Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[C:11]([OH:13])=O.S(Cl)([Cl:16])=O>>[CH3:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[C:11]([Cl:16])=[O:13]
Reactant: C[C@@H]1c2ccccc2C[C@@H]1C(=O)O
Reactant: O=S(Cl)Cl
Product: C[C@@H]1c2ccccc2C[C@@H]1C(=O)Cl

Procedure:
cis-2,3-Dihydro-1-methyl-1H-indene-2-carboxylic acid (52.6 g) is converted to its acid chloride by treatment with thionyl chloride (130 ml). Excess thionyl chloride is distilled off and the acid chloride is distilled, b.p. 86°-89° C./0.45 mmHg. The yield is 47.9 g, 83%.
Reaction SMILES: Cl[C:2]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[O:3]1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:2]2([OH:3])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:32]2[CH2:31][C:30]2[CH:33]=[CH:34][C:27]([Cl:26])=[CH:28][CH:29]=2)=[CH:13][CH:14]=1
Reactant: O=C1OC(Cl)(c2ccc(Cl)cc2)c2ccccc21
Reactant: NCc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.3 %

Procedure:
Distilled THF (25 mL) was added to 3-chloro-3-(4-chlorophenyl)-3H-isobenzofuran-1-one (1.071 g, 3.84 mmol) followed by triethylamine (855.1.1 mg, 8.45 mmol, 1.178 mL) and para-chlorobenzylamine (543.36 mg, 3.84 mmol, 0.467 mL) resulting in the formation of a white precipitate. The mixture was stirred at room temperature under nitrogen for 4 hours and monitored by TLC. Upon completion the mixture was then extracted with EtOAc (15 mL) and washed with saturated sodium bicarbonate (3×10 mL), water (3×10 mL) and dried (Na2SO4). The solvent was removed under reduced pressure and the resultant precipitate recrystallised (EtOAc, petrol) to give the title product as a fine white crystalline solid (1.191 g, 3.20 mmol, 83%). 1H NMR: (300 MHz, DMSO) δ ppm 4.23 (d, 1H, J=15.59, H9) 4.45 (d, 1H, J=15.62 H9′) 7.25 (m, 9H, H1-H5, H10-H13) 7.56 (m, 2H, H6-H7) 7.76 (d, 1H, H8). 13C NMR: (75 Hz, DMSO); δ 42.09 (N—CH2), 90.55 (O—C—N), 122.98, 123.19, 128.02, 128.39, 128.57, 129.76, 130.21, 130.66, 131.60, 133.07, 133.15, 137.44, 139.33, 149.52 (Ar), 167.16 (C═O). Mp: 156.2-156.9° C. IR: 1467, 1661, 3184 cm−1.
Reaction SMILES: [C:1]1([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH2:15][CH:16]([C:17]([O:19]C(C)C)=[O:18])[C:11]3=[CH:10][C:9]=2[CH3:23])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.CO.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]1([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:11]3=[CH:10][C:9]=2[CH3:23])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc2n(c1C(=O)c1cccs1)CCCC2C(=O)OC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cc2n(c1C(=O)c1cccs1)CCCC2C(=O)O

Procedure:
A solution of 900 mg. of isopropyl 3-(2-thenoyl)-2-methyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate in 15 ml. of methanol is treated with a solution of 125 g. of potassium carbonate in 10 ml. of water. The reaction mixture is refluxed under nitrogen atmosphere for 3 hours, cooled, and evaporated to dryness. The residue is taken up in 50 ml. of water, cooled to 0° and made acidic with 10% aqueous hydrochloric acid. The resultant mixture is extracted with ethyl acetate (3×50 ml.). The extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure, to give 3-(2-thenoyl)-2-methyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylic acid (XIIa, R=CH3, M=H, X=S, n=1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:8]2([CH3:25])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:12](=[O:23])[C@H:11]([CH3:24])[O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:26]([N-]C(C)C)(C)C.[Li+].IC>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@@:8]2([CH3:25])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:12](=[O:23])[C:11]([CH3:26])([CH3:24])[O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COc1ccc(CN2C(=O)[C@H](C)OC[C@@]2(C)c2cccc(Br)c2)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(CN2C(=O)C(C)(C)OC[C@@]2(C)c2cccc(Br)c2)cc1
Temperature: -75 °C
Reaction time: 0.25 h

Procedure:
A dried flask was charged under an argon atmosphere with a solution of the crude (2S,5R)-5-(3-bromo-phenyl)-4-(4-methoxy-benzyl)-2,5-dimethyl-morpholin-3-one (622 mg) in tetrahydrofuran (16 ml) which was cooled to −75° C. Lithium diisopropylamide (1.54 ml, 3 mmol) was rapidly added, followed by iodomethane (502 mg, 3.5 mmol). After 15 minutes at −75° C. the reaction was complete. For the workup, the cold reaction mixture was quenched with a saturated ammonium chloride solution (15 ml) and extracted with a mixture of dichloromethane (40 ml) and water (15 ml). The organic layer was dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel using a gradient of heptane and ethyl acetate=100/0 to 66/34 as the eluent. The (R)-5-(3-bromo-phenyl)-4-(4-methoxy-benzyl)-2,2,5-trimethyl-morpholin-3-one was obtained as a white solid (495 mg, 77% of theory). Mass (calculated) C21H24BrNO3 [418.334]; (found) [M+H]+=418, [M+2-H]+=420.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:13]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18])=[O:14].[CH2:24]([O:26][CH2:27][CH2:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[C:30]1[CH3:38])[CH3:25].[C:39](OC(=O)C)(=O)C.[OH-].[NH4+]>CCCCCC.C1(C)C=CC=CC=1>[CH2:24]([O:26][CH2:27][CH2:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:13]2([C:3]3[CH:4]=[CH:5][C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:7][C:2]=3[CH2:1][CH3:39])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17](=[O:18])[O:14]2)=[C:30]1[CH3:38])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1
Reactant: CCOCCn1c(C)cc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCOCCn1c(C)c(C2(c3ccc(N(CC)CC)cc3CC)OC(=O)c3ccccc32)c2ccccc21
Temperature: 25 °C

Procedure:
A mixture of 14.5 g of 2-(2-methyl-4-diethylaminophenyl)carbonylbenzoic acid (68.5 percent active). 9.0 g of 1-(2-ethoxyethyl) 2-methylindole and 60.0 ml acetic anhydride was maintained at approxmmately 70° C. for approximately three hours. After cooling to ambient temperature, the reaction solution was poured slowly into a mixture of toluene and 5 percent aqueous ammonium hydroxide. The toluene layer was separated and evaporated to dryness to obtain a gummy residue. The residue was triturated with hexane and the solid which separated was isolated by filtration. The solid was reslurried in 300.0 ml of hot hexane, filtered, and dried to obtain 11.5 g of 3-[1-(2-ethoxyethyl)-2-methylindol-3-yl]-3-(2-ethyl-4-diethylaminophenyl) phthalide (Formula I: R=C2H5OC2H4 ; R1 =R2 =CH3 ; R3 =R4 =C2H5 ; X=Y=H), a pale pink-colored solid which melted at 156°-158° C. Significant infrared maxima appeared at 1765 (C=O;s) and 1120 (C--O;s)cm-1. The nuclear magnetic resonance spectrum was in accord with the assigned structure. A toluene solution of the product spotted on an acidic clay or a phenolic resin developed a cyan-colored image.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[CH:13]=[C:14]([F:19])[C:15](F)=[N:16][CH:17]=1.O>C1COCC1.CCOC(C)=O>[CH2:3]([O:10][C:15]1[C:14]([F:19])=[CH:13][C:12]([Cl:11])=[CH:17][N:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: Fc1cc(Cl)cnc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cc(Cl)cnc1OCc1ccccc1
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To 60% NaH in mineral oil (1.0 g, 25.0 mmol) in THF (25 mL) was added benzyl alcohol (2.7 g, 2.6 mL, 25.0 mmol) dropwise. After 1 h, 5-chloro-2,3-difluoro-pyridine (3.73 g, 25.0 mmol) was added in THF (5 mL). After an additional 18 h, H2O was added and the mixture extracted with EtOAc (2×). The combined organics were washed with brine and dried. Silica gel chromatography (1-15% EtOAc in hexanes) gave 4.02 g (67% yield) of the title compound as a clear oil. 1H NMR (CDCl3): 7.91 (d, J=2.2 Hz, 1H), 7.48-7.46 (m, 2H), 7.39-7.32 (m, 4H), 5.44 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:11]([Mg]Cl)=[CH2:12].[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]([OH:6])[CH:11]=[CH2:12])[C:3]=1[OH:10]
Reactant: C=C[Mg]Cl
Reactant: O=Cc1cccc(Cl)c1O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1cccc(Cl)c1O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
After a solution of 3-chloro-2-hydroxybenzaldehyde (15.4 g, 98 mmol) in THF (100 ml) was cooled to 0° C., a solution of vinyl magnesium chloride in THF (1.9M, 126 ml, 240 mmol) was added thereto over 40 minutes. The mixture was gradually warmed to room temperature and stirred at room temperature for 14 hours. The mixture was cooled to 0° C. and a 20% aqueous ammonium chloride solution (200 ml) was added thereto at 0° C. The mixture was extracted with ethyl acetate. The organic layer was combined and successively washed with water and a saturated aqueous NaCl solution, followed by drying with anhydrous sodium sulfate. The solid was removed by filtration and the filtrate was concentrated to obtain a brown oil. This oil was purified by silica gel column chromatography (elution with hexane:ethyl acetate=5:1) to obtain 15.1 g of 2-chloro-6-(1-hydroxy-2-propenyl)phenol as a pale brown oil. 1H-NMR (500 MHz, CDCl3)•ppm: 7.28 (1H, dd, J=7.7 and 1.1 Hz), 7.16 (1H, s), 7.08 (1H, dd, J=7.7 and 1.1 Hz), 6.84 (1H, t, J=7.7 Hz), 6.12 (1H, ddd, J=17.0, 10.4, and 6.0 Hz), 5.44 (1H, d, J=4.4 Hz), 5.36 (1H, dt, J=17.0 and 1.1 Hz), 5.26 (1H, dt, J=10.4 and 1.1 Hz), 2.63 (1H, d, J=3.3 Hz).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[C-:13]#[N:14].[K+]>CN(C=O)C.O>[Cl:12][C:4]1[C:3]([CH2:2][C:13]#[N:14])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: [C-]#N
Reactant: O=C(O)c1cccc(CBr)c1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1cccc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(bromomethyl)-2-chlorobenzoic acid (6.39 g) in DMF (75 mL) was treated with a solution of potassium cyanide (3.34 g) in water (25 mL) and the resulting solution was stirred at room temperature overnight. The mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were discarded, whilst the aqueous phase was carefully acidified with concentrated hydrochloric acid (25 mL), venting any liberated HCN through a bleach solution via a stream of nitrogen. After being stirred for 2 hours, the aqueous phase was extracted twice more with ethyl acetate. The combined organic phases were washed three times with water, once with brine, then dried over anhydrous magnesium sulphate and concentrated in vacuo to afford the crude subtitled compound as a pale brown solid. Yield 4.12 g.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:8]=1[CH3:34])[CH3:6])=[O:4].[CH3:35][O:36][C:37]([NH:39][C:40]1[N:45]=[CH:44][C:43]([CH2:46][CH2:47][C:48](O)=[O:49])=[CH:42][CH:41]=1)=[O:38]>>[CH3:26][O:25][C:22]1[N:21]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:15][CH2:14][C:9]3[C:8]([CH3:34])=[C:7]([N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:48](=[O:49])[CH2:47][CH2:46][C:43]4[CH:42]=[CH:41][C:40]([NH:39][C:37](=[O:38])[O:36][CH3:35])=[N:45][CH:44]=4)[CH:12]=[CH:11][C:10]=3[CH3:13])[C:24]=2[N:23]=1
Reactant: COC(=O)Nc1ccc(CCC(=O)O)cn1
Reactant: COc1nc2c(OCc3c(C)ccc(N(C)C(=O)CN)c3C)cccc2n1Cc1ccccn1
Product: COC(=O)Nc1ccc(CCC(=O)NCC(=O)N(C)c2ccc(C)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2C)cn1

Procedure:
2-amino-N-(3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)-2,4-dimethylphenyl)-N-methylacetamide and 3-(6-((methoxycarbonyl)amino)pyridin-3-yl)propanoic acid were used to prepare 4 using the method described for 1. LCMS (+APCI) 666 (M+). 1H-NMR (CDCl3, δ ppm): 1H-NMR (CDCl3, δ ppm): 8.58 (m, 1H), 8.06 (d, J=1.6 Hz, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.55 (m, 3H), 7.20 (m, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.03 (m, 2H), 6.93 (d, J=8.0 Hz, 1H), 6.81 (m, 2H), 6.43 (bt, J=4.0 Hz, 1H), 5.41 (s, 2H), 5.28 (s, 2H), 4.20 (s, 3H), 3.79 (s, 3H), 3.69 (dd, J=4.4, 18.0 Hz, 1H), 3.47 (dd, J=4.0, 18.0 Hz, 1H), 3.21 (s, 3H), 2.88 (t, J=7.6 Hz, 2H), 2.49 (s, 3H), 2.47 (m, 2H), 2.31 (s, 3H). Calcd. for C36H39N7O6+0.8H2O: C, 63.57; H, 6.02; N, 14.42. Found: C, 63.64; H, 5.93; N, 14.53.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C.[NH2:55][C:56]1[O:57][CH:58]=[CH:59][N:60]=1>CN(C)C=O>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[C:35]([NH:55][C:56]2[O:57][CH:58]=[CH:59][N:60]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1ncco1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ncco1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Yield: 47 %

Procedure:
A solution of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (102 mg, 0.23 mmol), 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 38A, 60 mg, 0.21 mmol), N,N-diisopropylethylamine (73 μL, 0.42 mmol), and 2-aminooxazole (27 mg, 0.31 mmol) in dry N,N-dimethylformamide (1 mL) was stirred at 25° C. under nitrogen for 15 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed sequentially with a 1N aqueous hydrochloric acid solution, water, and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-oxazol-2-yl-propionamide (34.9 mg, 47%) as a white solid: mp 134-136° C.; EI-HRMS m/e calcd for C17H18Cl2N2O2(M+) 352.0745, found 352.0750.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[NH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([NH:21][C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=3)[C:11]3[C:6]([CH:5]=2)=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[CH:19]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Product: COc1cccc2c(Nc3ccc(C#N)cc3)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-amino-benzonitrile to give 4-[3-(5-methyl-1H-pyrazol-3-ylamino)-5-methoxy-isoquinolin-1-ylamino]-benzonitrile. LC-MS m/e 371(MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.C1(C)C=CC(S(O)(=O)=[O:16])=CC=1.[CH:20]1[CH:25]=CC=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]2[O:16][CH2:20][CH2:25][O:8]2)[S:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: c1ccccc1
Reactant: O=Cc1cc(Br)cs1
Product: Brc1csc(C2OCCO2)c1
Yield: 72 %

Procedure:
In a 100 mL roundbottom flask equipped with a dean stark trap and a reflux condenser, 4-bromothiophene-2-carboxaldehyde (25 g, 131 mMol) and a catalytic amount of p-toluenesulfonic acid were dissolved in benzene (50 mL). The mixture was heated to reflux overnight. The reaction was cooled, washed with sat'd sodium bicarbonate, water, dried (MgSO4) and concentrated. Purification by fractional distillation (80°-90° C., 0.5 mm Hg) afforded 24.23 g (72%) of the desired dioxolane as a clear liquid.
Reaction SMILES: [O-:1][S:2](C(F)(F)F)(=[O:4])=[O:3].[CH2:9]([O:16]C(=O)C(C)O)[C:10]1C=CC=CC=1.[CH2:22](N(CC)CC)[CH3:23]>ClCCl>[S:2]([O:1][CH2:22][CH3:23])([O:16][CH2:9][CH3:10])(=[O:4])=[O:3]
Reactant: CC(O)C(=O)OCc1ccccc1
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCOS(=O)(=O)OCC

Procedure:
Reaction Scheme A above begins with the triflate of a carboxyl-protected D-αhydroxycarboxylic acid derivative, e.g., lactic acid benzyl ester. By reacting this triflate with α-ethyl-γ-anilido-L-glutamate (prepared, for example, by reacting an amino-protected L-glutamic acid, such as Nα -Cbo-L-glutamic acid, with diethyl sulfate in triethylamine and dichloromethane at room temperature for about three days to give Nα -Cbo-α-ethyl-L-glutamate, forming the dicyclohexylamine salt of the thus-obtained glutamate by reaction with dicyclohexylamine in ethyl acetate at room temperature overnight, acidifying a suspension of the dicyclohexylamine salt and then reacting the isolated free acid with dicyclohexylcarbodiimide and aniline in dichloromethane, first in a dry ice/ice/acetone bath for one hour, and then at room temperature overnight), Nα -[1(L)-carbethoxy-3-carboxanilidopropyl]-L alanine benzyl ester is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C(#N)C.C(=O)(O)[O-].[Na+]>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.O.C(OCC)(=O)C>[OH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:5]1[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: OB(O)c1ccccc1O
Reactant: Nc1cnc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: Nc1cnc(-c2ccccc2O)cn1
Temperature: 150 °C
Yield: 255.3 %

Procedure:
To each of 8 microwave tubes was added 2-amino-5-bromopyrazine (174 mg, 1.00 mmol), 2-hydroxyphenylboronic acid (151 mg, 1.10 mmol), acetonitrile (3 mL), dichlorobis(triphenylphosphine)palladium(II) (36 mg, 0.05 mmol), and a 1M aqueous sodium bicarbonate solution (1 mL). The 8 tubes were microwave-heated at 150° C. for 15 min. The reaction mixture was cooled and then poured into a solution of ethyl acetate and water. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in hot methanol (100 mL). The methanol solution was concentrated in vacuo until a precipitate was observed. The precipitate was filtered. The filtrate was further concentrated and filtered to afford 5-(2-hydroxy-phenyl)-pyrazin-2-ylamine (478 mg, 32%) as a solid.
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN(C)[CH:24]=[O:25].Cl>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[Si:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]1[S:11][C:12]([CH:24]=[O:25])=[CH:13][CH:14]=1)([C:1]([CH3:2])([CH3:4])[CH3:3])([CH3:15])[CH3:16]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCCCc1cccs1
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCc1ccc(C=O)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyldimethyl(3-(thiophen-2-yl)propoxy)silane (787 mg, 3.07 mmol) in 15 mL 9:1 tetrahydrofuran/hexamethylphosphoramide under argon at −78° C. was added n-butyllithium (1.35 mL, 2.5 M in hexanes) dropwise over 5 minutes. The resulting solution was stirred at −78° C. for 1 h. Dimethylformamide (1.18 mL, 15.35 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature before being poured into 100 mL of 1 N hydrochloric acid. Organics were extracted with ether (2×75 m), dried over magnesium sulfate, filtered and concentrated to give crude 5-(3-((t-butyldimethylsilyl)oxy)propyl)thiophene-2-carbaldehyde. Used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]([CH:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=2)[CH2:19][CH2:18]1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37](Cl)=[O:38]>CC(C)=O.O>[CH3:7][N:8]([CH:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][Cl:32])[CH:25]=2)[CH2:19][CH2:18]1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CN(CCc1ccccc1)C1CCN(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)CCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CN(CCc1ccccc1)C1CCN(C(=O)c2cccc(NC(=O)CCCCCl)c2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1.3 g of potassium carbonate was added to a solution of 2.0 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-(3-aminobenzoyl)piperidine in 30 ml of acetone and 20 ml of water. Thereto was dropwise added 0.9 ml of 5-chlorovaleryl chloride with ice-cooling. The mixture was stirred at the same temperature for 20 minutes. The reaction mixture was poured into ice water. The mixture was extracted with methylene chloride. The extract was washed with a saturated aqueous sodium chloride solution, dried with magnesium sulfate, and concentrated under reduced pressure to obtain 2.2 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-[3-(5-chlorovalerylamino)benzoyl]piperidine as a colorless oil.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].FC(F)(F)C(O)=[O:11].[NH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:43]=[CH:42][C:23]([C:24]([NH:26][CH2:27][C@H:28]([NH:32][S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])[C:29]([OH:31])=[O:30])=[O:25])=[CH:22][CH:21]=1.[OH-].[Na+].Cl.[CH:47](=N)[O:48]C(C)C>O>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[OH2:11].[CH3:17][C:16]#[N:15].[CH:47]([NH:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH:26][CH2:27][C@H:28]([NH:32][S:33]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)(=[O:35])=[O:34])[C:29]([OH:31])=[O:30])=[O:25])=[CH:42][CH:43]=1)=[O:48]
Reactant: NCCCOc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)O)cc1
Reactant: CC(C)OC=N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC#N
Product: O=CNCCCOc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)O)cc1
Temperature: 25 °C

Procedure:
The TFA salt 9-1 (80 mg, 0.19 mmol) was dissolved in water at 0° and the pH of the solution was adjusted to 9 by addition of 1N NaOH. Isopropyl formimidate hydrochloride (130 mg, 0.95 mmol) was added in two portions 10 min apart maintaining pH 9 with additional 1N NaOH. After 60 rain at 0° the reaction was warmed to RT for 90 min, then lyophylized. Preparative HPLC (C-18, 0.1% TFA H2O/CH3CN) provided 9-2 as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH2:18][CH3:19])=[CH:4][CH:3]=1.[O:20]([C:22]#[N:23])[Na]>O.C(O)(=O)C>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:22]([NH2:23])=[O:20])=[CH:7][CH:6]=3)=[C:9]([CH2:18][CH3:19])[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: N#CO[Na]
Reactant: CCc1sc2ncnc(N)c2c1-c1ccc(N)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCc1sc2ncnc(N)c2c1-c1ccc(NC(N)=O)cc1
Yield: 95.7 %

Procedure:
A mixture of Example 78A (0.27 g, 1 mmol) and NaOCN (0.13 g, 2 mmol) in water (1.5 mL) and acetic acid (1.5 mL) was stirred overnight at room temperature and partitioned between water and ethyl acetate. The organic extract was washed with saturated aqueous NaHCO3 and brine, dried (MgSO4), filtered, and concentrated to provide 0.3 g of the desired product. MS (ESI(+)) m/e 314 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 1.15 (t, J=7.46 Hz, 3H); 2.63 (q, J=7.57 Hz, 2H); 5.94 (m, 2H); 7.24 (d, J=8.48 Hz, 2H); 7.56 (d, J=8.48 Hz, 2H); 8.25 (s, 1H); 8.75 (s, 1H).