)=[CH:11][CH:12]=[CH:13][C:8]=2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:31][CH:32]=1
Reactant: C=C(c1ccccc1)c1cccc(-c2cccc(Br)c2OCc2ccc(F)cc2)n1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: C=C(c1ccccc1)c1cccc(-c2cccc(-c3ccccc3)c2OCc2ccc(F)cc2)n1
Temperature: 25 °C
Yield: 94 %

Procedure:
Potassium carbonate (1.44 g, 10.5 mmol, 3.0 equiv) was dissolved in water (15 mL) and added to compound 9 (1.6 g, 3.5 mmol, 1.0 equiv) and phenylboronic acid (0.57 g, 4.2 mmol, 1.2 equiv) in dioxane (30 mL). A stream of nitrogen was bubbled through the solution for 15 min and tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.02 mmol, 0.005 equiv) was added to the reaction. The reaction was refluxed for 2 hr at which point LC/MS and TLC indicated the reaction to be complete. The reaction was allowed to cool to room temperature, diluted with ethyl acetate (50 mL), the organic layer was separated and washed with saturated brine (50 mL). The organic layer was dried over sodium sulfate and absorbed onto silica gel (5 g) by concentration under reduced pressure. This material was purified on a silica gel column (30 g) by eluting with ethyl acetate (1%) in heptanes (200 mL), ethyl acetate (2%) in heptanes (200 mL), ethyl acetate (3%) in heptanes (200 mL) and ethyl acetate (4%) in heptanes (200 mL). The desired product was isolated pure in 94% yield (1.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]3[CH:23]=[N:22][C:21]([C:24](OC)=[O:25])=[CH:20][N:19]=3)[CH2:10][CH2:9]2)[CH:7]=1.[NH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37]>CC(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]3[CH:23]=[N:22][C:21]([C:24]([NH:30][CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:25])=[CH:20][N:19]=3)[CH2:12][CH2:13]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COC(=O)c1cnc(NCCCN2CCN(c3cc(Cl)ccc3OC)CC2)cn1
Solvent: CC(C)O
Product: COc1ccc(Cl)cc1N1CCN(CCCNc2cnc(C(=O)NCCNC(=O)OC(C)(C)C)cn2)CC1

Procedure:
4 g (0.0095 mol) of methyl 2-[[3-[4-(5-chloro-2-methoxyphenyl)piperain-1-yl]propyl]amino]-pyrazine-5-carboxylate and 3.05 g (0.02 mol) of 1,1-dimethylethyl 2-aminoethylcarbamate are introduced into 10 ml of 2-propanol in a 0.5 l round-bottomed flask and the mixture is heated at reflux for 2 days.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH:6]1([N:12]([CH3:22])[C:13]([NH:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:23]([NH:27][CH3:28])[CH2:24][CH2:25][CH3:26].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH2:23]([N:27]([CH3:28])[C:13]([N:12]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:22])=[N:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:24][CH2:25][CH3:26]
Reactant: CN(C(=O)NC1CCCCC1)C1CCCCC1
Reactant: CCCCNC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCCCN(C)C(=NC1CCCCC1)N(C)C1CCCCC1
Reaction time: 2 h
Yield: 38821.3 %

Procedure:
18.38 g of cyclohexyl isocyanate (0.147 mol) are added dropwise to a solution of 19.12 g of N-methyl-N-cyclo-hexylamine (0.169 mol) in 160 ml of hexane and then the cloudy mixture is refluxed for 2 h and then evaporated to dryness, to give 35 g of crude N,N′-dicyclohexyl-N-methylurea. 12 g of POCl3 (78 mmol) is added, over 1 h, to a suspension of 17 g of said N,N′-dicyclohexyl-N-methylurea (71.33 mmol) in 65 ml of toluene, and then, after a few hours at 20° C., 15.5 g of N-butyl-N-methyl-amine (0.178 mmol) are added over 2 h, and then, after a further 2 h at 20° C., 50 ml of water are added. 49 g of 35% sodium hydroxide are then added while cooling, and the two-phase medium is then extracted with diisopropyl ether. After drying and evaporation to dryness, the oil obtained, 26.5 g, is distilled at 180° C. under 1 mbar, to give 21.25 g of the expected guanidine (yield 97%).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)([CH3:3])[CH3:2].[Li]CCCC.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1>C1COCC1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([N:5]2[C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][O:7][C:6]2=[O:9])=[O:24])=[CH:18][CH:17]=1
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[C@H]1COC(=O)N1C(=O)Cc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 53.5 %

Procedure:
To a solution of (4S)-4-iso propyl-1,3-oxazolidin-2-one (2.0 g, 15.5 mmol) in dry THF (20 mL) at −78° C. under argon, was added dropwise a 2.5M solution of n-BuLi in hexanes (6.2 mL, 15.5 mmol). After stirring at −78° C. for 15 min, (4-chlorophenyl)acetyl chloride (2.70 mL, 21.8 mmol) was added. The resulting reaction mixture was stirred at −78° C. for 30 min and 0° C. for 15 min, quenched with saturated NH4Cl (5 mL) and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and washed with saturated Na2CO3 following by brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (10%–15% EtOAc/hexane) to give 2.33 g (8.29 mmol, 53%) of (4S)-3-[(4-chlorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one: 1H NMR (400 MHz, CDCl3) δ 7.31–7.22 (m, 4H), 4.45–4.41 (m, 1H), 4.35–4.16 (m, 4H), 2.39–2.29 (m, 1H), 0.89 d, 3H, J=7.2 Hz), 0.80 (d, 3H, J=7.2 Hz); ESMS m/e: 282.2 (M+H)+.
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:8]2[CH:20]=[C:21]([Cl:23])[CH:22]=[C:7]2[C:6]=1[OH:24])=[O:4].[NH2:25][CH2:26][C:27]([O-:29])=[O:28].[Na+]>>[Cl:23][C:21]1[CH:22]=[C:7]2[C:6]([OH:24])=[C:5]([C:3]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:8]2[CH:20]=1
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(F)cc2)c1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(F)cc2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 6-chloro-4-hydroxy-2-oxo-1-(4-fluoro-benzyl)-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 394 (M+H)+.