Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=O)=[CH:4][CH:3]=1.C(OP([CH2:21][C:22](=[O:27])[NH:23][CH:24]1[CH2:26][CH2:25]1)(=O)OCC)C>>[CH:24]1([NH:23][C:22](=[O:27])/[CH:21]=[C:9]2\[CH2:8][CH2:7][CH2:6][C:5]3[C:10]\2=[CH:11][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:26][CH2:25]1
Reactant: O=C1CCCc2ccc(F)cc21
Reactant: CCOP(=O)(CC(=O)NC1CC1)OCC
Product: O=C(/C=C1\CCCc2ccc(F)cc21)NC1CC1

Procedure:
This compound was prepared in an analogous manner to Example 12f with the replacement of 5-fluoro 1-tetralone and diethyl (cyclopropylcarbamoyl)methyl phosphonate with 7-fluoro-1-tetralone (7.76 g, 0.05 mol) and diethyl(cyclopropylcarbamoyl)methylphosphonate (11.1 g, 0.05 mol). Chromatography on Silca gel using ethyl acetate:hexanes (1:2) as eluent gave 4.38 g (37%) of (E-N-Cyclopropyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetamide. m.p., 122.8-123.3° C.; NMR (DMSO-d6): d 8.00 (d, J=4.0 Hz, 1H), 7.32 (dd J=11.0 Hz, 1H), 7.04-7.23 (m, 2H), 6.33 (s, 1H), 3.06 (m, 2H), 2.69 (m, 3H), 1.70 (m, 2H), 0.66 (m, 2H), 0.40 (m, 2H); steady-state nOe: irradiation at 6.39 d, observed significant nOe at 7.32 d.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)([OH:16])[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[CH:29]1([CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([CH2:40]Cl)=[CH:36][CH:35]=2)[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>CS(C)=O>[CH:29]1([CH2:32][O:33][C:34]2[CH:35]=[CH:36][C:37]([CH2:40][N:13]3[CH2:12][CH2:11][CH:10]([C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:27])[F:28])=[CH:8][CH:7]=4)([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=4)[OH:16])[CH2:15][CH2:14]3)=[CH:38][CH:39]=2)[CH2:30][CH2:31]1
Reactant: ClCc1ccc(OCC2CC2)cc1
Reactant: OC(c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: OC(c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)C1CCN(Cc2ccc(OCC3CC3)cc2)CC1
Yield: 76.5 %

Procedure:
A solution of 20.5 grams (0.051 mole) of 4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine, 10.0 grams (0.051 mole) of 4-(cyclopropylmeth-oxy)phenylmethyl chloride (prepared as in Step A of Example 1), and 35.4 mL (0.203 mole) of N,N'-diisopropylethylamine in 200 mL of dimethyl sulfoxide was stirred at ambient temperature for about 18 hours. The reaction mixture was then poured into an aqueous solution saturated with sodium bicarbonate. The mixture was extracted with two portions of ethyl acetate, and the extracts combined. The combination was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel with 50% heptane in methylene chloride to 50% acetone in methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 22.0 grams of N-[4-(cyclopropylmethoxy)phenylmethyl]-4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9](Br)[CH:10]=[CH2:11].C(=O)(O)[O-].[Na+]>CS(C)=O.[I-].[Na+]>[C:2]1([CH2:1][NH:8][CH2:11][CH:10]=[CH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: C=CCBr
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C=CCNCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.2 %

Procedure:
To a solution of benzylamine (5.7 ml, 52.2 mmol) and sodium iodide (38 mg, 0.25 mmol) in DMSO (30 ml) was added dropwise allyl bromide (2.2 ml, 25.4 mmol) at 0° C. under argon. After stirring for 3 h at room temperature the reaction was complete as shown by TLC (cyclohexanes:ethyl acetate 1:1). Then saturated aqueous sodium bicarbonate solution was added, the product was extracted with diethyl ether (100 ml) and the organic layer was washed with brine. The crude product was purified via flash chromatography to give the title compound (2.1 g, 57%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.4-7.2 (m, 5H), 6.0-5.9 (m, 1H), 5.3-5.1 (m, 2H), 3.8 (s, 2H), 3.3 (d, 2H), 1.5 (bs, 1H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:18]2[CH:17]=[CH:16][C:15]([S:29][C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)=[C:14]([NH:13][C:2]3[C:3]4[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=4)[N:9]=[CH:10][CH:11]=3)[CH:19]=2)=[CH:23][CH:24]=1
Reactant: Nc1cc(COc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc2c(Nc3cc(COc4ccc(Br)cc4)ccc3Sc3ccc(O)cc3)ccnc2n1
Temperature: 80 °C

Procedure:
The product from Example 1d (0.03 g, 0.167 mmol) was reacted with the product from Example 223c (0.060 g, 0.15 mmol) for 17.5 h following the procedure from Example 1g. Consumption of starting material required a second addition of the product from Example 1d (0.016 g, 0.09 mmol) and continued heating at 80° C. (18 h). The crude title compound was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.056 g, 55%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.77 (s, 3H) 5.12 (s, 2H) 6.30 (d, J=6.99 Hz, 1H) 6.79 (d, J=8.82 Hz, 2H) 6.92-7.08 (m, 3H) 7.25 (d, J=8.82 Hz, 2H) 7.42-7.54 (m, 4H) 7.81 (d, J=8.82 Hz, 1H) 8.47 (d, J=6.99 Hz, 1H) 9.01 (d, J=8.46 Hz, 1H) 9.98 (s, 1H); MS (ESI+) m/z 546.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([N:13]=[CH:14][C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]2[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:6]=2[N:7]=1.[SH-:21].[Na+]>C(O)CC>[CH3:11][N:10]1[C:5]2[N:4]3[N:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:3]3[C:2]([SH:21])=[N:7][C:6]=2[C:8]([CH3:12])=[N:9]1
Reactant: CCOC(=O)c1cnn2c1c(Cl)nc1c(C)nn(C)c12
Reactant: [SH-]
Agent: [Na+]
Solvent: CCCO
Product: CCOC(=O)c1cnn2c1c(S)nc1c(C)nn(C)c12

Procedure:
5.86 gms. of 5-chloro-1,3-dimethyl-1H-dipyrazolo[1,5-a:4',3'-e]pyrazine-6-carboxylic acid, ethyl ester, are refluxed with 2 gms. of sodium bisulfide and 50 ml. of n-propanol for 3 hours. On cooling, the product, 1,3-dimethyl-5-mercapto-1H-dipyrazolo[1,5-a:4',3'-e]pyrazine-6-carboxylic acid, ethyl ester, crystallizes in the form of yellow filamentous needles which are recrystallized from n-propanol, yield 4.76 gms., m.p. 189°-191°.
Reaction SMILES: C[O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1.[N:54]([C:57]([CH3:61])([CH2:59][CH3:60])[CH3:58])=[C:55]=[O:56].[N-]=C=O>>[Cl:52][C:47]1[CH:46]=[C:45]([CH:50]=[CH:49][C:48]=1[Cl:51])[CH2:44][O:43][C:40]1[CH:39]=[CH:38][C:37]([C@H:35]2[CH2:34][O:33][C:29]3=[CH:30][C:31]4[CH2:32][C@@H:23]([C:21]([NH:20][C@@H:4]([CH2:5][C:6]5[CH:11]=[CH:10][C:9]([C:12]6[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=6[CH3:19])=[CH:8][CH:7]=5)[C:3]([OH:53])=[O:2])=[O:22])[N:24]([C:55](=[O:56])[NH:54][C:57]([CH3:61])([CH3:58])[CH2:59][CH3:60])[CH2:25][C:26]=4[CH:27]=[C:28]3[O:36]2)=[CH:42][CH:41]=1
Reactant: CCC(C)(C)N=C=O
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: [N-]=C=O
Product: CCC(C)(C)NC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccnc(C)c2C)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (20 mg) was reacted with 2-isocyanato-2-methyl-butane (prepared according to General Procedure AD) according to General Procedure I (with excess of isocyanate). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (7 mg). LCMS (m/z): 852.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:27][O:28][CH2:29][C:30]#[CH:31])[C:10]([NH:12][CH:13]2[C:25](=[O:26])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([O:20][CH3:21])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:27][O:28][CH2:29][C:30]#[CH:31])[C:10]([NH:12][CH:13]2[C:25](=[O:26])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([O:20][CH3:21])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(OC)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(OC)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.6 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer, 0.9 g.), conc. hydrochloric acid (0.9 ml.) and methanol (13.5 ml.) was stirred at room temperature for 4 hours. After concentrating the resultant solution in vacuo at 35° C., the residue was dissolved in water and washed with ethyl acetate. The aqueous solution was adjusted to pH 7.0 with sodium bicarbonate and washed with ethyl acetate and diethyl ether. After removing the organic solvent by bubbling nitrogen gas, the solution was adjusted to pH 3.0 with 10% hydrochloric acid and stirred under ice cooling. The precipitates were collected by filtration, washed with water and dried to give 7-[2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer, 0.25 g.), whitish yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][CH:14]2[CH2:16][CH2:15]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].C1COCC1>CO>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][CH:14]2[CH2:16][CH2:15]2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C#CC2CC2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C#CC2CC2)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.1 %

Procedure:
A mixture of methyl 2-chloro-4-(2-cyclopropylethynyl)benzoate (310 mg, 0.0013 mol), 2N aq. NaOH (3.0 mL), THF (5 mL), and MeOH (5 mL) was stirred at rt for 5 h. The mixture was concentrated under vacuum and the residue was treated with water and acidified with 1N HCl to pH 2-3, and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated under vacuum to give the product (270 mg, 93%) as a yellow solid. LC-MS: 3.18 min, 218.9 & 220.9 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[C:12]=2[N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1.[C:23](Cl)(=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(N(CC)CC)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[C:12]=2[N:13]2[CH2:18][CH2:17][N:16]([C:23](=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:15][CH2:14]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2oc3ccccc3c2N2CCNCC2)cc1
Reactant: CCCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCC(=O)N1CCN(c2c(-c3ccc(Cl)cc3)oc3ccccc23)CC1
Reaction time: 0.5 h

Procedure:
To the solution of 56 g of 1-(2-p-chlorophenyl-3-benzofuryl)piperazine in 25.2 g of triethylamine and 500 ml of methylene chloride, 31.7 g of pelargonic acid chloride in 300 ml of methylene chloride are added while stirring at 0° for 1/2 hour and stirring is continued for 15 hours. The mixture is washed successively with 1 N-hydrochloric acid, 2 N-aqueous sodium hydroxide and saturated aqueous sodium chloride, dried and evaporated to yield the 1-(2-p-chlorophenyl-3-benzofuryl)-4-pelargonylpiperazine as an oil showing in the 1R-spectrum characteristic bands at 1640 and 812 cm-1.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:6][CH:5]=[CH:4][C:3]1=2.[H-].[Na+].[CH3:19][O:20][CH2:21]Cl.O>CN(C=O)C>[CH3:19][O:20][CH2:21][N:12]([C:7]1[C:8]2[CH2:9][CH2:10][CH2:11][C:2](=[O:1])[C:3]=2[CH:4]=[CH:5][CH:6]=1)[S:13]([CH3:16])(=[O:15])=[O:14]
Reactant: COCCl
Reactant: CS(=O)(=O)Nc1cccc2c1CCCC2=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCN(c1cccc2c1CCCC2=O)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of Example 15A (4.0 g, 17 mmol) in anhydrous DMF (40 mL) under a nitrogen atmosphere was treated with a 60% dispersion of sodium hydride (0.74 g, 18 mmol) in portions over 5 minutes, stirred for 45 minutes, cooled to 0° C., treated dropwise with chloromethyl methyl ether (1.3 mL, 18 mmol), stirred at ambient temperature for 2 hours, treated with cold water (250 mL) and extracted with diethyl ether (3×). The combined diethyl ether extracts were washed with water, washed with brine, dried (MgSO4), filtered and concentrated. Purification of the residue on silica gel with 1:1 hexanes:ethyl acetate provided the desired product.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:15])[CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1)C(C)=O.[OH-].[Na+]>Cl>[NH2:1][C:5]1[CH:6]=[CH:7][C:8]([C:11](=[O:15])[CH2:12][CH2:13][CH3:14])=[CH:9][CH:10]=1
Reactant: CCCC(=O)c1ccc(NC(C)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCC(=O)c1ccc(N)cc1
Temperature: 0 °C

Procedure:
20 g of p-acetaminobutyrophenone are suspended in 40 ml of semi-concentrated hydrochloric acid and the suspension is heated under reflux for 25 minutes and poured into a mixture of 100 ml of ice and 30 ml of concentrated sodium hydroxide solution. The mixture is filtered with suction, then the residue is washed twice with ice-cold water, dried in the atmosphere and recrystallised from methanol/water (20 ml+100 ml). p-Aminobutyrophenone having a melting point of 93°-94° is obtained.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([S:22]([N:25](CC3C=CC(OC)=CC=3OC)[C:26]3[CH:31]=[CH:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[C:17]([F:43])[CH:16]=2)[C@@H:11]([C:44]2[N:48]([CH3:49])[N:47]=[CH:46][CH:45]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([S:22]([NH:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][N:27]=3)(=[O:23])=[O:24])=[C:17]([F:43])[CH:16]=2)[C@@H:11]([C:44]2[N:48]([CH3:49])[N:47]=[CH:46][CH:45]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3C[C@@H](OCc4ccccc4)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1C[C@H](OCc2ccccc2)C[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 81.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*,4S*)-4-(benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (143 mg, 0.207 mmol) prepared in Example 98b, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (91 mg, 81%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9](=[S:29])[NH:10][C:11]2[S:21][C:14]3[CH2:15][O:16][C:17]([CH3:20])([CH3:19])[CH2:18][C:13]=3[C:12]=2[C:22]([O:24]C(C)(C)C)=[O:23])=[O:7])=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9](=[S:29])[NH:10][C:11]2[S:21][C:14]3[CH2:15][O:16][C:17]([CH3:20])([CH3:19])[CH2:18][C:13]=3[C:12]=2[C:22]([OH:24])=[O:23])=[O:7])=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)c1c(NC(=S)NC(=O)c2ccc(F)cc2)sc2c1CC(C)(C)OC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)Cc2c(sc(NC(=S)NC(=O)c3ccc(F)cc3)c2C(=O)O)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
A solution of 40% v/v TFA/DCM (20 mL) was added to tert-butyl 2-(3-(4-fluorobenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.33 g, 0.71 mmol) and the mixture was stirred at RT for 1 hour. The volatiles were removed at 30° C. and the material was purified by reverse-phase chromatography (10-100% MeCN/water). 2-(3-(4-Fluorobenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylic acid (0.21 g, 0.51 mmol, 72% yield) was isolated as a pale, yellow solid. 1H NMR (400 MHz, DMSO) δ 14.81 (s, 1H), 13.36 (s, 1H), 11.83 (s, 1H), 8.11-8.00 (m, 2H), 7.38 (apparent t, J=8.9 Hz, 2H), 4.66 (s, 2H), 2.74 (s, 2H), 1.23 (s, 6H). 13C NMR (101 MHz, DMSO) δ 174.33, 166.13, 165.72, 165.35, 163.63, 146.76, 131.80, 131.70, 129.08, 128.60, 128.57, 124.06, 116.48, 115.54, 115.32, 70.12, 58.80, 37.25, 26.16. LCMS retention time: 3.206 min; LCMS purity at 214 nm=98%. HRMS m/z calculated for C18H18FN2O4S2 [M++1]: 409.0687. found 409.0687. Melting point 205.3° C., decomposition.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)=[O:3].[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1>FC(F)(F)S(O)(=O)=O>[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[C:18]([CH:19]=1)[C:8]([C:7]1[CH:11]=[CH:12][C:4]([S:2]([CH3:1])=[O:3])=[CH:5][CH:6]=1)=[O:9]
Reactant: Cc1ccc(F)cc1
Reactant: CS(=O)c1ccc(C(=O)Cl)cc1
Agent: O=S(=O)(O)C(F)(F)F
Product: Cc1ccc(F)cc1C(=O)c1ccc(S(C)=O)cc1

Procedure:
p-Methylsulfinylbenzoyl chloride (0.2 mole) and p-fluorotoluene (0.2 mole) are refluxed together in trifluoromethanesulfonic acid for 6 hours according to the procedure of Chodroff and Klein, J.A.C.S. 70, 7209 (1948).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Cl[CH2:23][C:24]1[C:25]2[C:30]([CH:31]=[C:32]3[C:37]=1[CH:36]=[CH:35][CH:34]=[CH:33]3)=[CH:29][CH:28]=[CH:27][CH:26]=2>>[CH:26]1[C:25]2[C:30](=[CH:31][C:32]3[C:37]([C:24]=2[CH2:23][N:8]2[C:9]([C:10](=[O:19])[C:11]4[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=4)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]2=[O:20])=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:29]=[CH:28][CH:27]=1
Reactant: ClCc1c2ccccc2cc2ccccc12
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2c3ccccc3cc3ccccc23)c1
Yield: 40.3 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 9-chloromethyl anthracene were reacted by the same way with the example 1 to obtain the titled compound (192 mg, yield: 40.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl[C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][N:27]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[CH:18]=[C:19]([CH:25]=[CH:26][N:27]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: CCOC(=O)c1ccnc(Cl)c1
Product: CCOC(=O)c1ccnc(-c2cc(OC)c(OC)c(OC)c2)c1

Procedure:
3,4,5-Trimethoxyphenylboronic acid (15.29 g) and ethyl 2-chloroisonicotinate (13.39 g) were reacted in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: [OH:1][C:2]([CH3:29])([CH3:28])[CH:3]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[O:4][C:5]1[C:6]([NH:15][S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2.ClC1C=CC=C(C(OO)=[O:38])C=1>ClCCl>[OH:1][C:2]([CH3:28])([CH3:29])[CH:3]([C:22]1[CH:23]=[N+:24]([O-:38])[CH:25]=[CH:26][CH:27]=1)[O:4][C:5]1[C:6]([NH:15][S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])=[N:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCS(=O)(=O)Nc1nc2ccccc2nc1OC(c1cccnc1)C(C)(C)O
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1nc2ccccc2nc1OC(c1ccc[n+]([O-])c1)C(C)(C)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
Compound 1 (89.6 mg, 0.215 mmol) obtained in Example 1 was dissolved in dichloromethane (5.0 mL). To the solution was added 65% meta-chloroperbenzoic acid (85.7 mg, 0.323 mmol) and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography (chloroform/methanol=9/1) to give Compound 2 (47.7 mg, 51% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[Cl:10][S:11](O)(=[O:13])=[O:12]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:11]([Cl:10])(=[O:13])=[O:12])=[C:4]([O:8][CH3:9])[CH:3]=1
Reactant: COc1cccc(Br)c1
Reactant: O=S(=O)(O)Cl
Product: COc1cc(Br)ccc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To chlorosulfonic acid (20 ml) at 0° C. was added dropwise 3-bromoanisole (18.7 g, 0.1 mol) at such a rate that the internal temperature remained below 5° C. The mixture was stirred at 0° C. for 1 hour and added dropwise to crushed ice. The mixture was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (1:25 ethyl acetate:pentane) to afford the title compound; 4-bromo-2-(methyloxy)benzenesulfonyl chloride (D30) 1H-NMR (CDCl3) δ 7.81 (1H, d, J 8 Hz), 7.28 (1H, d, J 2 Hz), 7.26 (1H, dd, J 8, 2 Hz), 4.07 (3H, s) and an isomer; 2-bromo-4-(methyloxy)benzenesulfonyl chloride 1H-NMR (CDCl3) δ 8.12 (1H, d), 7.33 (1H, d), 6.97 (1H, dd), 3.92 (3H, s).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][NH2:24])[CH2:19][CH2:18]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:24][CH2:23][CH:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]1
Reactant: CN1CCC(CN)CC1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1NCC1CCN(C)CC1
Yield: 51.1 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (250 mg, 1.0 mmol) was reacted with (1-methylpiperidin-4-yl)methanamine (160 mg, 1.3 mmol) to afford the desired product (170 mg, 49%) as a light yellow-brown solid: 1H NMR (500 MHz, CDCl3) δ 11.06 (br s, 1H), 8.95 (s, 1H), 8.10 (d, J=8.8 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 4.13 (t, J=6.4 Hz, 2H), 2.99-2.92 (m, 2H), 2.69 (s, 3H), 2.32 (s, 3H), 2.07-1.98 (m, 2H), 1.97-1.89 (m, 2H), 1.85-1.75 (m, 1H), 1.57-1.47 (m, 2H); ESI MS m/z 333 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11]([NH:17][CH2:18][C@@H:19]([OH:21])[CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:22]([O-])=O.[Na+]>C(O)(=O)C.O.[Zn]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12]([CH:13]=[N:22][N:17]2[CH2:18][C@@H:19]([OH:21])[CH3:20])=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](O)CNc1cc(OCc2ccccc2)ccc1C=O
Reactant: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: C[C@H](O)Cn1ncc2ccc(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 44.3 %

Procedure:
To a mixture of the product from Step C (16.0 g, 56.1 mmol) in acetic acid/water (150 mL/30 mL) at 0° C. was added sodium nitrite (7.75 g, 112 mmol) in portions over 40 min. The mixture was stirred for 50 min, cooled (ice bath), and zinc (14.7 g, 224 mmol) was added in portions. After 1 h the suspension was warmed to room temperature and more zinc was added (14.7 g, 224 mmol). The mixture was stirred for 1 h, concentrated, and extracted with EtOAc (2×300 mL). The extracts were filtered through a filter-aide, and the filtrate was washed with saturated aqueous disodium hydrogen phosphate (to pH 8) and brine, dried, and purifed by chromatrography (silica, 25% EtOAc/hexane) to afford an oil (7.01 g, 44%).