Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10]([CH3:12])([CH3:11])[S:9][CH2:8][CH2:7][N:6]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4].[C:23]1([C:29]#[C:30][CH2:31]O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:11][C:10]1([CH3:12])[S:9][CH2:8][CH2:7][N:6]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:31][C:30]#[C:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C@H:5]1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)C1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Reactant: OCC#Cc1ccccc1
Product: COC(=O)[C@@H]1N(S(=O)(=O)c2ccc(OCC#Cc3ccccc3)cc2)CCSC1(C)C
Yield: 55.3 %

Procedure:
According to the procedure of Step 2 of Example 248, Mitsunobu coupling of 0.345 g (1.0 mmol) of 4-(4-hydroxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid methyl ester and 0.159 g (1.2 mmol) of 3-phenyl-2-propyn-1-ol provided 0.254 g (55%) of methyl(3S)-2,2-dimethyl-4-({4-[(3-phenyl-2-propynyl)oxy]phenyl}sulfonyl)-3-thiomorpholine carboxylate as a pale yellow solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]2[O:15][C:14](=[O:16])[CH2:13][CH2:12]2)=[CH:4][CH2:3]1.C(O)(=O)C[C:19](O)=[O:20].[C:24](=O)(O)[O-].[Na+]>CO>[CH3:24][O:1][C:2]1([O:20][CH3:19])[CH2:7][CH2:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]2[O:15][C:14](=[O:16])[CH2:13][CH2:12]2)=[CH:4][CH2:3]1
Reactant: O=C([O-])O
Reactant: O=C1CC=C(CCCC2CCC(=O)O2)CC1
Reactant: O=C(O)CC(=O)O
Agent: [Na+]
Solvent: CO
Product: COC1(OC)CC=C(CCCC2CCC(=O)O2)CC1

Procedure:
To a solution of 41 parts of tetrahydro-5-[3-(4-oxo-1-cyclohexen-1-yl)propyl]furan-2-one in 320 parts of methanol is added a solution of 20 parts of malonic acid in 160 parts of methanol. The resultant mixture is stirred at room temperatures for 7 hours, then cooled to 0°-5° and maintained thereat while being made basic with aqueous 5% sodium bicarbonate. The mixture thus obtained is extracted with ether. The ether extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residue is taken up in a 50:50 (by volume) mixture of ethyl acetate and hexane, and the resultant solution is filtered through silica gel. Solvent is removed from the filtrate by vacuum distillation, affording tetrahydro-5-[3-(4,4-dimethoxy-1-cyclohexen-1-yl)propyl]furan-2-one as the residue, an oil. It has the formula ##STR9##
Reaction SMILES: C([O:4][C@H:5]([CH2:10]Br)[CH2:6][C:7]([OH:9])=[O:8])(=O)C.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>O>[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].[O:4]1[CH2:10][C@@H:5]1[CH2:6][C:7]([OH:9])=[O:8]
Reactant: CC(=O)O[C@H](CBr)CC(=O)O
Solvent: CC(C)(C)N
Solvent: O
Product: O=C(O)C[C@H]1CO1
Reaction time: 2 h

Procedure:
A solution of distilled water (10 ml), (S)-3-acetoxy-4-bromobutyric acid (0.9 g, 0.004 mol) and t-butylamine (0.08 g, 0.012 mol) was charged to 100 ml flask equipped with a thermometer, pH meter and agitator, and stirred at 0˜5° C. for 2 hours to give (S)-3,4-epoxybutyric acid t-butylamine salt. It was confirmed by a NMR analysis that more than 99% (S)-3,4-epoxybutyric acid t-butylamine salt was converted.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@H:11]([N:24]1[CH:28]=[C:27]([C:29](O)=[O:30])[N:26]=[CH:25]1)[CH2:12][CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][S:33]([NH2:36])(=[O:35])=[O:34].Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C1C=CN=CC=1.CN(C)C=O.O.C(OCC)(=O)C>[CH3:32][S:33]([NH:36][C:29]([C:27]1[N:26]=[CH:25][N:24]([C@H:11]([CH2:12][CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[C@@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:10])[CH:28]=1)=[O:30])(=[O:35])=[O:34]
Reactant: CS(N)(=O)=O
Reactant: C[C@H](OCc1ccccc1)[C@@H](CCc1cccc2ccccc12)n1cnc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](OCc1ccccc1)[C@@H](CCc1cccc2ccccc12)n1cnc(C(=O)NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 27.6 %

Procedure:
A mixture of 1-[(2S,3R)-2-benzyloxy-5-(1-naphthyl)-3-pentyl]imidazole-4-carboxylic acid (obtained in Example 30)(55 mg), methanesulfonamide (12.7 mg), 4-dimethylaminopyridine (24.3 mg), and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (51.2 mg) in N,N-dimethylformamide (2 ml) was stirred at room temperature for three days. Ethyl acetate and water were added, and the whole was acidified to pH 3 with hydrochloric acid. The organic layer was dried and evaporated. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (20:1) to give a pale yellow gummy oil of N-methylsulfonyl-1-[(2S,3R)-2-benzyloxy-5-(1-naphthyl)-3-pentyl]imidazole-4-carboxamide (18 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16]([N:24]=[C:25]=[O:26])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1>>[F:12][C:13]([F:27])([F:28])[C:14]1[CH:15]=[C:16]([NH:24][C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)=[O:26])[CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Nc1ccc2ncccc2c1

Procedure:
Prepared from 6-aminoquinoline and 3,5-bis(trifluoromethyl)phenyl isocyanate. m/z (ES+) 400 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]=O)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1([C:22]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:23]2[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1CCCC1>>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[CH:14]=[C:27]2\[CH2:28][N:23]([C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:24][CH2:25][C:26]\2=[O:29])[N:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)Nc1nc(C=O)cs1
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)Nc1nc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2=O)cs1
Yield: 36.2 %

Procedure:
Following a procedure similar to that described in Example 132-(c), 2-(t-butoxycarbonylamino)-1,3-thiazole-4-carbaldehyde (3.2 g) was subjected to the reaction with 1-(triphenylmethyl)piperidin-4-one (4.8 g) and pyrrolidine (0.24 ml), and the crude product was purified by silica gel chromatography using hexane, ethyl acetate, and dichloromethane (1:3:1 to 1:5:1) as eluents to afford the title compound (2.8 g, yield: 36%) as an oil.
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][N:6]=[C:7]([S:9][CH3:10])[CH3:8])=[O:4].N1C=CC=CC=1.[S:17](Cl)(Cl)=O.[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH3:1][N:2]([S:27]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[S:17])[C:3]([O:5][N:6]=[C:7]([S:9][CH3:10])[CH3:8])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: Sc1ccccc1
Reactant: CNC(=O)ON=C(C)SC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CSC(C)=NOC(=O)N(C)S(=S)c1ccccc1

Procedure:
A mixture of 3.3 g S-methyl N-[N'-methylcarbamoyloxy]thioacetimidate (0.02 mol), 1.9 g pyridine (0.024 mol) and 2.5 g thionyl chloride (0.021 mol), in 20 ml dry tetrahydrofuran was stirred at room temperature for 4 hours. Pyridine (1.9 g, 0.024 mol) was added and followed by 2.2 g benzenethiol (0.02 mol) added dropwise at water bath temperature. Stirring was continued for an additional hour, and the mixture was worked up as described for Example I. The resulting oily residue was purified by preparative thin-layer chromatography, and the NMR spectrum obtained.
Reaction SMILES: [F:1][C:2]([F:16])([C:6]([F:15])([F:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[C:3]([OH:5])=O.C(OC#C)C.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][C:28]#[N:29])=[CH:25][CH:24]=1.Cl>C(OCC)(=O)C>[F:16][C:2]([F:1])([C:6]([F:15])([F:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[C:3]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][C:28]#[N:29])=[CH:25][CH:24]=1)=[O:5]
Reactant: N#CCc1ccc(N)cc1
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: C#COCC
Agent: Cl
Solvent: CCOC(C)=O
Product: N#CCc1ccc(NC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.7 %

Procedure:
Perfluorovaleric acid (10 g), ethoxyacetylene (12.3 g) and ethyl acetate (175 mL) were stirred overnight at room temperature under a nitrogen atmosphere. 4-Aminobenzylcyanide (5.57 g) was added and the resulting mixture was allowed to stir at room temperature for 24 hours. The reaction mixture was cooled in ice and 10% aqueous HCl solution was added until a precipitate formed. The solid was collected and washed with water and hexane, sequentially, and dried in vacuo to yield 7.4 g (53%) of 2,2,3,3,4,4,5,5,5-nonafluoro-N-[4-(cyanomethyl)phenyl]pentanamide as a tan solid, m.p. 126°-128° C.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([OH:10])=O)=[O:4].[CH3:37][C:38]([NH2:41])([CH3:40])[CH3:39].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:38]([NH:41][C:8](=[O:10])[CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH:2]([OH:1])[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:23]=3[C:33]([F:36])([F:34])[F:35])[O:19][N:18]=2)=[CH:15][CH:16]=1)([CH3:40])([CH3:39])[CH3:37]
Reactant: CC(C)(C)N
Reactant: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)NC(=O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 36.4 %

Procedure:
(R/S)-3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Example 22, 22 mg, 0.044 mmol), 2-methylpropan-2-amine (4.80 mg, 0.066 mmol), 4-methylmorpholine (17.72 mg, 0.175 mmol), and HATU (21.65 mg, 0.057 mmol) were added to DMF (1 mL). This was stirred for 1 h and then purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 12 min, 20 mL/min, 220 nM, product retention=13.9) to provide (R/S)-N-tert-butyl-3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanamide (10 mg, 0.016 mmol, 37.1% yield): LCMS=558.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.16 (2 H, d, J=8.36 Hz), 7.53-7.74 (7 H, m), 5.11 (1 H, s), 3.41-3.53 (2 H, m), 2.27-2.41 (2 H, m), 1.30 (9 H, s); HPLC peak RT=9.4 min (Method A).
Reaction SMILES: C([C@H]1COC(=O)N1[C:14]([C@H:16]([CH2:20][CH2:21][C:22]1([CH3:27])[O:26][CH2:25][CH2:24][O:23]1)[CH2:17][CH:18]=O)=[O:15])C1C=CC=CC=1.Cl.Cl.[CH3:30][O:31][C:32](=[O:47])[CH2:33][CH:34]([C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)[CH2:35][CH2:36][CH2:37][NH2:38].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH3:30][O:31][C:32](=[O:47])[CH2:33][CH:34]([C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)[CH2:35][CH2:36][CH2:37][N:38]1[CH2:18][CH2:17][C@@H:16]([CH2:20][CH2:21][C:22]2([CH3:27])[O:26][CH2:25][CH2:24][O:23]2)[C:14]1=[O:15]
Reactant: CC1(CC[C@H](CC=O)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)OCCO1
Reactant: COC(=O)CC(CCCN)c1ccc(OC)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)CC(CCCN1CC[C@@H](CCC2(C)OCCO2)C1=O)c1ccc(OC)nc1
Reaction time: 16 h

Procedure:
To a stirred suspension of 1-11 (530 mg, 1.41 mmol), 1-6(460 mg, 1.41 mmol) and triethylamine (0.59 mL, 4.24 mmol) in 1,2-dichloroethane (15 mL) was added sodium triacetoxyborohydride (449 mg, 2.12 mmol) and the mixture was stirred for 16 h. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The reaction mixture was filtered and concentrated at reduced pressure. The resulting oil was purified by flash column chromatography (silica gel, 3:0.3:0.3 to 8:0.8:0.8% ethanol/ammonium hydroxide/water in ethyl acetate) to give 1-12 as an inseparable mixture of diastereomers.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:7]([Si:10]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[CH2:19][CH3:20])=[CH:14][CH:13]=1)([CH3:9])[CH3:8]>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH:25]([Si:10]([CH:7]([CH3:9])[CH3:8])([CH:22]([CH3:24])[CH3:23])[O:11][C:12]1[CH:13]=[CH:14][C:15](/[C:18](/[N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:19]\[CH3:20])=[CH:16][CH:17]=1)([CH3:27])[CH3:26]
Reactant: CCC(=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1
Reactant: C1COCCN1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: C/C=C(\c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1)N1CCOCC1
Temperature: 130 °C
Reaction time: 12 h

Procedure:
Titanium tetrachloride (28 mL) and morpholine (mL) were added in that order to a toluene (1.5 L) solution of 1-{4-[(triisopropylsilyl)oxy]phenyl}propan-1-one (130 g, 0.424 mol) synthesized in Reference Example 1-2-(1), and stirred at 130° C. for 12 hours. After cooled with ice, the insoluble matter in the reaction liquid was removed by filtration through Celite, and the mother liquid was concentrated to obtain a crude product (193 g) of the intended compound.
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][C:9]3[S:10][C:11]([C:16]([NH2:18])=[O:17])=[N:12][C:13]=32)=[CH:4][C:3]=1[F:19].[F:20][CH2:21][C:22]([CH3:26])([OH:25])[C:23]#[CH:24]>CS(C)=O.C(N(CC)CC)C.O>[F:19][C:3]1[C:2]([C:24]#[C:23][C:22]([OH:25])([CH3:26])[CH2:21][F:20])=[CH:15][C:14]2[C:13]3[N:12]=[C:11]([C:16]([NH2:18])=[O:17])[S:10][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:4]=1
Reactant: C#CC(C)(O)CF
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CC(O)(C#Cc1cc2c(cc1F)OCCc1sc(C(N)=O)nc1-2)CF

Procedure:
The title compound was prepared according to a procedure similar to that described in Procedure G. Into a 10-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed a suspension of 13-bromo-12-fluoro-9-oxa-5-thia-3-azatricyclo[8.4.0.0[2,6]]tetradeca-1(14),2(6),3,10,12-pentaene-4-carboxamide (200 mg, 0.58 mmol, 1.00 equiv), 1-fluoro-2-methylbut-3-yn-2-ol (360 mg, 1.76 mmol, 3.00 equiv) and Pd(PPh3)Cl2 (82 mg, 0.20 equiv) in DMSO (0.5 mL) and triethylamine (0.5 mL). The final reaction mixture was irradiated with microwave radiation for 1 h at 70° C. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted with 3×15 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM:MeOH (10:1). This resulted in 0.06 g (28%) of 8-Fluoro-9-(4-fluoro-3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide. LC-MS: (ES, m/z): 365[M+H]+; 1H-NMR: (400 MHz, CD3OD, ppm) δ 8.708 (d, 1H), 6.857 (d, 1H), 4.427 (t, 2H), 4.410 (d, 2H), 3.442 (t, 2H), 1.601 (s, 3H).
Reaction SMILES: [CH3:1][S:2][C:3](=[C:6]([C:9]#[N:10])[C:7]#[N:8])SC.[C:11]([CH2:13][C:14]([NH2:16])=[S:15])#[N:12].C(N(CC)CC)C.Cl>CN(C=O)C>[NH2:10][C:9]1[C:6]([C:7]#[N:8])=[C:3]([S:2][CH3:1])[C:13]([C:11]#[N:12])=[C:14]([SH:15])[N:16]=1
Reactant: N#CCC(N)=S
Reactant: CSC(SC)=C(C#N)C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1c(C#N)c(N)nc(S)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10 g (58.74 mmol) of [bis(methylthio)methylene]malononitrile and 6.5 g (64.61 mmol) of cyanothioacetamide are initially charged in 20 ml of DMF, and 16.4 ml (117.5 mmol) of triethylamine are added dropwise at room temperature. The mixture is stirred at room temperature for 8 h and allowed to stand for a further two days. The mixture is then added to 250 ml of 3 N hydrochloric acid. The resulting precipitate is filtered off with suction, washed with water and acetone and dried. This gives a yellow powder.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13]N=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[C:33](Cl)(=O)C>>[NH2:8][C:9]1[N:10]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][N:30]([C:3](=[O:5])[CH3:2])[CH2:29][CH2:28]2)[CH:33]=[CH:13][C:14]=1[C:15](=[O:16])[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[O:24][CH3:25]
Reactant: CC(=O)Cl
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Product: COc1ccc(F)cc1C(=O)c1ccc(NC2CCN(C(C)=O)CC2)nc1N

Procedure:
The title compound was prepared from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt (Example 22) and acetyl chloride (Aldrich 98.5%) using the procedure described in Example 24. HRMS, observed: 387.1833, Calcd for (M+H)+: 387.1827.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11](OC(=O)C)(=[O:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])(=[O:13])[CH3:12]
Reactant: Cc1ccc(C#N)c(O)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1cc(C)ccc1C#N
Yield: 97.2 %

Procedure:
To a solution of 2-Hydroxy-4-methylbenzonitrile (0.563 g, 4.23 mmol) in CH2Cl2 (21 mL) was added acetic anhydride (0.60 mL, 6.36 mmol) followed by triethylamine (1.20 mL, 8.61 mmol) and the resultant solution was stirred at room temperature for 30 minutes. The mixture was diluted with CH2Cl2 (60 mL), washed with saturated aqueous NaHCO3 (20 mL) and brine (2×20 mL). The organic phase was dried (Na2SO4) and concentrated and provided 0.72 g (97%) of (2-cyano-5-methyl-phenyl) acetate as a white solid. 1H NMR (CDCl3) δ2.38 (s, 3H), 2.43 (s, 3H), 7.08 (s, 1H), 7.13 (d, 1H, J=9 Hz), 7.54 (d, 1H, J=9 Hz).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5](=[O:22])[CH2:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)C.[OH-].[Na+]>CO.CC(O)=O.C(Cl)Cl>[O:22]=[C:5]([CH2:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:9]=1)[C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)C(=O)CC(=O)c1cccc(Sc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(O)C(=O)CC(=O)c1cccc(Sc2ccccc2)c1

Procedure:
In a manner similar to example AIV-2-1, 2,4-dioxo-4-(3-phenylsulfanyl-phenyl)-butyric acid ethyl ester was formed and the crude material was hydrolyzed in a manner similar to example AIV-3-1 using 1N NaOH to afford L-1 as a yellow solid. Rf=0.32 (6:6:94 MeOH/AcOH/CH2Cl2).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])([CH3:16])([CH3:15])[CH3:14].Br[CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>O1CCCC1.CCCCCC>[C:13]([NH:17][S:18]([CH2:21][CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:31])([CH3:33])[CH3:32])([CH3:28])[CH3:29])(=[O:20])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: CC(C)(C)NS(C)(=O)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)NS(=O)(=O)CCCCO[Si](C)(C)C(C)(C)C
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (3.7 ml) in tetrahydrofuran (18 ml) was added dropwise a 1.6 M solution (15 ml) of 1-butyllithium in n-hexane under a nitrogen atmosphere at an inside temperature of from −62° C. to −48° C. over 5 minutes. After stirring for 30 min under ice-cooling, a solution of N-tert-butylmethanesulfonamide(3.63 g) in tetrahydrofuran (12 ml) was added dropwise at an inside temperature of from −63° C. to −59° C. over 5 minutes. After stirring for 1 hr under ice-cooling, the mixture was cooled to an inner temperature of −60° C. again. 1-Bromo-3-(tert-butyldimethylsilyloxy)propane (3.35 ml) was added dropwise and the mixture was stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and saturated brine and the organic layer was dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1) to give N-tert-butyl-4-(tert-butyl-dimethylsilyloxy)butanesulfonamide (618 mg) as a pale-yellow oil.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[C:24]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[CH3:32])=[O:25]>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][S:12]([C:9]2[CH:10]=[CH:11][C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)=[CH:7][CH:8]=2)(=[O:14])=[O:13])=[C:18]([C:24]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][C:31]=2[CH3:32])=[O:25])[CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Reactant: Cc1ccncc1C(=O)c1cc(Cl)ccc1N
Product: Cc1ccncc1C(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(-c2cnco2)cc1

Procedure:
The title compound was prepared using 4-oxazol-5-yl-benzenesulfonyl chloride and (2-amino-5-chloro-phenyl)-(4-methyl-pyridin-3-yl)-methanone according to the general procedure for the preparation of the N-aryl-benzenesulfonamides.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[C:11](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:10][C:3]1[C:2]([O:1][CH3:11])=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: Cc1c(O)cccc1C#N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cccc(C#N)c1C

Procedure:
A mixture of 3-hydroxy-2-methylbenzonitrile [23.38 g described by S. Gabriel and A. Thieme, Ber., 52, 1079 (1919)] anhydrous potassium carbonate (26.7 g) and methyl iodide (16.43 ml) in acetone (255 ml) is refluxed for 4 hr, cooled and filtered. The filtrate is evaporated and dissolved in dichloromethane. The solution is washed with water, dried and evaporated. The residue is chromatographed on silica gel using dichloromethane-hexane(1:1) and the eluates are evaporated and crystallized from hexane to obtain 2-methyl-3-methoxybenzonitrile: (II: R1 =2-Me and Y=CN): mp 47°-48° C.; ir 2,220, 1,265 and 1,100 cm-1 ; and nmr (CDCl3) δ2.42 (s, 3H), 3.85 (s, 3H) and 7.15 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.[CH3:18][Br:19]>CC(C)=O>[Br-:19].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N+:11]([CH3:18])=[CH:10][C:9]=2[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cnccc1-c1ccc(F)cc1
Reactant: CBr
Solvent: CC(C)=O
Product: COC(=O)c1c[n+](C)ccc1-c1ccc(F)cc1
Product: [Br-]

Procedure:
The crude pyridine (5.95 g) was treated with methyl bromide (2.2 ml) in acetone (25 ml). After heating in a sealed vessel at 53° for 60 hours and cooling to 0°, the title pyridinium salt was collected by filtration, washed with acetone and dried (7.4 g, 88%), m.p. 165°-170° (decomp.).