Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[CH:5]([C:10]([OH:12])=[O:11])[CH:6]([OH:9])[CH2:7][S:8][C@H:3]12.[CH3:15][O:16][N:17]=[C:18]([C:22]([O:28][CH2:29][CH3:30])([O:25][CH2:26][CH3:27])[CH2:23][Br:24])[C:19](O)=[O:20].P(Cl)(Cl)(Cl)=O.CN(C)C=O>O1CCCC1.CC(C)=O.O>[CH3:15][O:16][N:17]=[C:18]([C:22]([O:28][CH2:29][CH3:30])([O:25][CH2:26][CH3:27])[CH2:23][Br:24])[C:19]([NH:1][CH:2]1[C:13](=[O:14])[N:4]2[CH:5]([C:10]([OH:12])=[O:11])[CH:6]([OH:9])[CH2:7][S:8][C@H:3]12)=[O:20]
Reactant: NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Reactant: CCOC(CBr)(OCC)C(=NOC)C(=O)O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCOC(CBr)(OCC)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Yield: 68.7 %

Procedure:
7-Amino-3-hydroxycepham-4-carboxylic acid (10.9 g, purity 84.8%), 2-methoxyimino-3,3-diethoxy-4-bromobutyric acid (syn isomer, 17.9 g), phosphorus oxychloride (6.8 ml), N,N-dimethylformamide (5.5 ml), water (100 ml), acetone (50 ml.) and tetrahydrofuran (44 ml) were treated in a similar manner to that of Example 25 (1) to give 7-(2-methoxyimino-3,3-diethoxy-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 17.1 g.). The I.R. spectrum and N.M.R. spectrum of the compound were the same as those of Example 28.
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](O)=[O:9])=[O:4].Cl.[CH:38]1([NH2:41])[CH2:40][CH2:39]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:38]1([NH:41][C:8](=[O:9])[CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH:2]([OH:1])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[N:21]=[C:20]([C:22]4[O:26][N:25]=[C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:23]=4[C:33]([F:36])([F:34])[F:35])[O:19][N:18]=3)=[CH:15][CH:16]=2)[CH2:40][CH2:39]1
Reactant: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1)NC1CC1
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), cyclopropanamine-HCl (6.15 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 before it was 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=13.3 min) to provide (R/S)-N-cyclopropyl-3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanamide (9 mg, 0.016 mmol, 35.5% yield): LCMS=542.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.36 Hz), 7.54-7.75 (7 H, m), 5.10 (1 H, s), 3.45-3.55 (2 H, m), 2.56-2.68 (1 H, m), 2.37 (2 H, t, J=6.49 Hz), 0.63-0.76 (2 H, m), 0.35-0.49 (2 H, m); HPLC peak RT=8.7 min (Method A).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1O[C:15](=O)[C:14]([C:18]#[N:19])=[C:13]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:12]=1.[H-].[Na+]>C1COCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:9]2[C:10]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[CH2:6][C:15]=2[C:14]([C:18]#[N:19])=[C:13]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:12]=1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2ccc3ccccc3c2)oc1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c(N2CCCCC2)cc(-c2ccc3ccccc3c2)c2c1Cc1ccccc1-2

Procedure:
A mixture of 6-(naphthalen-2-yl)-2-oxo-4-(piperidin-1-yl)-2H-pyran-3-carbonitrile (330 mg), indanone-2 (132 mg) and NaH (43 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 142-144° C.; ESIMS 401 (M++1); IR (KBr) 2215 cm−1 (CN).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH:17]=[CH2:18].C(N(CC)CC)C.O>C(O)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.ClCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH:18]=[CH:17][C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(C=CC(=O)OC(C)(C)C)ccc2[nH]1
Temperature: 120 °C
Yield: 28.5 %

Procedure:
A mixture of 5-bromoindole-2-carboxylic acid ethyl ester (2.68 g, 10 mmol), tert-butyl acrylate (4.4 mL, 30 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.7 g, 1 mmol) and triethylamine (17 mL) in acetic acid (17 mL) was heated at 120° C. in a closed vessel for 6 hrs. The cooled reaction mixture was poured into water and dichloromethane. The biphasic mixture was filtered through a pad of celite and the aqueous layer was extracted with dichloromethane (2×). The combined organic layers were washed with saturated sodium bicarbonate solution, brine, dried and concentrated. The residue was purified by column chromatography (10% of ethyl acetate in hexanes) to give 900 mg (28%) of 5-(2-tert-butoxycarbonyl-vinyl)-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:28]=1)[C:7]([N:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([CH3:15])[C@H:10]1[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])=[O:8].[F-].[Cs+].C([Sn](CCCC)(CCCC)[C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1)CCC>CN(C=O)C.CCOC(C)=O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:37]2[N:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[C:6]([CH:28]=1)[C:7]([N:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([CH3:15])[C@H:10]1[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])=[O:8]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2I)[C@@H]1CN1C(=O)c2ccccc2C1=O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-c2ncccn2)[C@@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 105 °C
Yield: 56.9 %

Procedure:
A suspension of the product of Step 228a (537 mg, 1.05 mmol), CsF (322 mg, 2.13 mmol), and CuI (40 mg, 0.210 mmol) in anhydrous DMF (5 mL) was flushed with argon gas for 10 min, then 2-(tributylstannyl)pyrimidine (582 mg, 1.58 mmol) and Pd(PPh3)4 (122 mg, 0.105 mmol) were added at rt. The reaction mixture was then heated to 105° C. under nitrogen for 16 h. After this time, the reaction mixture was cooled to rt, diluted with EtOAc (100 mL), and filtered through a short pad of diatomaceous earth. The filter cake was rinsed with EtOAc (50 mL) and water (50 mL). The layers of the combined filtrate were separated. The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with 10% aq. LiCl (3×50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 100% EtOAc/hexanes) to afford the title compound as a yellow foam (274 mg, 56%): ESI MS (M+H) 459.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][N:14]=[CH:15]3)=[CH:2]1.[H-].[Na+].I[CH3:23].CO>CN(C=O)C>[CH3:23][N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][N:14]=[CH:15]3)=[CH:2]1
Reactant: c1cc(-c2c[nH]c3ncccc23)c2ccncc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1cc(-c2cccc3cnccc23)c2cccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
53 mg (0.216 mmol) of 5-(1H-pyrrolo[2,3-b]pyridin-3-yl)isoquinoline are added to a suspension, kept under an argon atmosphere, of 26 mg (0.65 mmol) of sodium hydride, (60% suspension in paraffin oil) in 1 ml of DMF, and the reaction mixture is stirred at room temperature for 1 hour. 18 μl (0.65 mmol) of iodomethane are then added, and the reaction mixture is stirred at room temperature for a further 17 hours. 0.5 ml of methanol is then added, and the reaction mixture is subsequently evaporated in vacuo. The residue is chromatographed on a silica-gel column with dichloromethane/methanol as eluent, giving 5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)isoquinoline as colourless solid; MS (EI): 259 [M]+;
Reaction SMILES: [Cl-].[C:2]1([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[Br:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1>>[Br:32][C:33]1[CH:34]=[CH:35][C:36]2[CH:37]=[CH:12][C:2]3[C:3]([C:39]=2[CH:40]=1)=[CH:4][CH:5]=[C:6]1[C:11]=3[CH:10]=[CH:9][CH:8]=[CH:7]1
Reactant: O=Cc1ccc(Br)cc1
Reactant: c1ccc([P+](Cc2cccc3ccccc23)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Product: Brc1ccc2ccc3c4ccccc4ccc3c2c1

Procedure:
3-Bromochrysene was prepared from (1-napthylmethyl)triphenylphosphonium chloride and 4-bromobenzaldehyde using the procedure described in Example 1, part a.
Reaction SMILES: [NH2:1][C:2]([CH2:9][C:10](=[O:12])[O-:11])([CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6])O.[N:13]([C:16]1[CH:17]=[C:18]([N:22]2[CH:26]=[CH:25][CH:24]=[CH:23]2)[CH:19]=[CH:20][CH:21]=1)=[C:14]=[O:15]>>[N:22]1([C:18]2[CH:17]=[C:16]([NH:13][C:14](=[O:15])[NH:1][C@@H:2]([CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6])[CH2:9][C:10]([O-:11])=[O:12])[CH:21]=[CH:20][CH:19]=2)[CH:23]=[CH:24][CH:25]=[CH:26]1
Reactant: C[N+](C)(C)CC(N)(O)CC(=O)[O-]
Reactant: O=C=Nc1cccc(-n2cccc2)c1
Product: C[N+](C)(C)C[C@@H](CC(=O)[O-])NC(=O)Nc1cccc(-n2cccc2)c1
Yield: 63.7 %

Procedure:
According to the method described in example S11, aminocarnitine (1.28 HBr salt, 68 mg, 0.31 mmol) was reacted with 1-(3-isocyanatophenyl)-1H-pyrrole (116 mg, 0.63 mmol) to yield the title compound as a white solid (68 mg, 62%). 1H NMR (400 MHz, CD3OD) δ ppm=7.69 (t, J=1.89 Hz, 1 H), 7.29 (t, J=7.96 Hz, 1 H), 7.11-7.18 (m, 3 H), 6.25 (t, J=2.15 Hz, 1 H), 4.62 (br. s, 1 H), 3.76 (dd, J=13.64, 9.09 Hz, 1 H), 3.51-3.58 (m, 1 H), 3.23 (s, 9 H), 2.46-2.61 (m, 2 H). MS ESI [M+H]+, calcd for [C18H23N4O3+H]+: 344.41 found m/z 344.7 (100).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([Cl:22])=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:23]([O:26][CH2:27][C:28](Cl)=[O:29])(=[O:25])[CH3:24].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[C:23]([O:26][CH2:27][C:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:21]([Cl:22])=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1)=[O:29])(=[O:25])[CH3:24]
Reactant: Nc1ccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)cc1
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OCC(=O)Nc1ccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a suspension of 4-amino-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide (2 g; 4.49 mmol; 1 eq) in DCM (100 mL) is added acetoxyacetyl chloride (1.23 mL; 9 mmol; 2 eq) and N-ethyldiisopropylamine (2.3 mL; 13.5 mmol; 3 eq) and the reaction mixture is stirred at room temperature for 30 min. DCM is removed under reduced pressure and the crude residue is dissolved in EtOAc. The organic phase is washed twice with 10% citric acid then brine. The solvent is evaporated and the residue is taken up in iPrOH then refluxed and left at room temperature until precipitation. The precipitate is filtered off then dried under reduced pressure to afford 1.9 g (95%) of the title compound as a yellow powder. 1H NMR (DMSO-d6) δ 10.70 (s, 1H), 8.25 (m, 2H), 8.09 (m, 4H), 7.88 (m, 2H), 4.71 (s, 2H), 2.13 (s, 3H). HPLC (max plot) 98%; Rt 4.03 min. UPLC/MS (ES+) 435.2.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].C(=O)([O-])O.[Na+].[C:18](Cl)(=[O:22])[C:19]([CH3:21])=[CH2:20]>O.C(OCC)(=O)C>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])=[CH:11][CH:12]=1)([O-:4])=[O:3]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(C)C(=O)NCc1ccc([N+](=O)[O-])cc1

Procedure:
4-Nitrobenzylamine hydrochloride (1.51 g) and sodium hydrogencarbonate (4.13 g) were dissolved in water (25 mL), to which ethyl acetate (25 mL) was added, followed by being stirred in an ice bath. Methacryloyl chloride (1.26 g) was added dropwise thereto. After stirring for 10 minutes, the mixture was extracted with ethyl acetate. After washing with water and brine, the organic layer was dried over anhydrous sodium sulfate and evaporated. After that, the recrystallization was performed by using a mixture solvent of hexane and ethyl acetate. N-(4-Nitrobenzyl)methacrylamide was obtained as pale yellowish crystals. The yield was 1.05 g (60%). Spectrum data of 1H-NMR (400 MHz, CDCl3) is shown for the obtained compound.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:13]([C:18](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:19])([O:15][CH2:16][CH3:17])=[O:14].C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1.CO.O>[CH2:16]([O:15][C:13](=[O:14])[C:18]([CH3:19])=[CH:11][CH:8]1[CH2:7][CH2:6][CH:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:9]1)[CH3:17]
Reactant: CC(C)(C)C1CCC(C=O)CC1
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: CCOC(=O)C(C)=CC1CCC(C(C)(C)C)CC1

Procedure:
A mixture of 20.2 g of 4-tert.butyl-cyclohexane-1-carboxaldehyde, 52 g of (α-carbethoxy-ethylidene)-triphenyl-phosphorane and 3.6 g of benzoic acid in 120 ml of toluene is heated at reflux for 16 hours under nitrogen gasification and the toluene is evaported. The oily-crystalline residue is dissolved in 600 ml of methanol/water (4:1) and exhaustively extracted with hexane. The combined hexane extracts are washed with sodium bicarbonate solution and water, dried over sodium sulphate and evaporated. By distillation there is obtained pure 3-(4-tert.butyl-cyclohexyl)-2-methyl-acrylic acid ethyl ester of boiling point 99° C./0.03 Torr.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=O.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)=[CH:23][CH:22]=1.C[SiH2]O[Si](C)(C)C>C(Cl)Cl.O.C(#N)C>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[S:28][C:29]([CH2:7][C:6]3[CH:10]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=3[CH3:11])=[CH:30][CH:31]=2)=[CH:25][CH:26]=1
Reactant: Cc1ccc(I)cc1C(=O)O
Reactant: Fc1ccc(-c2cccs2)cc1
Agent: C[SiH2]O[Si](C)(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccc(I)cc1Cc1ccc(-c2ccc(F)cc2)s1
Temperature: 22 °C

Procedure:
DCM (350 ml, 1 L/mol) was added to 91.7 g 5-iodo-2-methylbenzoic acid (91.7 g, 0.35 mol) and the resulting heterogeneous mixture stirred at 22° C. To the resulting mixture was then added thionyl chloride (42.5 g, 0.35 mol) via an addition funnel. The resulting mixture was warmed slowly to reflux temperature (over which time the mixture became a colorless solution and gas evolution was observed), then stirred for 1 hr, then cooled to 2° C. Aluminum chloride granules (56.0 g, 0.42 mol) were added to the resulting mixture, which was then stirred for 15 min at 2° C. A solution of 2-(4-fluorophenyl)thiophene (0.35 mol, 89.7% w/w) in DCM (0.5 L/mol) was then added via addition funnel over 10 minutes, allowing the temperature to rise during addition to 20° C. The resulting mixture was stirred at 20° C. for 2 hrs, then cooled to 2° C. Additional aluminum chloride granules (107.3 g, 0.805 mol) were added and the resulting mixture stirred for 15 min. Acetonitrile (210 ml, 0.6 L/mol) was added via addition funnel over 20 minutes at T≦20° C. Tetramethyldisiloxane (131.6 g, 0.98 mol) was then added via addition funnel over 5 minutes. The resulting mixture was slowly warmed to reflux temperature (42° C.), maintained at reflux for 3 hours, allowed to cool to 22° C. and then stirred for 16 hrs. Water (420 ml, 1.2 L/mol) was added over 30 minutes at T≦35° C. and the resulting mixture stirred strongly for 15 min. The resulting layers were separated, the organic layer washed with water (70 ml, 0.2 L/mol), then concentrated in vacuo at 50° C. to yield the title compound as a residue.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=2[C:3]=1[CH3:15].CC1(C)C(C)(C)OB([C:24]2[CH:25]=[N:26][N:27](C(OC(C)(C)C)=O)[CH:28]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[CH3:14][N:5]1[C:4]2[C:3]([CH3:15])=[C:2]([C:24]3[CH:25]=[N:26][NH:27][CH:28]=3)[S:10][C:9]=2[C:8](=[O:11])[NH:7][C:6]1([CH3:13])[CH3:12]
Reactant: Cc1c(Br)sc2c1N(C)C(C)(C)NC2=O
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Cc1c(-c2cn[nH]c2)sc2c1N(C)C(C)(C)NC2=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
A mixture of 6-bromo-1,2,2,7-tetramethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (145 mg, 0.50 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazole-1-carboxylate (441 mg, 1.50 mmol), cesium carbonate (815 mg, 2.50 mmol), 1,2-dimethoxyethane (5 mL) and water (1.25 mL) was purged with argon. Then, 1,1′-bis(diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (40.8 mg, 0.050 mmol) was added, and the mixture was purged with argon again. The mixture was stirred at 90° C. overnight. The mixture was poured into water (100 mL) and EtOAc (100 mL). The insoluble materials were filtered off, and the organic layer was collected from the filtrate. This organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residual oil was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc then to 80:20 EtOAc/MeOH), then triturated with EtOAc/hexane. The solid was collected by filtration to afford the title compound (65.2 mg, 47%) as a white solid:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:13]([CH3:14])[C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)=[C:4]([F:17])[CH:3]=1.[CH:18]([S:21](Cl)(=[O:23])=[O:22])([CH3:20])[CH3:19].N1C=CC=CC=1>O>[C:15]([C:12]1[N:13]([CH3:14])[C:9]([C:5]2[C:4]([F:17])=[CH:3][C:2]([NH:1][S:21]([CH:18]([CH3:20])[CH3:19])(=[O:23])=[O:22])=[C:7]([F:8])[CH:6]=2)=[CH:10][CH:11]=1)#[N:16]
Reactant: Cn1c(C#N)ccc1-c1cc(F)c(N)cc1F
Reactant: CC(C)S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)S(=O)(=O)Nc1cc(F)c(-c2ccc(C#N)n2C)cc1F
Temperature: 100 °C
Yield: 12 %

Procedure:
5-(4-amino-2,5-difluorophenyl)-1-methyl-1H-pyrrole-2-carbonitrile (150 mg, 0.64 mmol) was dissolved in isopropyl sulfonyl chloride (1.0 mL, 9.0 mmol), pyridine (0.2 mL) was added and the mixture was heated to 100° C. for 6 hours. The mixture was then cooled, diluted with water and extracted with ethyl acetate. The organics were combined, washed with water, brine, dried over MgSO4, and concentrated. Flash chromatography (0%-100% ethyl acetate in hexane) afforded N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2,5-difluorophenyl]propane-2-sulfonamide (26 mg).
Reaction SMILES: N[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].N([O-])=O.[Na+].Cl.C([O-])(=O)C.[K+].C(=S)(OCC)[S-:28].[K+]>O>[F:12][C:11]([F:14])([F:13])[C:9]1[CH:10]=[C:2]([SH:28])[C:3](=[CH:7][CH:8]=1)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=S)[S-]
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: O=C(O)c1ccc(C(F)(F)F)cc1S
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
A mixture of 2-amino-4-trifluoromethylbenzoic acid (5.0 g, 24 mmol), sodium hydroxide (1.0 g, 25 mmol), sodium nitrite (1.7 g, 24 mmol) and water (40 ml) was added dropwise to a mixture of concentrated hydrochloric acid (10 ml) and ice (10 g) while the reaction temperature had been kept at 0 to 5° C. The reaction mixture was stirred at the same temperature for 30 minutes, neutralized with potassium acetate and added to a solution of potassium O-ethyl dithiocarbonate (11.7 g, 73 mmol) in water (40 ml). The reaction mixture was stirred at 80° C. for 20 minutes and acidified by use of concentrated hydrochloric acid to pH 3. The water layer was separated, and the oily substance was added to 10% aqueous sodium hydroxide solution (25 g) and stirred at 80° C. for 2 hrs. Sodium hydrosulfite (3 g) was added to the mixture, and the mixture was stirred at 80° C. for 10 minutes. The reaction mixture was filtered and the filtrate was cooled and acidified by use of concentrated hydrochloric acid to pH 4. The precipitated crystals were collected by filtration, dissolved in methanol (5 ml) and diisopropylether (100 ml) and dried. The solvent was evaporated under reduced pressure to give the titled compound (4.1 g, 77%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[CH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1.[S:32]1[CH2:36][C:35](=[O:37])[NH:34][C:33]1=[O:38].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1.CO.C(OCC)C>[CH3:1][O:2][C:3](=[O:31])[C:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]=[C:36]3[S:32][C:33](=[O:38])[NH:34][C:35]3=[O:37])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[CH:5][C:6]1[CH:7]=[C:8]([O:14][CH3:15])[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1
Reactant: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(C=O)cc2)cc1
Reactant: O=C1CSC(=O)N1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Temperature: 4 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To a stirred suspension of 9 (352 g, 0.82 mol) in anhydrous toluene (2.5 L), 2,4-thiazolidinedione (98.6 g, 0.84 mol), benzoic acid (134 g, 1.10 mol) and piperidine (107.4 g, 1.26 mol) was added sequentially and heated at reflux temperature with continuous removal of water with the help of Dean-Stark apparatus for 5 h. Toluene (1.0 L) was removed from the reaction mixture and cooled overnight at 4° C. Solid separated was filtered and mother liquor was evaporated to dryness under reduced pressure. The residue obtained was re-dissolved in a mixture of MeOH-diethylether (1:1, 3.0 L). On standing overnight at 4° C., the solution yielded more solids. Solid from both the lots were combined and dried overnight in vacuum oven at 40° C. to give 10 as yellow solid (362.5 g, 86%): mp 106-108° C.; mp 225-226° C.; 1H NMR (360 MHz, DMSO-d6): δ 12.53 (br s, 1H), 7.78 (s, 1H), 7.73 (s, 1H), 7.63 (d, J=9.2 Hz, 2H), 7.25 (d, J=9.2 Hz, 2H), 7.13 (overlapped d, J=8.3 Hz, 2H), 7.11 (overlapped d, J=8.6 Hz, 2H), 6.42 (t, J=2.2 Hz, 1H), 6.27 (d, J=2.2 Hz, 2H), 3.73 (s, 3H), and 3.59 (s, 6H); MS (EI) m/z 518[M]+; Anal. (C28H23NO7S) C, H, N.