Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[S:10][C:9]([O:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[N:23]=[CH:22][C:21]([CH2:24][CH2:25][CH3:26])=[CH:20][N:19]=4)[CH2:14][CH2:13]3)=[N:8][C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=2)O1.C(C1C=NC(N2CCC(OC3SC4C=C(C5CCN(C(OC(C)(C)C)=O)CC=5)C=CC=4N=3)CC2)=NC=1)CC>>[CH2:24]([C:21]1[CH:20]=[N:19][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([O:11][C:9]3[S:10][C:4]4[C:5]([N:8]=3)=[N:6][CH:7]=[C:2]([C:35]3[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=3)[CH:3]=4)[CH2:13][CH2:14]2)=[N:23][CH:22]=1)[CH2:25][CH3:26]
Reactant: CCCc1cnc(N2CCC(Oc3nc4ncc(Br)cc4s3)CC2)nc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4s3)CC2)nc1
Product: CCCc1cnc(N2CCC(Oc3nc4ncc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4s3)CC2)nc1

Procedure:
Compound 21E was prepared from Compound 21D and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate in a similar manner to the procedure described for Compound 1D in Example 1. 1H NMR (400 MHz, chloroform-d) δ ppm 8.55 (d, J=2.2 Hz, 1H), 8.17 (s, 2H), 7.93 (d, J=2.2 Hz, 1H), 6.10 (br. s., 1H), 5.52-5.66 (m, 1H), 4.21-4.33 (m, 2H), 4.12 (br. s., 2H), 3.68 (t, J=5.5 Hz, 2H), 3.50-3.64 (m, 2H), 2.56 (br. s., 2H), 2.41 (t, J=7.4 Hz, 2H), 2.24 (ddd, J=9.8, 6.2, 3.3 Hz, 2H), 1.94 (dddd, J=12.8, 8.8, 8.7, 3.8 Hz, 2H), 1.53-1.71 (m, 3H), 1.45-1.54 (m, 9H), 0.94 (t, J=7.4 Hz, 3H). LC/MS (m/z)=537 (M+H)+.
Reaction SMILES: NN1CCCC1.[CH3:7][C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:15][CH:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[CH:9]=1.[F:21][C:22]([F:35])([F:34])[O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(Cl)(Cl)Cl.O>[CH3:7][C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:15][CH:16]2[CH2:20][CH2:19][N:18]([C:31](=[O:32])[CH2:30][C:27]3[CH:28]=[CH:29][C:24]([O:23][C:22]([F:34])([F:21])[F:35])=[CH:25][CH:26]=3)[CH2:17]2)[CH:9]=1
Reactant: Cc1cc(C)nc(NC2CCNC2)c1
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN1CCCC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(C)nc(NC2CCN(C(=O)Cc3ccc(OC(F)(F)F)cc3)C2)c1
Yield: 65.3 %

Procedure:
A mixture of 2-amino-4,6-dimethylpyridine (2.0 g), 1-benzylpyrrolidin-3-one (2.9 g), acetic acid (2.9 mL), and chloroform (34 mL) was ice-cooled, followed by addition of sodium triacetoxyborohydride (4.9 g), and the mixture was stirred for 18 h while heating slowly to room temperature. To the reaction mixture was added 1 M aqueous sodium hydroxide to make it basic, and then the mixture was extracted with chloroform. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=65:35) to obtain 1-benzyl-3-(4,6-dimethylpyridin-2-ylamino)pyrrolidine (1.3 g). (2) 1-Benzyl-3-(4,6-dimethylpyridin-2-ylamino)pyrrolidine (1.3 g) was dissolved in methanol (13 mL), followed by addition of 20% Pd(OH)2/C (0.26 g), and the mixture was stirred at room temperature for 20 h under hydrogen atmosphere. The catalyst was removed by Celite filtration, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, chloroform/methanol=19:1) to obtain 3-(4,6-dimethylpyridin-2-ylamino)pyrrolidine (0.10 g). (3) A mixture solution of 3-(4,6-dimethylpyridin-2-ylamino)pyrrolidine (0.73 g), 4-trifluoromethoxyphenylacetic acid (0.12 g), EDC.HCl (0.12 g), HOBt.H2O (0.12 g), and chloroform (1.0 mL) was stirred at room temperature. After completion of the reaction, the reaction mixture was diluted with chloroform and washed with 1 M aqueous sodium hydroxide and brine. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=19:1) and then crystallized with hexane and diethyl ether to obtain the title compound (0.14 g).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1.CC([O-])=O.[Na+].[O:33]1[CH:37]=[CH:36][CH2:35][CH2:34]1>CN(C)C=O.[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].CC([O-])=O.CC([O-])=O.[Pd+2]>[O:33]1[CH2:37][CH:36]=[CH:35][CH:34]1[C:2]1[C:10]2[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1
Reactant: C1=COCC1
Reactant: C[Si](C)(C)CCOCn1cc(Br)c2c(-c3cccc([N+](=O)[O-])c3)ncnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(C2C=CCO2)c2c(-c3cccc([N+](=O)[O-])c3)ncnc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a degassed solution of 5-bromo-4-(3-nitrophenyl)-7-[[2-(trimethylsilyl)ethoxy]methyl]-7H-pyrrolo[2,3-d]pyrimidine (1.30 g, 2.89 mmol) in N,N-dimethylformamide (40 mL), was added Pd(OAc)2 (650 mg, 2.90 mmol), Bu4NCl (1.00 g, 3.60 mmol), NaOAc (714 g, 8.71 mol) and 2,3-dihydrofuran (2.00 g, 28.5 mmol). The reaction was stirred for 2 hours at 50° C. and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate (×3), and the organic layers were combined, washed with water, brine, then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The reaction was purified by chromatography using silica gel, eluting with 1-50% EtOAc/petroleum ether. The product was collected and concentrated in vacuo to afford 5-(2,5-dihydrofuran-2-yl)-4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine as a yellow oil. LRMS (ESI) calc'd for C22H27N4O4Si [M+H]+: 439, found 439.
Reaction SMILES: C(Cl)CCl.[CH3:5][C:6]([O:9][C:10]([NH:12][C@H:13]([C:17]([OH:19])=[O:18])[CH2:14][CH:15]=[CH2:16])=[O:11])([CH3:8])[CH3:7].[CH:20]1(O)[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:6]([O:9][C:10]([NH:12][C@@H:13]([CH2:14][CH:15]=[CH2:16])[C:17]([O:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:18])=[O:11])([CH3:5])([CH3:7])[CH3:8]
Reactant: OC1CCCC1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68.9 %

Procedure:
To a stirred solution of DMAP (0.057 g, 0.465 mmol) in DCM (20 ml) was added EDC (0.980 g, 5.11 mmol). A solution of Boc-L-allylglycine (1.0 g, 4.65 mmol) in DCM (5 ml) was added and the mixture stirred for 20 minutes at RT. Cyclopentanol (0.506 ml, 5.58 mmol) was then added and the mixture stirred overnight at RT for complete reaction. After concentration of the reaction solvent in vacuo, the residue was subjected to column chromatography eluting with 6% EtOAc in hexanes. Yield=0.907 g, 3.20 mmol, 68.9% yield. m/z 284 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([NH:9][C:10](=[O:16])[C@@H:11]([NH2:15])[CH2:12][CH2:13][CH3:14])=[N:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][C:18]1=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH:1]([C:4]1[S:8][C:7]([NH:9][C:10](=[O:16])[C@@H:11]([NH:15][CH:23]2[CH2:24][CH2:25][C:26]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)[CH2:12][CH2:13][CH3:14])=[N:6][CH:5]=1)([CH3:2])[CH3:3]
Reactant: O=C1CCc2ccccc2C1
Reactant: CCC[C@H](N)C(=O)Nc1ncc(C(C)C)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC[C@H](NC1CCc2ccccc2C1)C(=O)Nc1ncc(C(C)C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(S)-amino-pentanoic acid (5-isopropyl-thiazol-2-yl)-amide (350 mg, 1.4 mmol) and 2-tetralone (318 mg, 2.2 mmol)in 20 mL of methylene chloride and 5 drops of acetic acid was treated with sodium triacetoxyborohydride (462 mg, 2.2 mmol) and stirred at room temperature overnight. The mixture was concentrated and eluted through SPEC SCX cartridge and concentrated to dryness. The residue was purified by silica gel column chromatography to give 2-(S)-(1,2,3,4-Tetrahydro-naphthalen-2-ylamino)-pentanoic acid (5-isopropyl-thiazol-2-yl)-amide as a solid, LC-MS, RT=1.9 min, M+1=372.
Reaction SMILES: C1(OC(=S)O[CH:10]([C:35]2[CH:40]=[CH:39][N:38]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=3)[C:37](=[O:48])[CH:36]=2)[C:11]2[N:12]=[CH:13][N:14]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]=2)C=CC=CC=1.C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[Cl:47][C:43]1[CH:42]=[C:41]([N:38]2[CH:39]=[CH:40][C:35]([CH2:10][C:11]3[N:12]=[CH:13][N:14]([C:16]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:15]=3)=[CH:36][C:37]2=[O:48])[CH:46]=[CH:45][CH:44]=1
Reactant: O=c1cc(C(OC(=S)Oc2ccccc2)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)ccn1-c1cccc(Cl)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: O=c1cc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)ccn1-c1cccc(Cl)c1
Temperature: 85 °C

Procedure:
To a solution of the thiocarbonate from Step 5 (0.95, 1.4 mmol) in benzene (40 ml) at room temperature was added tributyl tin hydride (1.13 ml, 4.19 mmol) and AIBN (46 mg, 0.28 mmol). The mixture was degassed by bubbling argon through for 15 min and the mixture was heated at 85° C. for 18 hrs while distilling off most of solvent. The residue was chromatographed (silica gel, MeOH: CH2Cl2 2:98 to 4:96 gradient elution) to afford the title compound.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:19][C:20]([N:22]1[CH2:30][C@H:29]2[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:23]1)=[O:21])[C:9]([O:11]CC1C=CC=CC=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[CH2:1]([C@@H:8]([CH2:19][C:20]([N:22]1[CH2:23][C@H:24]2[C@H:29]([CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:30]1)=[O:21])[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)[C@H](CC(=O)N1C[C@H]2CCCC[C@H]2C1)Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)[C@H](CC(=O)N1C[C@H]2CCCC[C@H]2C1)Cc1ccccc1
Reaction time: 16 h
Yield: 73 %

Procedure:
To a solution of benzyl (S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate (400 mg) in ethyl acetate (3 ml) was added 10% Pd-C (60 mg) and the mixture was hydrogenolyzed at room temperature and atmospheric pressure for 16 hours. After the catalyst was filtered off, the solvent was evaporated under reduced pressure to give 227 mg of (S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid as a colorless viscous oil.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:20]=[CH:19][C:7]([O:8][CH:9]2[CH2:12][N:11]([CH2:13][CH2:14][CH2:15][C:16](O)=[O:17])[CH2:10]2)=[CH:6][CH:5]=1.S(Cl)([Cl:25])=O>>[F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:20]=[CH:19][C:7]([O:8][CH:9]2[CH2:12][N:11]([CH2:13][CH2:14][CH2:15][C:16]([Cl:25])=[O:17])[CH2:10]2)=[CH:6][CH:5]=1
Reactant: O=C(O)CCCN1CC(Oc2ccc(OC(F)(F)F)cc2)C1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCCN1CC(Oc2ccc(OC(F)(F)F)cc2)C1
Yield: 97 %

Procedure:
4-(3-(4-(trifluoromethoxy)phenoxy)azetidin-1-yl)butyric acid (412 mg, 1.29 mmol) was dissolved in thionyl chloride, raised the temperature to reflux for 3 h, spun dry, residuals were washed by an appropriate amount of ethyl ether, generated 421 mg target product, yield was 97%, directly put to the next reaction step.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12]Br)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[I:14].[CH2:15]([O:17][P:18]([O:22]CC)[O:19][CH2:20][CH3:21])[CH3:16]>>[Br:1][C:2]1[C:3]([I:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][C:8]([CH2:12][P:18](=[O:22])([O:19][CH2:20][CH3:21])[O:17][CH2:15][CH3:16])=[CH:7]2
Reactant: CCOP(OCC)OCC
Reactant: BrCc1ccc2c(Br)c(I)ccc2c1
Product: CCOP(=O)(Cc1ccc2c(Br)c(I)ccc2c1)OCC

Procedure:
To 1-bromo-6-(bromomethyl)-2-iodonaphthalene (270 mg) from step 4 was added triethylphosphite (4 mL). The reaction mixture was heated at reflux for 1 hour followed by removal of excess triethylphosphite under high vacuum distillation yielding the titled product.
Reaction SMILES: COC(OC)C(CCCCCC)=CC1C=CC=CC=1.C([C@@H]([C@H](C(OC)=O)O)O)(OC)=O.[CH2:32](/[C:38](/[CH:46]1[O:50][C@@H:49]([C:51]([O:53][CH3:54])=[O:52])[C@H:48]([C:55]([O:57][CH3:58])=[O:56])[O:47]1)=[CH:39]/[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].[K+].[Br-]>>[CH2:32](/[C:38](/[CH:46]1[O:50][C@@H:49]([C:51]([O:53][CH3:54])=[O:52])[C@H:48]([C:55]([O:57][CH3:58])=[O:56])[O:47]1)=[CH:39]\[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCC/C(=C/c1ccccc1)C1O[C@@H](C(=O)OC)[C@H](C(=O)OC)O1
Agent: CCCCCCC(=Cc1ccccc1)C(OC)OC
Agent: COC(=O)[C@H](O)[C@@H](O)C(=O)OC
Agent: [Br-]
Product: CCCCCC/C(=C\c1ccccc1)C1O[C@@H](C(=O)OC)[C@H](C(=O)OC)O1

Procedure:
In a fashion similar to that described in Example 4, α-hexylcinnamaldehyde dimethyl acetal and dimethyl L-tartrate were condensed to provide a mixture of (E)-and (Z)-(4R,5R)-2-(1-hexyl-2-phenyl-1-ethenyl)-4,5-dicarbomethoxy-1,3-dioxolane in an approximate ratio of 90:10 Crystallization provided the pure E-isomer, mp 49°-50° C., [α]D25 -2.2 (c, 0.2, methanol). 1H-NMR (CDCl3) δ7.35-7.26 (5H,m), 6.74 (1H,s), 5.84 (1H,s) 4.86 (1H, d, J=4.4 Hz), 4.70 (1H, d, J=4.4 Hz), 3.85 (3H,s), 3.80 (3H,s), 2.34-2.27 (2H,m), 1.58-1.55 (2H,m), 1.37-1.26 (6H,m), 0.93-0.87 (3H,m), IR (KBr) 2900, 2840, 1730, 1430, 1340, 1200, 1100, 1060, 1030, 980, 950, 915, 870, 790, 750, 730, 690 cm-1. MS m/e (% abundance) 305 (4), 292 (17), 291 (100), 145 (18), 142 (25), 131 (73), 129 (76), 128 (26), 117 (74), 116 (17), 115 (51), 104 (29), 91 (57), 59 (31), 41 (25).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:10]1[CH:15]=CC=CC=1.[C]=O.Cl[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1Cl>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:19]1([N:10]=[C:15]=[O:2])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccncc1
Reactant: Clc1ccccc1Cl
Agent: [C]=O
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C=Nc1ccccc1

Procedure:
1.8 g of this catalyst as well as 10 g of nitrobenzene and 1 g of pyridine are charged into the autoclave used in Example 2 and the volume is made up to a total volume of 100 ml with the addition of ortho-dichlorobenzene. By operating in an identical fashion with Example 2 at 240° C. under 200 bars of carbon monoxide at 20° C., a T.T.G. (overall conversion rate) of nitrobenzene of 100% and a phenylisocyanate selectivity of 62% are obtained.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.Cl.[NH:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>CS(C)=O>[OH:28][C@@H:25]1[CH2:26][CH2:27][N:23]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:24]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: O[C@@H]1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CC[C@@H](O)C3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into an 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), (R)-pyrrolidin-3-ol hydrochloride (212 mg, 1.72 mmol, 4.00 equiv), potassium carbonate (200 mg, 1.55 mmol, 3.00 equiv), toluene (5 mL), DMSO (1.7 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of 20 ml of water. The resulting solution was extracted with 5×10 mL of dichloromethane and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (70:1). This resulted in 147.4 mg (95%) of (R)-methyl 3-(3-hydroxypyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([F:11])[CH:4]=1)#[CH:2].[H][H]>CCOC(C)=O.[Pd]>[CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([F:11])[CH:4]=1)[CH3:2]
Reactant: C#Cc1ccc(C#N)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1ccc(C#N)c(F)c1
Reaction time: 2 h
Yield: 89.6 %

Procedure:
A solution of 4-ethynyl-2-fluoro-benzonitrile (1.29 g, 8.9 mmol) in EtOAc (30 mL) was placed in a Parr pressure bottle and palladium on carbon (130 mg of 10% on carbon) was added. The bottle was placed on the Parr hydrogenation apparatus and shaken under 10 psi of hydrogen pressure. After shaking for two hours the black suspension was filtered through a pad of Celite. The pad was washed thoroughly with EtOAc, and the combined filtrates were concentrated under reduced pressure. The residue was taken up in toluene and concentrated under reduced pressure to afford 4-ethyl-2-fluoro-benzonitrile (1.19 g, 89% yield). 1H-NMR (400 MHz, CDCl3): δ 7.55-7.50 (1H, m), 7.11-7.03 (2H, m), 2.72 (2H, q, J=7.6 Hz), 1.26 (3H, t, J=7.6 Hz).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C:6]([NH:8]C1C(I)=C(C(=O)NC)C(I)=C(C=1I)C(Cl)=O)=[O:7])(=[O:3])[CH3:2].[OH:30][CH:31]([CH2:57][OH:58])[CH2:32][N:33](NC(=O)C)[C:34](=[O:52])[C:35]1[C:44]([I:45])=[C:43](OC(=O)C)[C:42]([I:50])=[C:37]([C:38]([NH:40][CH3:41])=[O:39])[C:36]=1[I:51].C(OCC(NC1C(I)=C(C(=O)NC)C(I)=C(C=1I)C(Cl)=O)=O)(=O)C>>[OH:30][CH:31]([CH2:57][OH:58])[CH2:32][NH:33][C:34](=[O:52])[C:35]1[C:44]([I:45])=[C:43]([NH:8][C:6](=[O:7])[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:25][O:26][C:27](=[O:29])[CH3:28])[C:42]([I:50])=[C:37]([C:38]([NH:40][CH3:41])=[O:39])[C:36]=1[I:51]
Reactant: CNC(=O)c1c(I)c(NC(=O)C(COC(C)=O)OC(C)=O)c(I)c(C(=O)Cl)c1I
Reactant: CNC(=O)c1c(I)c(OC(C)=O)c(I)c(C(=O)N(CC(O)CO)NC(C)=O)c1I
Agent: CNC(=O)c1c(I)c(NC(=O)COC(C)=O)c(I)c(C(=O)Cl)c1I
Product: CNC(=O)c1c(I)c(NC(=O)C(COC(C)=O)OC(C)=O)c(I)c(C(=O)NCC(O)CO)c1I

Procedure:
Compound (12) is prepared from compound (11) in the same manner according to the procedure described for the preparation of compound (4) from compound (3) in Example I, C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([NH2:10])(=[O:9])[CH3:8].[Br:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14](Br)[CH:13]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:11][C:12]1[CH:13]=[C:14]([NH:10][C:7](=[O:9])[CH3:8])[CH:15]=[C:16]([F:18])[CH:17]=1
Reactant: CC(N)=O
Reactant: Fc1cc(Br)cc(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(F)cc(Br)c1
Temperature: 80 °C
Yield: 139.7 %

Procedure:
To a mixture of tris(dibenzylideneacetone)dipalladium (0.20 g, 0.22 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphine)xanthene (0.13, 0.22 mmol) and cesium carbonate (5.0 g, 15.41 mmol) under N2 gas was added acetamide (0.90, 14.73 mmol), 1,3-dibromo-5-fluorobenzene (2.8 g, 10.83 mmol) and dioxane (22 mL). The reaction mixture was heated at 80° C. overnight and concentrated under reduced pressure. Purification by flash chromatography (silica, 50:50 ethyl acetate/hexane) gave N-(3-bromo-5-fluorophenyl)acetamide (3.51 g, quantitative). Retention time (min)=1.945, method [4], MS (ESI) 232.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[Br:20][C:21]1[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=1[C:23]([N:25]=[C:26]=[S:27])=[O:24]>C1COCC1>[Br:20][C:21]1[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=1[C:23]([NH:25][C:26](=[S:27])[NH:1][C:2]1[S:12][C:5]2[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:24]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(C)(C)OC2
Reactant: O=C(N=C=S)c1ccccc1Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(NC(=S)NC(=O)c2ccccc2Br)sc2c1CC(C)(C)OC2
Temperature: 50 °C
Yield: 49 %

Procedure:
tert-Butyl 2-amino-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.28 g, 1.00 mmol) and 2-bromobenzoyl isothiocyanate (0.24 g, 1.00 mmol) were dissolved in THF (5 mL) and heated at 50° C. for 22 hours. The solvent was removed and EtOH (10 mL) was added. The product was filtered and rinsed with EtOH (2×10 mL). tert-Butyl 2-(3-(2-bromobenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.26 g, 0.49 mmol, 49% yield) was isolated as a white solid. 1H NMR (400 MHz, CDCl3) δ 14.64 (s, 1H), 9.04 (s, 1H), 7.75 (apparent dd, J=7.6, 1.8 Hz, 1H), 7.67 (apparent dd, J=7.9, 1.1 Hz, 1H), 7.45 (apparent td, J=7.5, 1.3 Hz, 1H), 7.40 (apparent td, J=7.7, 1.9 Hz, 1H), 4.74 (apparent t, J=1.5 Hz, 2H), 2.77 (t, J=1.5 Hz, 2H), 1.63 (s, 9H), 1.31 (s, 6H).
Reaction SMILES: I[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14](=[O:25])[NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]#[CH:23])[C:17]1=[O:24])([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>C(#N)C.O.CCOC(C)=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.[Cu](I)I>[C:9]([O:13][C:14](=[O:25])[NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[O:8][C:7]3[C:2](=[N:3][CH:4]=[CH:5][CH:6]=3)[CH:23]=2)[C:17]1=[O:24])([CH3:12])([CH3:10])[CH3:11]
Reactant: Oc1cccnc1I
Reactant: C#CCN1CC[C@H](NC(=O)OC(C)(C)C)C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2cc3ncccc3o2)C1=O
Temperature: 120 °C

Procedure:
A mixture of 2-iodo-3-hydroxy-pyridine (0.44 g, 2 mmol), (2-oxo-1-prop-2-ynyl-pyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester (0.6 g, 2.5 mmol), bis(triphenylphosphine)-palladium(II) chloride (Pd(PPh3)2Cl2) (50 mg), copper iodide (25 mg) and triethylamine (3 mL) in 3 mL of acetonitrile is heated in a sealed tube at 120° C. for 2 hours. After cooling, the reaction mixture is diluted with water and EtOAc and the layers are separated. The aqueous layer is extracted with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, then dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 25% EtOAc/CH2Cl2 to 90% EtOAc/CFH2Cl2 to yield the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][C:20]=3[C:25]#[N:26])[C:15]([O:27][CH3:28])=[CH:14][N:13]=2)=[N:6]1.S(=O)(=O)(O)[OH:34].[OH-].[Na+]>>[F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][C:20]=3[C:25]([NH2:26])=[O:34])[C:15]([O:27][CH3:28])=[CH:14][N:13]=2)=[N:6]1
Reactant: O=S(=O)(O)O
Reactant: COc1cnc(-c2cc(OC)n(Cc3ccccc3F)n2)nc1Nc1ccncc1C#N
Agent: [Na+]
Agent: [OH-]
Product: COc1cnc(-c2cc(OC)n(Cc3ccccc3F)n2)nc1Nc1ccncc1C(N)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 126 mg of 4-({2-[1-(2-fluorobenzyl)-5-methoxy-1H-pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino)pyridine-3-carbonitrile 2-1-7 (0.294 mmol, 1.0 eq.) were given at rt with caution 0.446 mL of sulfuric acid. The mixture was stirred for 24 hours at rt. Then the reaction mixture was dropped into ice water and set with aqueous 2 M sodium hydroxide solution to an alkaline pH. This aqueous layer was extracted three times with DCM/propan-2-ol 4:1. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The crystallization from methanol provided 37.0 mg (0.08 mmol, 28%) of analytically pure target compound.