Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:6]([OH:11])=[N:7][CH:8]=[CH:9][CH:10]=1)#[N:4].[Br-].[Li+].[Cl:14][C:15]1[CH:16]=[C:17]([C@@H:22]2[O:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][C@H:23]2[CH2:36]OS(C)(=O)=O)[CH:18]=[CH:19][C:20]=1[Cl:21]>COCCOC.O.CN(C=O)C>[C:3]([C:5]1[C:6](=[O:11])[N:7]([CH2:36][C@H:23]2[C@H:22]([C:17]3[CH:18]=[CH:19][C:20]([Cl:21])=[C:15]([Cl:14])[CH:16]=3)[O:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:24]2)[CH:8]=[CH:9][CH:10]=1)#[N:4]
Reactant: N#Cc1cccnc1O
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](COS(C)(=O)=O)C1
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](Cn2cccc(C#N)c2=O)C1
Reaction time: 0.08 h
Yield: 86.2 %

Procedure:
60% Sodium hydride (0.086 g) was added to a mixed solution of 3-cyano-2-hydroxypyridine (0.206 g) in 1,2-dimethoxyethane (4 ml)-DMF (2 ml) under ice-cooling, and the mixture was stirred for 5 min. To the reaction solution was added lithium bromide (0.248 g), and the mixture was stirred at room temperature for 0.5 hr. To the reaction solution was added a solution of tert-butyl (6S,7R)-7-(3,4-dichlorophenyl)-6-{[(methylsulfonyl)oxy]methyl}-1,4-oxazepane-4-carboxylate (0.65 g) in 1,2-dimethoxyethane (4 mL), and the mixture was stirred at 60° C. overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.59 g, 86%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:17][CH2:16][C@@H:15]([CH:18]([NH2:24])[C:19]3S[CH:21]=[CH:22][N:23]=3)[CH2:14]2)[C:9]([F:25])=[C:8]2[C:3]=1[C:4](=[O:33])[C:5]([C:30]([OH:32])=[O:31])=[CH:6][N:7]2[C@@H:26]1[CH2:28][C@@H:27]1[F:29].N[C:35]1C(F)=C(F)C(F)=C2[C:36]=1C(=O)C(C(O)=O)=CN2[C@@H]1C[C@@H]1F>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:17][CH2:16][C@@H:15]([CH:18]([NH2:24])[C:19]3[CH:36]=[CH:35][CH:21]=[CH:22][N:23]=3)[CH2:14]2)[C:9]([F:25])=[C:8]2[C:3]=1[C:4](=[O:33])[C:5]([C:30]([OH:32])=[O:31])=[CH:6][N:7]2[C@@H:26]1[CH2:28][C@@H:27]1[F:29]
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Reactant: Nc1c(F)c(N2CC[C@@H](C(N)c3nccs3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Solvent: CC#N
Product: Nc1c(F)c(N2CC[C@@H](C(N)c3ccccn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Yield: 66.7 %

Procedure:
3-(R)-[1-Tert-butoxycarbonylamino-1-(2-pyridyl)methyl]pyrrolidine [F1] (339 mg, 1.22 mmol) was added to an acetonitrile suspension (10 ml) of 5-amino-6,7,8-trifluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (316 mg, 1.00 mmol), and the mixture was heated under reflux for 14 hours in the presence of triethylmine (0.5 ml). After cooling, the solvent of the reaction solution was evaporated under a reduced pressure. The resulting residue was dissolved in chloroform (150 ml), this was washed with 10% citric acid (80 ml) and saturated brine (80 ml) and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was mixed with concentrated hydrochloric acid (10 ml) under ice-cooling, further mixed with 1 mol/l hydrochloric acid aqueous solution (5 ml) at roan temperature and then washed with chloroform (50 ml×4), and the insoluble matter was removed by filtration. This hydrochloric acid aqueous solution was adjusted to an alkaline liquid property adding 10 mol/l sodium hydroxide aqueous solution. This suspension was adjusted to a liquid property of pH 7.4 by adding concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then extracted with chloroform (150 ml×4). The resulting organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under a reduced pressure to obtain the crude title compound as light yellow crystals. This was purified by recrystallizing from ethanol to obtain 316 mg (67%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH2:56]([O:58][C:59]([C:61]1[CH:66]=[N:65][C:64]([NH2:67])=[CH:63][N:62]=1)=[O:60])[CH3:57]>ClCCl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:67][C:64]2[N:65]=[CH:66][C:61]([C:59]([O:58][CH2:56][CH3:57])=[O:60])=[N:62][CH:63]=2)=[O:30])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CCOC(=O)c1cnc(N)cn1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cn1
Reaction time: 8 h
Yield: 26.2 %

Procedure:
A solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (79.9 mg, 0.171 mmol) in dichloromethane (3 ml) was treated with DIPEA (89.0 mg, 0.685 mmol) and DIPHENYLPHOSPHINIC CHLORIDE (103 mg, 0.428 μmol, Aldrich) and stirred for 30 mins under argon before 5-AMINO-PYRAZINE-2-CARBOXYLIC ACID ETHYL ESTER (30.4 mg, 0.173 mmol, Ark Pharm) was added and the reaction was stirred overnight. The reaction mixture was diluted with dichloromethane and extracted with H2O. The organic layer was washed with sat NaHCO3, H2O, and sat NaCl and purified by flash chromatography using ethyl acetate and n-hexanes to give ethyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)pyrazine-2-carboxylate (27.6 mg, 26%) which was used in the next step.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)[OH:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[CH2:25]([NH2:29])[CH:26]([CH3:28])[CH3:27]>CN1C(=O)CCC1.CC(OC)(C)C>[CH2:25]([NH:29][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)[OH:12])=[CH:9][N:10]=2)[N:7]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: OC(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Reactant: CC(C)CN
Agent: [F-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN1CCCC1=O
Product: CC(C)CNc1ccc2ncc(C(O)c3ccc4ncccc4c3)n2n1
Temperature: 160 °C
Reaction time: 7 h

Procedure:
(rac)-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-quinolin-6-yl-methanol (Stage 1.1, 80 mg, 0.257 mmol) and KF (30 mg, 0.515 mmol) were suspended in NMP (2 mL). Isobutylamine (129 μL, 1.287 mmol) was then added and the RM was stirred at 160° C. for 7 h. The mixture was diluted with TBME and washed with water (3×). The aqueous layer was then extracted with TBME (3×). The combined layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (Flashmaster) to afford the title compound as a yellow foam (tR 4.11 min (conditions 4), MH+=348.0, 1H-NMR in DMSO-d6: 8.86 (m, 1H); 8.32 (m, 1H); 8.02 (m, 1H); 7.94 (d, 1H); 7.80 (m, 1H); 7.61 (d, 1H); 7.51 (dd, 1H); 7.31 (s, 1H); 6.88 (t, 1Ht); 6.61 (d, 1H); 6.24 (m, 1H); 6.12 (d, 1H); 2.98 (m, 2H); 1.82 (m, 1H); 0.86 (m, 6H)).
Reaction SMILES: [F:1][CH:2]([F:48])[C:3]1[C:11]2[C:10]([F:13])([F:12])[CH2:9][CH2:8][C:7]([F:15])([F:14])[C:6]=2[N:5]([CH2:16][C:17]([NH:19][C@H:20]([C:30]2[C:35]([C:36]3[CH:37]=[CH:38][C:39]([F:45])=[C:40]([CH:44]=3)[C:41]([NH2:43])=[O:42])=[CH:34][N:33]=[C:32]([NH:46][CH3:47])[N:31]=2)[CH2:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)=[O:18])[N:4]=1.NC[CH2:51][OH:52].BrC1C([C@@H](NC(=O)CN2C3C(F)(F)CCC(F)(F)C=3C(C(F)F)=N2)CC2C=C(F)C=C(F)C=2)=NC(S(C)(=O)=O)=NC=1>>[F:48][CH:2]([F:1])[C:3]1[C:11]2[C:10]([F:12])([F:13])[CH2:9][CH2:8][C:7]([F:14])([F:15])[C:6]=2[N:5]([CH2:16][C:17]([NH:19][C@H:20]([C:30]2[C:35]([C:36]3[CH:37]=[CH:38][C:39]([F:45])=[C:40]([CH:44]=3)[C:41]([NH2:43])=[O:42])=[CH:34][N:33]=[C:32]([NH:46][CH2:47][CH2:51][OH:52])[N:31]=2)[CH2:21][C:22]2[CH:23]=[C:24]([F:29])[CH:25]=[C:26]([F:28])[CH:27]=2)=[O:18])[N:4]=1
Reactant: CNc1ncc(-c2ccc(F)c(C(N)=O)c2)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Reactant: NCCO
Agent: CS(=O)(=O)c1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Product: NC(=O)c1cc(-c2cnc(NCCO)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F

Procedure:
The title compound (26) was prepared according to the method presented for the synthesis of compound 14B of Example 14 starting with 2-aminoethanol and 12C. 1H NMR (400 MHz, CD3OD) δ 8.83 (d, J=7.7 Hz, 1H), 8.06 (s, 2H), 7.49-7.32 (m, 2H), 7.21 (dd, J=10.7, 8.5 Hz, 1H), 7.02-6.58 (m, 2H), 6.45 (d, J=6.1 Hz, 2H), 5.22 (m, 1H), 5.05 (s, 2H), 3.86-3.58 (m, 4H), 3.18-2.85 (m, 2H), 2.66-2.23 (m, 4H). MS (m/z) 716.23 [M+H]+.
Reaction SMILES: [CH2:1]([Si:3]([CH2:13][CH3:14])([CH2:11][CH3:12])[C:4]1[O:5][CH:6]=[C:7]([CH:9]=[O:10])[CH:8]=1)[CH3:2].[Li]N(C)CCN(C)C.FC(F)(F)S(O[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=O)=O.[Cl-]>[Pd].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.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>[CH2:13]([Si:3]([CH2:11][CH3:12])([CH2:1][CH3:2])[C:4]1[O:5][C:6]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:7]([CH:9]=[O:10])[CH:8]=1)[CH3:14]
Reactant: O=S(=O)(Oc1ccccc1)C(F)(F)F
Reactant: CC[Si](CC)(CC)c1cc(C=O)co1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]N(C)CCN(C)C
Product: CC[Si](CC)(CC)c1cc(C=O)c(-c2ccccc2)o1

Procedure:
Treatment of 2-triethylsilyl-4-furaldehyde with lithio N,N,N'-trimethylethylenediamine, followed by phenyl trifluoromethanesulfonate in the presence of anhydrous zinz chloride and tetrakis (triphenylphosphine) palladium (o) and work up gives the titled aldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[C:12]([F:22])[C:8]2[NH:9][CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4].CO.C1C(=O)N([I:32])C(=O)C1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([I:32])=[CH:17][C:16]=2[CH3:21])=[C:12]([F:22])[C:8]2[NH:9][CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2nc[nH]c2c(F)c1Nc1ccccc1C
Reactant: O=C1CCC(=O)N1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1cc2nc[nH]c2c(F)c1Nc1ccc(I)cc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
7-Fluoro-6-o-tolylamino-1H-benzoimidazole-5-carboxylic acid methyl ester 7a (1.47 g, 4.92 mmol) is suspended in 1:1 THF:MeOH mixture (44 mL) and cooled to −78° C. under a nitrogen atmosphere. A solution of NIS (1.66 g, 7.39 mmol) in THF (2 mL) is added followed by a MeOH (2 mL) solution of TsOH.H2O (1.87 g, 9.84 mmol). After 30 minutes, the reaction mixture is warmed to 0° C. and 1 mL methylene chloride is added. The reaction is slowly allowed to warm to room temperature with stirring over 16 hours. The reaction mixture is quenched by the addition of 10% Na2S2O4 solution. The reaction mixture is then diluted with water and ethyl acetate and the layers separated. The aqueous layer is extracted with ethyl acetate. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure. The recovered solid is triturated with MeOH to give 1.45 g (69%) pure desired product: MS ESI (+) m/z 426 (M+1) detected; MS ESI (−) m/z 424 (M−1) detected.
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[K+].Cl>C(O)C>[Si:1]([O:8][CH:9]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCCCCCC(CCCCCCCCCCC(=O)OCC)O[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCC(CCCCCCCCCCC(=O)O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
Next, the ethyl 12-(tert-butyldimethylsilyloxy)octadecanoate thus obtained was introduced into a 100-ml flask equipped with a stirrer and 20 ml of ethanol and 2.24 g (20 mmol) of a 50% aqueous solution of KOH were added thereto. The obtained mixture was stirred at room temperature for 4 hours. After the completion of the reaction, the reaction mixture thus obtained was neutralized with hydrochloric acid and extracted with chloroform. After removing the solvent under reduced pressure, 4.0 g of 12-(tert-butyldimethylsilyloxy)octadecanoic acid was obtained (yield: 96.4 %).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[CH:9]([CH3:16])[O:8][C:6]=2[CH:7]=1.[OH:17][CH2:18][C@@H:19]([N:24]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:34])[CH2:20][CH:21]([CH3:23])[CH3:22].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:22][CH:21]([CH3:23])[CH2:20][C@H:19]([N:24]1[C:25](=[O:34])[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]1=[O:33])[CH2:18][O:17][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[CH:9]([CH3:16])[O:8][C:6]=2[CH:7]=1
Reactant: CC1Oc2cc(Br)ccc2-c2ccncc21
Reactant: CC(C)C[C@@H](CO)N1C(=O)c2ccccc2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H](COc1ccc2c(c1)OC(C)c1cnccc1-2)N1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Yield: 64 %

Procedure:
To a stirred solution of 8-bromo-5-methyl-5H-chromeno[3,4-c]pyridine (200 mg, 0.724 mmol) in toluene (4 mL), were added (S)-2-(1-hydroxy-4-methylpentan-2-yl)isoindoline-1,3-dione (537 mg, 2.173 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (185 mg, 0.435 mmol), cesium carbonate (354 mg, 1.086 mmol) and palladium (II) acetate (48.8 mg, 0.217 mmol). Nitrogen was bubbled through the reaction mixture for 10 min and the mixture was heated at 80° C. 12 h. The reaction mixture was cooled to room temperature and filtered through celite and residue rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified via prep TLC (60% ethyl acetate in pet ether) to afford 2-((2S)-4-methyl-1-(5-methyl-5H-chromeno[3,4-c]pyridin-8-yloxy)pentan-2-yl)isoindoline-1,3-dione (205 mg, 0.463 mmol, 64% yield). LCMS (ESI) m/e 443.2 [(M+H)+, calcd for C27H27N2O4 443.2]; LC/MS retention time (Method C): tR=2.27 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@@:13]3([CH3:21])[OH:14])[C:4]=2[N:5]=[CH:6][N:7]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+]>O.CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C:2]1[C:3]2[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:9][N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@@:13]3([CH3:21])[OH:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OB(O)c1ccccc1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc(I)c2c(N)ncnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc(-c2ccccc2)c2c(N)ncnc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
An argon purged mixture of compound 6 from Step 2 (49 mg, 0.12 mmol), phenylboronic acid (25 mg, 0.20 mmol), Na2CO3 (144 mg, 1.36 mmol), TPPTS (15.5 mg, 0.027 mmol) and Pd(OAc)2 (1.4 mg, 6.2 μmol) in water/MeCN (2:1, 1.8 ml) was stirred at 80° C. for 1 h. After cooling, volatiles were removed by evaporation and the residue was purified by reverse phase chromatography (0→100% MeOH in water) affording title compound 7a as white solid (30 mg, 70%). Mp 129° C. [α]20D −55.7 (c 0.226, MeOH). 1H NMR (600 MHz, DMSO-d6): 0.75 (s, 3H, CH3); 3.65 (bdd, 1H, Jgem=12.2, J5′b,4′=2.9, H-5′b); 3.82 (bdd, 1H, Jgem=12.2, J5′a,4′=2.1, H-5′a); 3.86 (ddd, 1H, J4′,3′=9.1, J4′,5′=2.9, 2.1, H-4′); 4.02 (d, 1H, J3′,4′=9.1, H-3′); 5.15 (bs, 3H, OH-2′,3′,5′); 6.10 (bs, 2H, NH2); 6.23 (s, 1H, H-1′); 7.36 (m, 1H, H-p-Ph); 7.44-7.50 (m, 4H, H-o,m-Ph); 7.70 (s, 1H, H-6); 8.16 (s, 1H, H-2). 13C NMR (151 MHz, DMSO-d6): 20.00 (CH3); 59.60 (CH2-5′); 72.01 (CH-3′); 78.88 (C-2′); 82.39 (CH-4′); 90.51 (CH-1′); 100.09 (C-4a); 116.41 (C-5); 120.75 (CH-6); 127.05 (CH-p-Ph); 128.64 (CH-o-Ph); 129.23 (CH-m-Ph); 134.89 (C-i-Ph); 150.67 (C-7a); 151.94 (CH-2); 157.49 (C-4). IR (KBr): 3480, 3431, 3400, 1631, 1622, 1585, 1566, 1537, 1489, 1464, 1445, 1299, 1178, 1123, 1073, 1058, 1029, 799, 763, 705, 550. MS (FAB) m/z 357 (M+H). HRMS (FAB) for C18H21N4O4: [M+H] calcd: 357.1563. found: 357.1557. Anal. Calcd for C18H20N4O4.1.6H2O: C, 56.13; H, 6.07; N, 14.54. Found: C, 56.52; H, 5.74; N, 14.14.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20]3)=[CH:15][C:14]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:5]=1)(=[O:3])[CH3:2].CO[CH:36](OC)[N:37]([CH3:39])[CH3:38]>C(#N)C>[CH2:27]([O:26][C:14]1[CH:15]=[C:16]([N:19]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20]2)[CH:17]=[CH:18][C:13]=1[N:6]1[CH:7]=[C:8]([O:11][CH3:12])[C:9](=[O:10])[C:4]([C:1](=[O:3])[CH:2]=[CH:36][N:37]([CH3:39])[CH3:38])=[N:5]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(OC)N(C)C
Reactant: COc1cn(-c2ccc(-n3cc(F)c(F)c3)cc2OCc2ccccc2)nc(C(C)=O)c1=O
Solvent: CC#N
Product: COc1cn(-c2ccc(-n3cc(F)c(F)c3)cc2OCc2ccccc2)nc(C(=O)C=CN(C)C)c1=O

Procedure:
A mixture of 3-acetyl-1-[2-(benzyloxy)-4-(3,4-difluoro-1H-pyrrol-1-yl)phenyl]-5-methoxypyridazin-4(1H)-one (3.70 g), N,N-dimethylformamide dimethyl acetal (40 mL) and acetonitrile (40 mL) was heated under reflux for 6 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethanol to give the title compound (3.85 g).
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][CH:13]1[CH2:15][CH2:14]1)[C:8]([CH3:16])=[N:7]2.C([Sn](CCCC)(CCCC)[C:23]([O:25]CC)=[CH2:24])CCC.[F-].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[CH:13]1([NH:12][C:9]2[C:8]([CH3:16])=[N:7][C:6]3[C:11]([N:10]=2)=[C:2]([C:23](=[O:25])[CH3:24])[C:3]([F:17])=[CH:4][CH:5]=3)[CH2:15][CH2:14]1
Reactant: Cc1nc2ccc(F)c(Br)c2nc1NC1CC1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)c1c(F)ccc2nc(C)c(NC3CC3)nc12
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 87.4 %

Procedure:
A 150-mL round bottomed flask was charged with 8-bromo-N-cyclopropyl-7-fluoro-3-methylquinoxalin-2-amine (283a) (1.60 g, 5.40 mmol), tributyl(1-ethoxyvinyl)tin (Sigma-Aldrich) (2.74 mL, 8.10 mmol), Pd2dba3 (Strem Chemicals) (0.15 g, 0.16 mmol), Xphos (Strem Chemicals) (0.15 g, 0.32 mmol), Cut (Strem Chemicals) (0.21 g, 1.08 mmol) and cesium fluoride (Sigma-Aldrich) (2.46 g, 16.21 mmol) in dioxane (27.0 mL). The flask was purged with argon for 3 min, placed into a pre-heated (80° C.) bath and stirred 2.5 h while under inert atmosphere. The progress of the reaction was monitored by LCMS, which showed desired material. The mixture was removed from the heat bath and cooled to RT. The mixture was treated with 1 N HCl (20 mL) and stirred at RT 30 min. The mixture was filtered through AW Standard Super-Celt NF (Sigma-Aldrich). The filter cake was washed with EtOAc and water. The aq. layer was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by chromatography through a SiliCycle SiliaSep HP pre-packed silica-gel column (SiliCycle, Quebec City, Canada; 40 gram), eluting with a gradient of 0-20% EtOAc in DCM, to provide 1-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)ethanone (283b) (1.22 g, 4.72 mmol, 87% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.82 (dd, J=9.00, 6.06 Hz, 1H), 7.51 (dd, J=2.74, 0.39 Hz, 1H), 7.23 (t, J=9.29 Hz, 1H), 2.78-2.97 (m, 1H), 2.76 (s, 3H), 2.46 (s, 3H), 0.70-0.83 (m, 2H), 0.52-0.70 (m, 2H). m/z (ESI, +ve) 260 (M+H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12](O)=[O:13])[CH:9]=[CH:8][C:7]=2[N:15]2[C:18]3([CH2:21][O:20][CH2:19]3)[CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[NH2:22][C@@H:23]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:24]([NH:26][CH3:27])=[O:25]>>[CH3:30][C:29]([CH3:32])([CH3:31])[CH2:28][C@H:23]([NH:22][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[C:18]3([CH2:21][O:20][CH2:19]3)[CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:13])[C:24](=[O:25])[NH:26][CH3:27]
Reactant: CNC(=O)[C@@H](N)CC(C)(C)C
Reactant: O=C(O)c1ccc(N2CCC23COC3)c(OCC2CC2)n1
Product: CNC(=O)[C@H](CC(C)(C)C)NC(=O)c1ccc(N2CCC23COC3)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(cyclopropylmethoxy)-5-(6-oxa-1-azaspiro[3.3]heptan-1-yl)picolinic acid and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials. MS (EI): m/e=431.1 [M+H]+.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:23])[F:22])=[C:16]([O:24][CH:25]([F:27])[F:26])[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH:32]=[C:31]([CH2:33][C:34](O)=[O:35])[N:30]=[CH:29]1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:22])[F:23])=[C:16]([O:24][CH:25]([F:27])[F:26])[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:34](=[O:35])[CH2:33][C:31]1[NH:30][CH:29]=[N:28][CH:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: FC(F)Oc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC(F)F
Product: O=C(Cc1cnc[nH]1)N1CCN(c2ccc(OC(F)F)c(OC(F)F)c2)C[C@@H]1Cc1ccccc1
Yield: 45 %

Procedure:
Prepared using the same procedure described in Example 189 from (S)-3-benzyl-1-(3,4-bis-difluoromethoxy-phenyl)-piperazine and (1H-imidazol-4-yl)-acetic acid to afford the title compound as colorless solid (55 mg, 45%). LC/MS (Method B) 2.72 min, [M+1]+ 493.