Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][C:25]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28]>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][CH:32]=[C:33]([CH3:34])[C:25]=3[CH3:24])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Cc1cccc(C(=O)NC[C@@H]2C[C@@H]3C[C@@H]3N2C(=O)c2nc(N)sc2-c2cccc(F)c2)c1C

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 2,3-dimethyl-benzoic acid. LC-MS (basic): tR=0.83 min; [M+H]+=465.2.
Reaction SMILES: O=[C:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:21])[CH2:8][CH2:7]1.[ClH:28].Cl.[NH2:30][CH2:31][CH2:32][O:33][NH2:34].N1C=CC=CC=1>C(O)C>[ClH:28].[ClH:28].[NH2:30][CH2:31][CH2:32][O:33][N:34]=[C:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:21])[CH2:8][CH2:7]1
Reactant: NCCON
Reactant: O=C(CCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: NCCON=C(CCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1ccccc1
Reaction time: 3 h
Yield: 47.8 %

Procedure:
A mixture of 1-[1-(4-oxo-4-phenylbutyl)-4-piperidinyl]-1,3-dihydro-2-benzimidazolone (3.85 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (1.89 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for three hrs. The reaction mixture was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was taken up in toluene and evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and evaporated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. The solvent was evaporated and the residue was taken up in hot 2-propanol and chilled. The precipitate was collected and recrystallized from 2-propanol and then twice from ethanol/ether to give 1.5 g (29%) of product, mp 175°-180° C. (dec).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([N:34]([S:39]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)(=[O:41])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])[C:31]([OH:33])=[O:32])=[O:24])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:49][CH2:50][CH:51]([CH2:53]O)[OH:52].C(Cl)CCl>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([N:34]([S:39]([C:42]2[CH:43]=[CH:44][C:45]([CH3:48])=[CH:46][CH:47]=2)(=[O:41])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])[C:31]([O:33][CH2:53][CH:51]([OH:52])[CH2:50][OH:49])=[O:32])=[O:24])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)cc1
Reactant: OCC(O)CO
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)NCCCC[C@@H](C(=O)OCC(O)CO)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 8 h
Yield: 38.9 %

Procedure:
A solution of Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-[N′α-(4-methylbenzenesulfonyl)-L-tryptophanyl]-L-lysine (product of example 2, 70 mg, 0.1 mmol) in DMF (1 mL) was treated with glycerol (100 mg) and EDC (100 mg, 0.5 mmol) and stirred overnight. The solution is then poured in 5% citric acid and extracted with EtOAc (5 mL). The solvent was evaporated and the residue was purified by preparative HPLC to yield 30 mg (40%) of the desired ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]3([CH2:20][NH2:21])[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[N:12]=2)=[CH:4][CH:3]=1.[F:22][C:23]([F:39])([F:38])[C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:30]=[N:31][CH:32]=[C:33]([CH:37]=2)[C:34](O)=[O:35])[N:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]3([CH2:20][NH:21][C:34](=[O:35])[C:33]4[CH:37]=[C:29]([C:26]5[N:25]=[C:24]([C:23]([F:39])([F:38])[F:22])[O:28][N:27]=5)[CH:30]=[N:31][CH:32]=4)[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Reactant: CN1CCC(CN)(c2csc(-c3ccc(Cl)cc3)n2)CC1
Product: CN1CCC(CNC(=O)c2cncc(-c3noc(C(F)(F)F)n3)c2)(c2csc(-c3ccc(Cl)cc3)n2)CC1
Yield: 11 %

Procedure:
This compound was synthesized from (4-(2-(4-chlorophenyl)thiazol-4-yl)-1-methylpiperidin-4-yl)methanamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (17 mg, yield 11%). 1H NMR (400 MHz, MeOD) δ 9.36 (d, J=2.0 Hz, 1H), 9.09 (d, J=2.0 Hz, 1H), 8.72 (t, J=2.0 Hz, 1H), 7.95-7.93 (d, J=8.5 Hz, 2H), 7.59 (br s, 1H), 7.44-7.42 (d, J=8.6 Hz, 2H), 3.73 (m, 2H), 3.50-3.49 (m, 2H), 2.87-2.83 (m, 7H), 2.21-2.16 (m, 2H). MS (ESI) m/z: Calculated for C25H22ClF3N6O2S: 562.12. found: 563.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:24]=[CH:23][S:22][C:21]=4[C:25]([NH2:27])=[O:26])[N:16]=[CH:15]3)=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][NH:3]1.[C:28]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[CH3:28][N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:24]=[CH:23][S:22][C:21]=4[C:25]([NH2:27])=[O:26])[N:16]=[CH:15]3)=[CH:12][CH:13]=2)[C:2]1=[O:1]
Reactant: O=C([O-])[O-]
Reactant: NC(=O)c1sccc1Cc1cn(-c2ccc(-c3ccc[nH]c3=O)cc2)cn1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cccc(-c2ccc(-n3cnc(Cc4ccsc4C(N)=O)c3)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-chloro-N-((1-(4-(2-oxo-1,2-dihydropyridin-3-yl)phenyl-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (0.02 g, 0.05 mmol) in DMF (0.5 mL) was added Cs2CO3 (0.049 g, 0.15 mmol) and MeI (0.01 mL, 0.15 mmol). After stirring for 30 min at ambient temperature, the mixture was purified by preparative HPLC to give 5-chloro-N-((1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (MS 425.1, 427.1 (M+H) Cl pattern).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][CH2:18][C:17]([CH3:24])([C:21]([OH:23])=[O:22])[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH3:24][C:17]1([C:21]([OH:23])=[O:22])[CH2:18][CH2:19][CH2:20][NH:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C)(C(=O)O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C(=O)O)CCCNC1
Reaction time: 3 h

Procedure:
TFA was added to a solution of 1-(tert-butoxycarbonyl)-3-methylpiperidine-3-carboxylic acid (1 eq) in CH2Cl2 (0.5 M). After stirring for 3 h at it the reaction mixture was concentrated in vacuo and azeotroped once with toluene to give 3-methylpiperidine-3-carboxylic acid (TFA salt). The crude product was used for the next step without further purification.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[CH3:22]O>>[CH3:22][O:5][C:3](=[O:4])[C@@H:2]1[CH2:6][C:7]([CH3:10])([CH3:9])[CH2:8][NH:1]1
Reactant: CC1(C)C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1CC(C)(C)CN1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of Boc-Pro(4,4-diMe)-OH (0.5 g, 2.06 mmol) in anhydrous methanol (8 ml) was added dropwise thionylchloride (448 g, 6.18 mmol) and the reaction was stirred for six hours at room temperature. The reaction mixture was concentrated to an amorphous solid (377 mg, 95%).
Reaction SMILES: [CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][NH:17][C@H:16]([CH3:20])[CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:27]1[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=1)=[N:9][C:10]=2[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:2]([CH3:4])[CH3:3].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[OH:59][C@H:60]([CH3:65])[CH2:61][C:62](O)=[O:63]>CN(C)C=O>[NH2:33][C:30]1[N:31]=[CH:32][C:27]([C:8]2[N:7]=[C:6]3[C:11]([N:12]=[C:13]([N:14]4[CH2:19][CH2:18][N:17]([C:62](=[O:63])[CH2:61][C@H:60]([OH:59])[CH3:65])[C@H:16]([CH3:20])[CH2:15]4)[N:5]3[CH2:1][CH:2]([CH3:4])[CH3:3])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)=[CH:28][N:29]=1
Reactant: CC(C)Cn1c(N2CCN[C@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reactant: C[C@@H](O)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)Cn1c(N2CCN(C(=O)C[C@@H](C)O)[C@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Temperature: 40 °C
Reaction time: 16 h
Yield: 50.6 %

Procedure:
5-{9-Isobutyl-8-[(3R)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (150 mg, 0.33 mmol), dicyclohexylcarbodiimide (103 mg, 0.5 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol), and (R)-3-hydroxybutyric acid (70 mg, 0.67 mmol) were dissolved in dimethylformamide (5 ml) and the resulting mixture was stirred at 40° C. for 16 hours. The solvent was evaporated under reduced pressure and then the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (90 mg, 50%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Br:10])=[CH:4][C:3]=1[CH2:11][OH:12]>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Br:10])=[CH:4][C:3]=1[CH:11]=[O:12]
Reactant: COc1cc(Br)cc(CO)c1N
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1cc(Br)cc(C=O)c1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 0.15 M chloroform solution of (2-amino-5-bromo-3-methoxyphenyl)methanol (10.16 g, 43.96 mmol) was added manganese dioxide (19.9 g, 280.5 mmol). The mixture was stirred under argon at room temperature for 16 hours. The resulting mixture was filtered through celite and washed with dichloromethane. The filtrate was concentrated to dryness and used in next step. ES/MS m/z 228/230 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:25]=[CH:24][C:13]2[C@:14]3([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=2[CH:11]=1)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]3)([O-:3])=[O:2].[C:26](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:26][N:18]1[C@H:19]2[C@@:14]([CH3:23])([C:13]3[CH:24]=[CH:25][C:10]([C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N+:1]([O-:3])=[O:2])=[CH:11][C:12]=3[CH2:21][CH2:20]2)[CH2:15][CH2:16][C:17]1=[O:22]
Reactant: CC(C)(C)O
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3ccccc3[N+](=O)[O-])ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccccc4[N+](=O)[O-])cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(2-nitrophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (60 mg, 0.18 mmol), 0.3 mL of t-butanol, and potassium t-butoxide (60 mg, 0.54 mmol). Methyl iodide (0.034 mL, 0.54 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 50 mg (80%) of the title compound as a white solid. mp 130°-131°. FDMS: m/e=350.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[S:6][CH:7]=[CH:8][C:2]1=2.[Li]C(C)(C)C.[CH3:14][Sn:15](Cl)([CH3:17])[CH3:16]>O1CCCC1>[CH3:14][Sn:15]([CH3:17])([CH3:16])[C:5]1[S:1][C:2]2[CH:8]=[C:7]([Sn:15]([CH3:17])([CH3:16])[CH3:14])[S:6][C:3]=2[CH:4]=1
Reactant: c1cc2sccc2s1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1cc2sc([Sn](C)(C)C)cc2s1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
In a 3-neck round bottom flask equipped with an argon inlet and an addition flannel, thieno[3,2-b]thiophene (7.5 g, 54 mmol) was dissolved in tetrahydrofuran (1 L). After the solution was cooled to −78° C. using an isopropanol/dry ice bath, t-BuLi (100 mL, 170 mmol) was transferred by cannula to the addition funnel. The organolithium reagent was then added dropwise. After completion of the addition, the mixture was stirred for 20 min at −78° C. then warmed up with an isopropanol bath at room temperature for 30 minutes during which a yellow precipitate formed. The solution was cooled back at −78° C., and after cannula transfer to the addition funnel, trimethyltin chloride (200 mL of 1 M solution in THF, 200 mmol) was added dropwise. During addition of trimethyltin chloride, the precipitate disappeared and the solution turned light brown. After warming to room temperature the solution was stirred for 30 minutes then was poured into ice-cold water. The aqueous phase was further extracted with hexane. The combined organic phase were washed with cold water then dried with magnesium sulfate. After filtration, the solvent is evaporated under vacuum to yield a grey-brown solid. The product was purified by precipitation of a chloroform solution into methanol followed by filtration (13.2 g, 53%).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[C:15]2[N:16](COCC[Si](C)(C)C)[C:17]([CH3:30])=[C:18]3[C:23]=2[CH:22]=[C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[NH:20][C:19]3=[O:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.C([O-])(=O)C.[K+]>ClCCl>[CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[C:15]2[NH:16][C:17]([CH3:30])=[C:18]3[C:23]=2[CH:22]=[C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[NH:20][C:19]3=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1cc2c(-c3cc(F)ccc3OC3CCCCC3)n(COCC[Si](C)(C)C)c(C)c2c(=O)[nH]1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2c(-c3cc(F)ccc3OC3CCCCC3)[nH]c(C)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
To a solution of Example 48a (0.020 g, 0.037 mmol) in dichloromethane was added TFA (2.84 μL, 0.037 mmol). The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated by rotary evaporation. The residue was concentrated down from toluene (2×) then taken up in methanol/tetrahydrofuran. Potassium acetate (0.145 g, 1.474 mmol) was added, and the reaction mixture was heated at reflux for 2 hours. The reaction mixture was concentrated by rotary evaporation. The residue was partitioned between ethyl acetate and water. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography (silica gel, 20-80% ethyl acetate in hexanes) to give the title compound (0.010 g, 66% yield). 1H NMR (300 MHz, DMSO-d6) δ 12.01 (s, 1 H), 9.29 (s, 1 H), 7.18 (s, 1 H), 6.93-7.09 (m, 3 H), 4.15-4.21 (m, 1 H), 4.12 (q, J=7.12 Hz, 2 H), 2.49 (s, 3 H), 1.69-1.75 (m, 2 H), 1.38-1.45 (m, 2 H), 1.20-1.33 (m, 2 H), 1.13 (t, J=7.02 Hz, 3 H), 1.07-1.18 (m, 4 H). MS (ESI+) m/z 413.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=1)=[O:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:30][C:31]([C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=3)=[O:32])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: O=C(CBr)c1ccc2ccccc2c1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc4ccccc4c3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1.5 g), 2-bromo-1-(2-naphthyl)ethanone (1.16 g) and N,N-dimethylformamide (20 mL) was added 60% sodium hydride (0.19 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.84 g, 39%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:28])[C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:24]([N+:25]([O-])=O)=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl>CCO.[Pd]>[NH2:25][C:24]1[C:19]([C:16]2[CH:15]=[CH:14][C:13]([C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=3)=[O:28])=[CH:18][CH:17]=2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3[N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3N)cc2)cc1

Procedure:
The product from Example 2 (720 mg, 2.18 mmol) was hydrogenated (balloon apparatus) as a solution in 30 mL of 1:1 EtOH:CH2Cl2 over 10% Pd/C overnight at room temperature. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to provide the title compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.04–8.08 (m, 2H), 7.95 (dd, J=4.4 Hz, 1.7 Hz, 1H), 7.70–7.84 (m, 2H), 7.36–7.40 (m, 2H), 7.19 (dd, j=8.2 Hz, 1.7 Hz, 1H), 7.11 (dd, J=8.1 Hz, 4.4 Hz, 1H), 1.29 (s, 9H); MS (ESI+) m/z 346 (M+H)+.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[CH:23]1([CH2:26][C:27]2([S:30]([NH2:33])(=[O:32])=[O:31])[CH2:29][CH2:28]2)[CH2:25][CH2:24]1>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:33][S:30]([C:27]2([CH2:26][CH:23]3[CH2:24][CH2:25]3)[CH2:28][CH2:29]2)(=[O:31])=[O:32])=[O:21])=[CH:19][CH:18]=1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: NS(=O)(=O)C1(CC2CC2)CC1
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(=O)(=O)C1(CC2CC2)CC1

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with 1-cyclopropylmethyl-cyclopropanesulfonic acid amide as described in the preparation of compound 1 to yield the title compound. MS (M−H) calcd for C19H22FN2O6S: 425.1. Found: 425.0. 1H NMR (500 MHz, CDCl3) δ: 0.12 (m, 2), 0.50 (m, 2), 0.70 (m, 1), 1.14 (m, 2), 1.75 (m, 2), 1.88 (m, 2), 3.69 (s, 3), 4.79 (s, 2), 6.54 (s, 1), 7.03 (m, 2), 7.30 (m, 2), 8.83 (s, 1). Anal calcd for C19H23FN2O6S; C, 53.51; H, 5.43; N, 6.56. Found: C, 53.43; H, 5.64; N, 6.51.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7]([NH2:12])[CH:6]=1)[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7]([NH:12][C:14](=[O:16])[CH3:15])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(N)nc(Cl)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(Cl)nc(NC(C)=O)c1

Procedure:
A mixture of 14 g 2-amino-6-chloro-isonicotinic acid ethyl ester (Temple et al. J. Heterocycl. Chem. 1970, 7, 451) (70 mmol) in 150 ml acetic anhydride (large excess) and 150 ml pyridine (large excess) is stirred at 60° C. in the presence of 244 mg (2 mmol) DMAP for 16 h. The mixture is concentrated in vacuo, taken up in EtOAc and washed with 1N HCl, brine and 10% aq Na2CO3 to yield the title compound in the form of yellowish crystals (EtOH).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([SH:8])[CH2:4][CH2:3]1.CN(C)C=O.[H-].[Na+].[F:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[C:19](F)[CH:18]=1>O>[F:16][C:17]1[CH:18]=[C:19]([S:8][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Reactant: CN1CCC(S)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(Sc2cc(F)cc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 10.7 %

Procedure:
Combine 1-methyl-piperidine-4-thiol (1.4 g, 10.67 mmol) and N,N-dimethylformamide (10 mL) and cool to 0° C. Add 95% sodium hydride (0.28 g, 11.20 mmol), warm to ambient temperature and stir. After 40 min., add 1,3-difluoro-5-nitro-benzene (1.21 mL, 10.67 mmol), stir and heat at 65° C. After 3 hr., cool to ambient temperature and add water (50 mL). Extract with ethyl acetate (3×50 mL), wash combined organic layers with water (3×50 mL), aqueous NaCl solution (50 mL), dry organic layer over sodium sulfate, filter and concentrate. Purify residue by silica gel flash chromatography eluting with 10% (2M NH3/methanol)/methylene dichloride to obtain the title compound (0.31 g, 11%). Mass spectrum (electrospray): m/z=271.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:15][C:16](=[O:22])[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH:5]=[CH:6][C:7]=1[C:8]1(O)[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:20][CH:19]([CH3:21])[CH2:18][O:17][C:16](=[O:22])[NH:15][C:4]1[CH:5]=[CH:6][C:7]([C:8]2[CH2:13][CH2:12][S:11][CH2:10][CH:9]=2)=[C:2]([F:1])[CH:3]=1
Reactant: CC(C)COC(=O)Nc1ccc(C2(O)CCSCC2)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)COC(=O)Nc1ccc(C2=CCSCC2)c(F)c1
Reaction time: 3 h

Procedure:
2-Methylpropyl [3-fluoro-4-(tetrahydro-4-hydroxy-2H-thiopyran-4-yl)phenyl]carbamate (IV, EXAMPLE 2, 50 g, 152.7 mmol) is slurried in 150 ml methylene chloride. Trifluoroacetic acid (21.1 ml, 274.9 mmol, 1.8 equiv.) is added and the resulting mixture is stirred at 25° for 3 hr. The reaction is quenched with 75 ml of 47% aqueous potassium carbonate and stirred at 25° for 2 hr to dissolve any salts. Water (75 ml) is added and the phases are separated. The organic layer is collected, washed with 75 ml saline followed by 75 ml water. The organic phase is then concentrated and dried under reduced pressure over night to give 2-methylpropyl[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]carbamate. TLC Rf=0.85 (methanol/methylene chloride, 5/95); mp=99-100°; NMR (CDCl3) d 7.28, 7.12, 6.99, 6.74, 5.99, 3.95, 3.33-3., 2.84, 2.63, 2.02-1.91 and 0.96; CMR (CDCl3) d 159.5, 153.4, 138.4, 134.5, 129.6, 126.8, 124.0, 113.8, 106.2, 71.5, 29.3, 27.9, 25.8, 25.1 and 18.9; MS (CI, NH3) m/z (relative intensity) 327 (80), 310 (100), 309(87), 281 (23), 264 (38), 235 (30), 224(33), 189 (20), 165(25) and 161 (23).