Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[N:15]1([C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=2[F:28])[CH2:18][CH2:17][CH2:16]1.[CH3:30][O:31][CH2:32][C:33]1[CH:34]=[CH:35][C:36]([N:39]2[CH2:44][CH2:43][CH:42]([C@H:45]3[CH2:47][C@H:46]3[CH2:48][CH2:49]O)[CH2:41][CH2:40]2)=[N:37][CH:38]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[N:15]1([C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:49][CH2:48][C@@H:46]3[CH2:47][C@@H:45]3[CH:42]3[CH2:43][CH2:44][N:39]([C:36]4[CH:35]=[CH:34][C:33]([CH2:32][O:31][CH3:30])=[CH:38][N:37]=4)[CH2:40][CH2:41]3)=[CH:23][C:22]=2[F:28])[CH2:18][CH2:17][CH2:16]1
Reactant: COCc1ccc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Reactant: O=C(Cc1ccc(O)cc1F)N1CCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COCc1ccc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N4CCC4)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
DIAD (38.2 μl, 0.196 mmol) was added to a stirred mixture of 1-(azetidin-1-yl)-2-(2-fluoro-4-hydroxyphenyl)ethanone (41.1 mg, 0.196 mmol), 2-[(1S,2R)-2-{1-[5-(methoxymethyl)pyridin-2-yl]piperidin-4-yl}cyclopropyl]ethanol (57 mg, 0.196 mmol), and triphenyl phosphine (51.5 mg, 0.196 mmol) in toluene (327 μl). The mixture was degassed (3×) and stirred at RT for 2 hours. The mixture was diluted with ethyl acetate (20 mL), washed with water (20 ml), the layers separated, the aqueous phase extracted with EtOAc (20 ml), the organic fractions combined, washed with brine (35 ml), dried over sodium sulfate, filtered and the volatiles removed in vac. The residue was purified by column chromatography on silica gel, Biotage 25 g, using a gradient eluant of 0-100% EtOAc/hexanes to afford the title compound. LC/MS (m/z): 482 (M+H)+. GPR119 Human EC50: 0.94 nM
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].[CH3:30][S:31](Cl)(=[O:33])=[O:32].CN1CCOCC1>C(Cl)Cl>[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:12])[CH2:5][CH2:6][N:7]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:8][CH2:9]1)#[N:3]
Reactant: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCNCC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CS(=O)(=O)N1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CC1

Procedure:
The title compound is prepared by treatment of morpholine-4-carboxylic acid [1-(4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide hydrochloride with methanesulfonyl chloride and a tertiary amine base such as N-methylmorpholine in a solvent such as methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#N)=[CH:4][N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CO.S(=O)(=O)(O)[OH:23]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:23])=[CH:4][N:3]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(Cl)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=Cc1ccc(Cl)nc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a cooled (5° C.), stirred solution of 2-chloro-5-cyanopyridine (25.0 g) in anhydrous toluene (540 mL) was added a 1 M solution of diisobutylaluminum hydride (189 mL) over a 30-min period. The resulting red-colored solution was treated with methanol (50 mL) and 2M sulfuric acid (150 mL), sequentially. The resulting biphasic solution was allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was extracted with ethyl acetate, the combined organic layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous brine. The organic phase was stirred over activated charcoal for 20 min, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 23.5 g of the title compound (I-2a) as a light-yellow colored solid.
Reaction SMILES: Cl.CN([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[C:7]1=[O:18])C.Cl.[C-:20]#[N:21].[K+]>O>[C:20]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[C:7]1=[O:18])#[N:21]
Reactant: [C-]#N
Reactant: COc1ccc2c(c1)CCC(CN(C)C)C2=O
Agent: Cl
Agent: [K+]
Solvent: O
Product: COc1ccc2c(c1)CCC(CC#N)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
13.5 g of 2-dimethylaminomethyl-6-methoxy-1-tetralone hydrochloride (C. A. 41, 6253 g) are dissolved in 200 ml of water and 4 ml of concentrated hydrochloric acid are added, followed by the concentrated aqueous solution of 6.5 g of potassium cyanide, introduced below the surface of the liquid. The mixture is refluxed for one hour, stirred at room temperature overnight and filtered, to yield the 2-cyanomethyl-6-methoxy-1-tetralone melting at 90°-93°. Similarly prepared are the following nitriles: 2-cyanomethyl-1-tetralone, b.p. 125°-30°/0.005 mm Hg; 2-cyanomethyl-6,7-dimethoxy-1-tetralone, m.p. 116°-118°; 2-cyanomethyl-7-methoxy-1-tetralone, m.p. 80°-84°: 2-cyanomethyl-5-methoxy-1-tetralone, m.p. 91°-94°.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4]([CH3:11])[N:3]=1.[CH3:12][O-:13].[Na+]>CO.O>[C:8]([C:7]1[C:2]([O:13][CH3:12])=[N:3][C:4]([CH3:11])=[CH:5][C:6]=1[CH3:10])#[N:9]
Reactant: Cc1cc(C)c(C#N)c(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(C)cc(C)c1C#N
Temperature: 60 °C
Yield: 64.6 %

Procedure:
A solution of 2-chloro-3-cyano-4,6-dimethylpyridine (4.60 g, 27.7 mmol) in methanol (30 mL) is added to a stirred solution of sodium methoxide (2.09 g, 38.78 mmol) in methanol (20 mL) and the reaction mixture is heated at 60° C. for 4 hr. After cooling, the reaction is diluted with water (150 mL) and the solids are collected by filtration, washed with water and dried to yield 3-cyano-4,6-dimethyl-2-methoxypyridine (2.90 g, 65%) as an off-white solid containing the same impurity as the starting material. LC/MS: MS m/e=163 (M+H); RT 3.29 min; 1H NMR (CDCl3, δ ppm) 6.69, (1H, s), 4.00 (3H, s), 2.43 (6H, s).
Reaction SMILES: [OH:1][C:2]1([C:10]#[N:11])[CH2:7][CH2:6][N:5]([O:8][CH3:9])[CH2:4][CH2:3]1.CN(C)C1C=CN=CC=1.CN(C1C=CN=CC=1)C.[CH3:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:32]=1[CH2:39][C:40](Cl)=[O:41].O>ClCCl>[C:10]([C:2]1([O:1][C:40](=[O:41])[CH2:39][C:32]2[C:31]([CH3:30])=[CH:36][C:35]([CH3:37])=[CH:34][C:33]=2[CH3:38])[CH2:3][CH2:4][N:5]([O:8][CH3:9])[CH2:6][CH2:7]1)#[N:11]
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Reactant: CON1CCC(O)(C#N)CC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CON1CCC(C#N)(OC(=O)Cc2c(C)cc(C)cc2C)CC1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−20° C.) solution of 4-hydroxy-1-methoxy-piperidine-4-carbonitrile (0.32 g, 2.05 mmol) in 2 ml dichloromethane was added 4-dimethylaminopyridine DMAP (13 mg, 0.05 mmol) under argon. Then (2,4,6-trimethyl-phenyl)-acetyl chloride (0.52 g, 2.64 mmol) dissolved in dichloromethane (3 ml) was added dropwise. The reaction mixture was stirred at −20° C. for 30 minutes, then 30 minutes at 0° C. and finally left stirring overnight at room temperature. The reaction mixture was poured into water and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatography on silica gel to give pure (2,4,6-trimethyl-phenyl)-acetic acid 4-cyano-1-methoxy-piperidin-4-yl ester (compound P3.5) as white solid, mp 75-78° C. Yield: 480 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=[C:12]3[C:11]2=[O:21])=[C:6]([CH2:22][OH:23])[CH:5]=1)([O-])=O.[H][H]>[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=[C:12]3[C:11]2=[O:21])=[C:6]([CH2:22][OH:23])[CH:5]=1
Reactant: [H][H]
Reactant: O=C1c2ccc(Cl)cc2C(=O)N1c1ccc([N+](=O)[O-])cc1CO
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1ccc(N2C(=O)c3ccc(Cl)cc3C2=O)c(CO)c1

Procedure:
The mixture of 3.0 g of N-(4-nitro-2-hydroxymethylphenyl)-4-chlorophthalimide, 1.5 g of Raney nickel and 250 ml of ethyl acetate is hydrogenated at room temperature and atmospheric pressure until the hydrogen uptake ceases. It is filtered, the filtrate evaporated and the residue recrystallized from ethyl acetate-diethyl ether, to yield the N-(4-amino-2-hydroxymethylphenyl)-4-chlorophthalimide melting at 228°-230°.
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:19][CH2:18]2)=[C:13]([CH3:31])[CH:12]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:19][CH2:18]2)=[C:13]([CH3:31])[CH:12]=1
Reactant: ON=C1CCCCCC1
Reactant: CCOC(=O)CCCN1CCC(c2ccc(Cl)cc2C)CC1
Product: Cc1cc(Cl)ccc1C1CCN(CCCc2onc3c2CCCCC3)CC1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-chloro-2-methylphenyl)piperidin-1-yl)-n-butyrate, 3-(3-(4-(4-chloro-2-methylphenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: C(O[CH2:5][C:6]1[N:10]2[C:11]3[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=3[O:13][C:14]3([CH2:19][CH2:18][N:17](CC4C=CC=CC=4)[CH2:16][CH2:15]3)[C:9]2=[CH:8][CH:7]=1)(=O)C.C(O)(=O)C>C(OCC)(=O)C.[Pd]>[CH3:5][C:6]1[N:10]2[C:11]3[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=3[O:13][C:14]3([CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[C:9]2=[CH:8][CH:7]=1
Reactant: CC(=O)OCc1ccc2n1-c1ccccc1OC21CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc2n1-c1ccccc1OC21CCNCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 34.1 %

Procedure:
To a solution of (1′-benzylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-yl)methyl acetate (300 mg, 0.75 mmol) in ethyl acetate (30 mL) was added acetic acid (17 μL, 0.30 mmol). The reaction was flushed with nitrogen then 10% Pd/C (40 mg, 0.37 mmol) was added. The reaction was placed under hydrogen gas and was stirred for 20 h at room temperature. The suspension was filtered through celite, concentrated, then purified by column chromatography (silica gel: 0.1-15% methanol in dichloromethane) to give 1-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] (65 mg, 34%). ESI-MS m/z calc. 254.3. found 255.3 (M+1)+; Retention time: 1.93 minutes (3 min run). NMR (400 MHz, CDCl3) δ 7.56 (d, J=7.9 Hz, 1H), 7.16-6.99 (m, 3H), 6.03 (d, J=3.2 Hz, 1H), 5.94 (d, J=3.4 Hz, 1H), 3.14 (t, J=12.2 Hz, 2H), 2.94 (d, J=12.3 Hz, 2H), 2.56 (s, 3H), 2.19 (m, 1H), 2.04 (d, J=12.7 Hz, 2H), 1.97-1.84 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][C:22](O)=[O:23])[CH2:9][C:10]([N:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O[C:38]1[C:46]2[N:45]=N[NH:43][C:42]=2C=[CH:40][CH:39]=1.Cl.N1CCC[C@H]1C#N>CN(C)C=O.C(N(CC)CC)C>[C:42]([C@@H:46]1[CH2:38][CH2:39][CH2:40][N:45]1[C:22](=[O:23])[CH2:21][N:8]([CH2:9][C:10]([N:12]1[CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20]1)=[O:11])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])#[N:43]
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)CC(=O)N1Cc2ccccc2C1
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N#C[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC(=O)N1Cc2ccccc2C1)CC(=O)N1CCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 21 h
Yield: 90.4 %

Procedure:
{t-Butoxycarbonyl-[2-(1,3-dihydroisoindol-2-yl)-2-oxoethyl]amino}acetic acid (260 mg), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (150 mg) and hydroxybenzotriazole (120 mg) were dissolved in N,N-dimethylformamide (5.0 ml). Triethylamine (110 μl) and (S)-pyrrolidine-2-carbonitrile hydrochloride (100 mg) were added thereto, and the mixture was stirred for 21 hours at room temperature. The reaction mixture was concentrated under reduced pressure, then ethyl acetate and 10% citric acid solution were added to the residue, and the organic phase was separated. The organic phase was washed with 4% sodium bicarbonate solution and a saturated saline solution and dried over sodium sulfate anhydrous. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluting solvent; dichloromethane:methanol 20:1) to give t-butyl (S)-[2-(cyanopyrrolidin-1-yl)-2-oxoethyl]-[2-(1,3-dihydrois oindol-2-yl)-2-oxoethyl]carbamate (290 mg, Y.:90%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[ClH:19].Cl.[NH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([NH2:31])=[NH:30])[CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC(C)=CC=1C>CN(C)C=O>[ClH:19].[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29](=[NH:30])[NH2:31])[CH2:25][CH2:24]1)[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Reactant: N=C(N)N1CCC(CN)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)NCC1CCN(C(=N)N)CC1)C1CCCCC1

Procedure:
The title compound was prepared using (S)-tert-butoxycarbonylamino-cyclohexyl-acetic acid (10.1 g, 39.28 mmol), 4-aminomethyl-piperidine-1-carboxamidine dihydrochloride (9.0 g, 39.28 mmol) , HATU (14.9 g, 39.28 mmol), and collidine (15.6 ml, 117.8 mmol) in dimethylformamide as described in example 223 a).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4]2[CH:13]=[CH:14][C:15]([NH:17][C:18]([NH2:20])=[S:19])=[CH:16][C:3]1=2.[CH2:21](I)[CH3:22]>CS(C)=O>[CH2:21]([S:19][C:18](=[NH:20])[NH:17][C:15]1[CH:14]=[CH:13][C:4]2[NH:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[NH:8][C:2](=[O:1])[C:3]=2[CH:16]=1)[CH3:22]
Reactant: NC(=S)Nc1ccc2c(c1)C(=O)Nc1ccccc1N2
Reactant: CCI
Solvent: CS(C)=O
Product: CCSC(=N)Nc1ccc2c(c1)C(=O)Nc1ccccc1N2
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.7 %

Procedure:
To a solution of (11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-2-yl)-thiourea (Example 9, 100 mg, 0.35 mmol) in DMSO was added ethyl iodide (28.2 μL, 0.35 mmol). The mixture was stirred at room temperature for 48 hr. DMSO was removed under vacuum and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was dried with magnesium sulfate, filtered and the solvent evaporated to give a yellow semi-solid which was chromatographed on silica gel (10% methanol/90% ethyl acetate) to give a yellow solid (109 mg, 55%). H1 NMR (DMSO d6) δ: 8.96 (s, 1H), 7.34 (s, 1H), 7.09-7.03 (m, 2H), 6.99-6.93 (m, 4H), 6.88-6.86 (m, 3H), 3.0-2.95 (q, 1H, J=7), 1.30-1.27 (t, 3H, J=7), MS (ES): MH+ 313.2.
Reaction SMILES: C(N[C:9]([C:11]1[C:16]([NH:17][C:18](=[O:23])[CH2:19][CH:20]([CH3:22])[CH3:21])=[N:15][CH:14]=[CH:13][N:12]=1)=[O:10])C1C=CC=CC=1.NC1C(C(O)=[O:32])=NC=CN=1.C(N(C(C)C)CC)(C)C.C(Cl)(=O)CC(C)C>CN(C=O)C>[CH3:21][CH:20]([CH3:22])[CH2:19][C:18]([NH:17][C:16]1[C:11]([C:9]([OH:10])=[O:32])=[N:12][CH:13]=[CH:14][N:15]=1)=[O:23]
Reactant: CC(C)CC(=O)Nc1nccnc1C(=O)NCc1ccccc1
Reactant: Nc1nccnc1C(=O)O
Agent: CC(C)CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)CC(=O)Nc1nccnc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(3-Methyl-butyrylamino)-pyrazine-2-carboxylic acid benzylamide: To a solution of DMF (200 mL), 3-aminopyrazine-2-carboxylic acid (10.0 g, 71.9 mmol) and diisopropylethyl amine (25.0 mL, 144 mmol) was added isovaleryl chloride (12.4 mL, 86.3 mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature for two hours after which the solvent was removed under reduced pressure and the residue dried under vacuum overnight, to afford 3-(3-methyl-butyrylamino)-pyrazine-2-carboxylic acid as a solid residue. The solid residue was dissolved in acetic anhydride (200 mL) and the mixture stirred at 100° C. overnight. The excess acetic anhydride was removed by distillation under reduced pressure, leaving a residue that was then cooled to room temperature and washed with hexane to give the corresponding oxazinone compound of Formula 103, 2-isobutyl-pyrazino[2,3-d][1,3]-oxazin-4-one, which was carried forward without additional purification. A solution of chloroform (200 mL), the oxazinone of Formula 103, and benzylamine (16.0 mL, 144 mmol) was stirred at 60° C. for two hours. After the complete consumption of the oxazinone, as monitored by reverse phase HPLC, the chloroform was removed under reduced pressure and the residue purified by silica gel chromatography using hexane-EtOAc (1:2) as eluent to obtain the title bis amide, 3-(3-methyl-butyrylamino)-pyrazine-2-carboxylic acid benzylamide (4.5 g 20.0%, three steps). MS (Cl) M/E: 313.1.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:8]=[CH:7]2)(=[O:3])[CH3:2].[CH2:19](OCC)C>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:14]([CH3:18])[C:15]([O:17][CH3:19])=[O:16])[CH:8]=[CH:7]2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2cc(C(C)C(=O)O)ccc2c1
Reactant: CCOCC
Product: COC(=O)C(C)c1ccc2cc(C(C)=O)ccc2c1

Procedure:
To a mixture of 24 g. of 6-acetyl-2-naphthyl-α-methylacetic acid and 200 ml. of diethyl ether are added 4.2 g. of diaxomethane in 100 ml. of diethyl ether. The resulting mixture is evaporated to give methyl 6-acetyl-2-naphthyl-α-methylacetate. The product is added to 200 ml. of aqueous 20% sodium hypochlorite. The resulting mixture is allowed to stand for four hours at room temperature. The mixture is acidified by the addition of aqueous 1N hydrochloric acid and extracted with diethyl ether. The extracts are combined, washed with water to neutrality, dried over sodium sulfate, filtered, and evaporated to give 6-carboxy-2-naphthyl-α-methylacetic acid.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][SH:7].[CH2:13]([S:20][CH2:21][C:22](=[CH2:26])[C:23]([OH:25])=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH2:13]([S:20][CH2:21][CH:22]([CH2:26][S:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[O:3][CH:2]([F:12])[F:1])[C:23]([OH:25])=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=C(CSCc1ccccc1)C(=O)O
Reactant: FC(F)Oc1ccccc1CS
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: O=C(O)C(CSCc1ccccc1)CSCc1ccccc1OC(F)F
Reaction time: 24 h
Yield: 63 %

Procedure:
A solution of 2-difluoromethoxybenzyl mercaptan (0.534 g, 2.81 mmol), 2-benzylsulfanylmethyl-acrylic acid (0.585 g, 2.81 mmol) and 4-dimethylaminopyridine (36 mg, 0.3 mmol) in DMF (1.5 ml) was stirred at room temperature for 20 hours. An additional amount of 2-difluoromethoxybenzyl mercaptan (0.201 g) was added to the reaction mixture and stirring was continued for another 24 hours. The reaction mixture was poured into dilute, cold, aqueous HCl and the product extracted with ethyl acetate. The extracts were washed with saturated aqueous sodium chloride and then dried over magnesium sulfate. The solvent was removed by rotary evaporation at reduced pressure and the residue was chromatographed on silica gel eluting with ethyl acetate/hexane to give 2-Benzylsulfanylmethyl-3-[2-(1,1-difluoro-methoxy)-benzylsulfanyl]-propionic acid (0.706 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].N12CCCN=[C:32]1[CH2:31][CH2:30][CH2:29][CH2:28]C2.BrC1CCCC1.O>C(O)C>[CH:28]1([O:1][C:2]2[CH:3]=[C:4]([C:10]3[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]4[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=4)[N:14]=3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: COc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1O
Reactant: C1CCC2=NCCCN2CC1
Agent: BrC1CCCC1
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1OC1CCCC1

Procedure:
A 0.15 g quantity of the N-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide obtained in Example 17 and 0.5 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 4 ml of ethanol, and 0.13 g of bromocyclopentane was added thereto. The mixture was heated and refluxed for 3 hours. The reaction mixture was allowed to cool, water was then added thereto, and extraction was performed with ethyl acetate. The extract was washed with water twice, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give 0.11 g of white powdery N-[2-(3-cyclopentyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:17])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:24][S:25](O)(=[O:27])=[O:26].P(Cl)(Cl)(Cl)=O>ClCCl>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH2:19][C:20]([CH3:22])([CH3:21])[CH3:23])([CH3:18])[CH3:17])=[CH:12][C:11]=1[S:25]([Cl:24])(=[O:27])=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(C(C)(C)CC(C)(C)C)cc1
Reactant: O=S(=O)(O)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(C(C)(C)CC(C)(C)C)cc1S(=O)(=O)Cl

Procedure:
In 900 ml of dichloromethane was dissolved 159 g of Compound A and the solution was stirred while cooling with an ice bath. After slowly adding dropwise 41.5 ml of chlorosulfonic acid to the solution, the mixture was stirred for 1.5 hours. Then, dichloromethane was removed while reducing the pressure by a tap aspirator and 480 ml of N,N-dimethylacetamide and 150 ml of acetonitrile were added to the residue formed. After adding dropwise 93.2 ml of phosphorous oxychloride to the mixture over a period of 40 minutes, the resultant mixture was stirred for 1.5 hours at 40° C. The solution was extracted four times with 500 ml of hexane and the hexane layer was collected and concentrated to provide 229 g of a crude product of 2-octyloxy-5-t-octylbenzenesulfonyl chloride (Compound B). The crude product was used as it was in the subsequent reaction.
Reaction SMILES: C([O:4][C:5]1[C:16]2[S:17][CH:18]=[CH:19][C:15]=2[CH:14]=[C:7]2[S:8][C:9]([C:11](=[O:13])[CH3:12])=[CH:10][C:6]=12)(=O)C.CC([OH:23])C.C(Cl)(Cl)Cl>CC(O)=O>[C:11]([C:9]1[S:8][C:7]2[C:14](=[O:23])[C:15]3[CH:19]=[CH:18][S:17][C:16]=3[C:5](=[O:4])[C:6]=2[CH:10]=1)(=[O:13])[CH3:12]
Reactant: CC(C)O
Reactant: CC(=O)Oc1c2cc(C(C)=O)sc2cc2ccsc12
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cc2c(s1)C(=O)c1ccsc1C2=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a suspension of crude 8 (7.5 g) in HOAc (30 mL) was added CrO3 (5.7 g, 57 mmol). After stirring for 1 h, i-PrOH (20 mL) and CHCl3 (300 mL) were added and stirred for 30 min. The resulting solution was poured into ice water, and the aqueous layer was extracted with CHCl3 three times. The combined extracts were dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, CHCl3) to give 9 (mp 223-225° C.) in a 45% yield. IR (KBr) 1650, 1670 (C═O) cm−1; 1H NMR (CDCl3) δ 2.67 (s, 3H, CH3), 7.68 (d, J=5.1 Hz, 1H, H-7), 7.74 (d, J=5.1 Hz, 1H, H-6), 8.12 (s, 1H, H-3); 13C NMR (CDCl3): δ 26.9 (C-2-CH3), 126.9 (C-7), 129.4 (C-3), 134.3 (C-6), 170.0 (C-4), 174.4 (C-8), 190.7 (C-2-C═O); MS m/z 262 (M+); Anal. (C12H6O3S2) C, H.