Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([OH:14])=O.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[NH2:19]>>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:12]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]=2[OH:1])=[O:14])[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: O=C(O)c1c(O)ccc2ccccc12
Reactant: Nc1cc(Cl)cc(Cl)c1
Product: O=C(Nc1cc(Cl)cc(Cl)c1)c1c(O)ccc2ccccc12
Yield: 51.2 %

Procedure:
Using 2-hydroxynaphthalene-1-carboxylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:22]([O:1][C:2]1([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH2:3][CH2:4][C:5](=[O:8])[CH2:6][CH2:7]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCC(O)(c2ccc(F)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC1(c2ccc(F)cc2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 28 h
Yield: 82 %

Procedure:
To a solution of 4-hydroxy-4-(4-fluorophenyl)cyclohexanone (520 mg, 2.5 mmol), pyridine (2 ml) and 4-dimethylaminopyridine (46 mg) in CH2Cl2 (25 ml) at 0° C. was added dropwise a solution of acetic anhydride (1 ml) in CH2Cl2 (5 ml). The mixture was warmed to room temperature and stirred for 28 h before being quenched with water (30 ml). The organic phase was washed with 1 M HCl (2×30 ml) and brine (30 ml), dried over MgSO3, and concentrated in vacuo. The residue was purified by flash chromatography (25% ether in petroleum ether) to afford the desired ketone (510 mg, 82%) as a colorless solid. mp 113-115° C. 1H NMR (500 MHz, CDCl3) δ2.11 (s, 3H), 2.20 (m, 2H), 2.43 (m, 2H), 2.68 (m, 2H), 2.86 (m, 2H), 7.05 (t, J=8.3, 2H), 7.35-7.38 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6]([NH:8][C:9]1[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:7])([O-])=O.CO>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6]([NH:8][C:9]1[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:7]
Reactant: CCOC(=O)c1ccccc1NC(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccccc1NC(=O)c1ccccc1N
Reaction time: 5 h

Procedure:
Nitro compound 20 (2.24 g, 7.14 mmol) and Pd/C (220 mg) was dissolved in EtOAc (50 mL) and MeOH (20 mL) and stirred vigorously under H2 atmosphere (1 atm). After 5 h, the Pd/C was filtered off over a pad of celite and florisil to leave pure aniline compound 21 in quant. yield (1.98 g) over two steps.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:23]3[CH:24]=[C:25]4[O:30][CH2:29][O:28][C:26]4=[CH:27][C:22]=3[CH2:21][C:20]([CH3:31])=[N:19][N:18]=2)=[CH:13][CH:12]=1>C(OCC)C>[C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:23]4[CH:24]=[C:25]5[O:30][CH2:29][O:28][C:26]5=[CH:27][C:22]=4[CH2:21][C:20]([CH3:31])=[N:19][N:18]=3)=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Solvent: CCOCC
Product: CC1=NN=C(c2ccc(NC(=O)Nc3ccccc3)cc2)c2cc3c(cc2C1)OCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
0.22 ml (2.04 mmol) of phenyl isocyanate was added to solution of 0.50 g (1.7=mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in 4 ml of dimethylformamideand the reaction mixture was stirred at 25° C. for one hour. Then it was diluted with 20 ml of diethyl ether and filtered at 5 ° C. The crystals were washed with 2×5 ml of diethyl ether and dried at 60°-100° C. The resulting 0.70 g of raw product, m.p. 239°-240° C. (sintering at 180 ° C.) was refluxed in 15 ml of ethanol, filtered after cooling, washed with 3×1 ml of ethanol and dried at 100 ° C. to yield 0.55 g (78.6%) of the aimed product, m.p. 240°-241° C. (decomp.).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.C(=O)([O-])[O-].[K+].[K+].[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:18][SH:19].O>CN(C=O)C>[F:10][C:7]1[CH:8]=[CH:9][C:2]2[S:19][C:18]([C:17]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][C:3]=2[CH:6]=1
Reactant: CCOC(=O)CS
Reactant: O=Cc1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cc(F)ccc2s1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a mixture of 2,5-difluorobenzaldehyde (217.28 μL, 2 mmol) and potassium carbonate (595.53 mg, 2.5 mmol) in DMF (3 mL) was added ethyl thioglycolate (219.30 μL, 2 mmol) dropwise with ice cooling.7 The mixture was stirred at room temperature for 30 min and at 60° C. for 12 h, poured into water, and extracted with EtOAc. The extract was washed with water, dried, and concentrated, and the residue was suspended in EtOH and collected by filtration gave 8 as crystals; (271.34 mg, 60.5%). 1H-NMR (300 MHz, CDCl3): δ 8.00 (s, 1H), 7.83-7.78 (m, 1H), 7.55-7.51 (m, 1H), 7.26-7.19 (m, 1H), 4.46-4.39 (q, 2H), 1.46-1.41 (t, 3H). 13C NMR (300 MHz, CDCl3): δ 162.47, 159.25, 139.63, 137.60, 136.29, 129.75, 124.11, 116.24, 110.65, 61.74, 14.29.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH3:19])=[C:16]([NH2:18])[N:17]=3)[CH:14]=2)=[CH:5][CH:4]=1.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH3:19])=[C:16]([NH:18][C:25]([CH:22]4[CH2:24][CH2:23]4)=[O:26])[N:17]=3)[CH:14]=2)=[CH:20][CH:21]=1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc(COc2ccc3nc(N)c(C)n3c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1ccc(COc2ccc3nc(NC(=O)C4CC4)c(C)n3c2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
To a solution of 6-[(4-methoxybenzyl)oxy]-3-methylimidazo[1,2-a]pyridin-2-amine (1.0 g, 3.53 mmol) in N,N-dimethylacetamide (10 mL) was added cyclopropanecarbonyl chloride (352 μL, 3.88 mmol), and the mixture was stirred at 0° C. for 2 hr. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate and collected by filtration to give the title compound (750 mg, 60%) as a slightly-yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH3:13][N:14]([CH3:25])[S:15]([N:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH:23]=[O:24])(=[O:17])=[O:16].[Cl-].[NH4+]>C(OCC)C.C(OCC)(=O)C.O1CCCC1.CCCCCC>[CH3:13][N:14]([CH3:25])[S:15]([N:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH:23]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[OH:24])(=[O:16])=[O:17]
Reactant: CN(C)S(=O)(=O)n1ccnc1C=O
Reactant: Brc1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)n1ccnc1C(O)c1ccccn1
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
To a solution of 4.37 g of 2-bromopyridine in diethyl ether (40 ml) was added 16.5 ml of a 1.6 M hexane solution of n-butyllithium at −78° C. in a nitrogen atmosphere. After stirring for 30 minutes, a tetrahydrofuran solution (20 ml) of 4.34 g of N,N-dimethyl-2-formylimidazole-1-sulfonamide was added thereto. Then the reaction mixture was brought back to room temperature and distributed into ethyl acetate and an aqueous solution of ammonium chloride. The organic layer was extracted and washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 2.02 g of the title compound as a pale yellow oily substance.
Reaction SMILES: [F:1][CH2:2][CH:3]([OH:6])[CH2:4][F:5].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[C:21]#[N:22]>C1COCC1.O>[F:1][CH2:2][CH:3]([CH2:4][F:5])[O:6][C:24]1[CH:23]=[C:20]([CH:19]=[CH:18][C:25]=1[N+:26]([O-:28])=[O:27])[C:21]#[N:22]
Reactant: OC(CF)CF
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc([N+](=O)[O-])c(OC(CF)CF)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1,3-Difluoro-propan-2-ol (4.2 g) was dissolved under argon in THF (250 ml) and cooled to 0° C. LiHMDS (28 ml) was added to the mixture and stirred at rt for 1 hour. Then the mixture was cooled to 0° C. and 3-fluoro-4-nitrobenzonitrile (1.95 ml) was added in portions and stirred for 2 hours. The mixture was poured in water and extracted with DCM. The organic layer was washed with water, dried and concentrated.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]>CO.Cl.[Pd]>[NH2:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:2]=1[F:1]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1ccc(N)cc1F
Yield: 190.8 %

Procedure:
A solution of 2-fluoro-4-nitrobenzonitrile (0.541 g, 2.43 mmol) in methanol (20 mL) and 6N hydrochloric acid (3 mL) was hydrogenated (55 psi) over 10% palladium on carbon (164 mg) for 22 h. The reaction mixture was filtered and concentrated in vacuo to afford 77A (0.65 g, 100%). 1H NMR (400 MHz, CD3OD) δ 4.23 (s, 2H), 7.29 (d, J=8.79 Hz, 2H), 7.68 (t, J=7.91 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8](Br)=[CH:9][CH:10]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.CC(C)([O-])C.[Na+].[CH3:59][O:60][C:61]1[CH:62]=[C:63]([CH:65]=[CH:66][CH:67]=1)[NH2:64]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([NH:64][C:63]2[CH:65]=[CH:66][CH:67]=[C:61]([O:60][CH3:59])[CH:62]=2)=[CH:9][CH:10]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1c(F)cc(O)cc12
Reactant: COc1cccc(N)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: COc1cccc(Nc2ccc3c(c2)[C@@]2(COC(N)=N2)c2cc(O)cc(F)c2O3)c1
Temperature: 100 °C
Yield: 51.6 %

Procedure:
A vial was charged with (S)-2-amino-7′-bromo-4′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (400 mg, 1.095 mmol), di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (81 mg, 0.192 mmol), Pd2 dba3 (50.2 mg, 0.055 mmol), sodium tert-butoxide (316 mg, 3.29 mmol) and 3-methoxyaniline (245 μL, 2.191 mmol). Toluene (2191 μL) was added and the vial was flushed with argon, sealed and shaken to combine all the components. The resulting dark mixture was heated at 100° C. for 16 hrs. The mixture was diluted with water (5 ml) and ethyl acetate (15 ml) and neutralized with saturated NH4Cl solution. The organic layer was loaded onto a 5 g SCX column and washed with EtOAc and MeOH. The material was recovered from the column by washing with 2M NH3 in MeOH. Concentration and separated by silica gel chromatography (10-80% CH2Cl2/MeOH/NH4OH in CH2CO provided (S)-2-amino-4′-fluoro-7′-(3-methoxyphenylamino)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (230 mg, 0.565 mmol, 51.5% yield). MS m/z=408.0 [M+H].
Reaction SMILES: ClC1C(Cl)=NC2C(=CC=C([N+]([O-])=O)C=2)N=1.Cl[C:17]1[C:26](Cl)=[N:25][C:24]2[C:19](=[CH:20][C:21]([N+:29]([O-:31])=[O:30])=[C:22]([Cl:28])[CH:23]=2)[N:18]=1.[K][S:33][C:34](=[C:37]([C:40]#[N:41])[C:38]#[N:39])[S:35][K]>>[Cl:28][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[N+:29]([O-:31])=[O:30])[N:18]=[C:17]1[S:33][C:34](=[C:37]([C:40]#[N:41])[C:38]#[N:39])[S:35][C:26]1=[N:25]2
Reactant: N#CC(C#N)=C(S[K])S[K]
Reactant: O=[N+]([O-])c1cc2nc(Cl)c(Cl)nc2cc1Cl
Agent: O=[N+]([O-])c1ccc2nc(Cl)c(Cl)nc2c1
Product: N#CC(C#N)=C1Sc2nc3cc(Cl)c([N+](=O)[O-])cc3nc2S1
Yield: 66 %

Procedure:
The process of Example 13 is followed except that the 2,3-dichloro-6-nitroquinoxaline is replaced by 1.5 g of 2,3,6-trichloro-7-nitroquinoxaline and 1.4 g of the di(potassiomercapto)methylenemalononitrile is used. The recovered material is a rust colored powder weighing 1.23 g with a calculated overall yield of 66 percent and has a melting point of 297° to 299° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[C:6]([CH2:11]Br)[N:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1.[SH:13][C:14]1[NH:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[C:10]2[C:5](=[C:6]([CH2:11][S:13][C:14]3[NH:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)[N:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1
Reactant: BrCc1nccc2c(Br)csc12
Reactant: Sc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1csc2c(CSc3nc4ccccc4[nH]3)nccc12
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A mixture of 158 mg (0.515 mmol) of 3-bromo-7-bromomethylthieno[2, 3-c]pyridine (i-1), 85 mg (1.1 equivalents) of 2-mercaptobenzimidazole, 284 mg (4 equivalents) of anhydrous K2CO3 and 4 ml of anhydrous DMF was stirred for 1 hr. at room temperature. Water was added to the mixture, and crystals separated out. The crystals collected by filtration were dried, whereby 183 mg (94.5%) of 2-[(3-bromothieno[2, 3-c]pyridin-7-yl)methylthio]benzimidazole (Ia-6) was obtained as an objective compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[N:5]=[C:4]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:34][CH2:33][N:32]([CH:35]([CH3:37])[CH3:36])[CH2:31][CH2:30]4)=[O:28])=[CH:23][CH:22]=3)[CH:18]=[N:19][CH:20]=2)[CH:3]=1.[CH3:38][OH:39]>>[CH:35]([N:32]1[CH2:33][CH2:34][N:29]([C:27]([C:24]2[CH:25]=[CH:26][C:21]([C:17]3[CH:18]=[N:19][CH:20]=[C:15]([C:4]4[CH:3]=[C:2]([O:39][CH3:38])[N:7]=[C:6]([C:8]5[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=5)[N:5]=4)[CH:16]=3)=[CH:22][CH:23]=2)=[O:28])[CH2:30][CH2:31]1)([CH3:37])[CH3:36]
Reactant: CO
Reactant: Cc1cccc(-c2nc(Cl)cc(-c3cncc(-c4ccc(C(=O)N5CCN(C(C)C)CC5)cc4)c3)n2)n1
Product: COc1cc(-c2cncc(-c3ccc(C(=O)N4CCN(C(C)C)CC4)cc3)c2)nc(-c2cccc(C)n2)n1

Procedure:
This compound is prepared from (4-{5-[6-chloro-2-(6-methyl-pyridin-2-yl)-pyrimidin-4-yl]-pyridin-3-yl}-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone (Ex. 7) and methanol analogously to Example 2: [M+H]+=509 as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C:13]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[C:17](=[O:29])[C:16]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][N:35]=2)=[O:31])=[CH:15][C:14]=1[C:44]1[N:48]([CH3:49])[N:47]=[CH:46][CH:45]=1.[S:50]([C:54]1C=CC(C)=CC=1)([O-:53])(=[O:52])=[O:51].CS(O)(=O)=O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[CH3:12][C:13]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:26])[F:28])[CH:20]=2)[C:17](=[O:29])[C:16]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][N:35]=2)=[O:31])=[CH:15][C:14]=1[C:44]1[N:48]([CH3:49])[N:47]=[CH:46][CH:45]=1.[S:50]([O-:53])(=[O:52])(=[O:51])[CH3:54]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: CS(=O)(=O)O
Agent: Cc1c(-c2ccnn2C)cc(C(=O)NCc2ccc(S(C)(=O)=O)cn2)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CS(=O)(=O)[O-]

Procedure:
Compound (I) mesylate was synthesised using an analogous method to that described for the synthesis of compound (I) tosylate in Example 8a from compound (I) (2.0 g, 3.67 mmol) and methane sulfonic acid (0.35 g, 3.67 mmol) to give the title product; yield 2.2 g, 3.45 mmol, 94%.
Reaction SMILES: [CH3:1][C:2]1([C:12]([OH:14])=[O:13])[S:9](=[O:11])(=[O:10])[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH2:3]1.S1(=O)(=O)C2SC=CC=2[CH2:17][CH:16]1C(O)=O.[H-].[Na+].C(I)CC>CN(C=O)C>[CH2:1]([C:2]1([C:12]([OH:14])=[O:13])[S:9](=[O:11])(=[O:10])[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH2:3]1)[CH2:16][CH3:17]
Reactant: CC1(C(=O)O)Cc2ccsc2S1(=O)=O
Reactant: O=C(O)C1Cc2ccsc2S1(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC1(C(=O)O)Cc2ccsc2S1(=O)=O
Yield: 90 %

Procedure:
The title compound was prepared in substantially the same way was 2,3-dihydro-2-methylthieno[2,3-b]thiophene-2-carboxylic acid-1,1-dioxide. Thus, 2,3-dihydrothieno[2,3-b]thiophene-2-carboxylic acid-1,1-dioxide (10.5 g, 0.048 mol) when reacted with NaH (5.76 g, 60% dispersion in oil) and n-propyl iodide (14 mL, 0.047 mol) in DMF (200 mL) gave the title compound as a gum (11.3 g, 90%).
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[C:14]([CH2:17][N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH:20]([NH:28][C:29]([C:31]2[NH:32][C:33]3[C:38]([CH:39]=2)=[CH:37][C:36]([Cl:40])=[CH:35][CH:34]=3)=[O:30])[C:19]1=[O:41])(O)=[O:15].[Li+].[BH4-]>C1COCC1>[Cl:40][C:36]1[CH:37]=[C:38]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([C:29]([NH:28][CH:20]1[CH2:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:18]([CH2:17][CH2:14][OH:15])[C:19]1=[O:41])=[O:30])=[CH:39]2
Reactant: O=C(O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1Cc2ccccc2N(CCO)C1=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 1 h
Yield: 77 %

Procedure:
Triethylamine (0.168 mL, 1.21 mmol) then ethyl chloroformate (0.115 mL, 1.21 mmol) were added to N-[1-(carboxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-5-chloroindole-2-carboxamide (Example 2, 437 mg, 1.10 mmol) in anhydrous THF (10 mL) at 0° C. followed by stirring for 1 h. LiBH4 (2.0 M in THF, 0.69 mL, 1.37 mmol) was added slowly and the mixture stirred for a further 30 min. The reaction was carefully quenched with 1M HCl (50 mL) and EtOAc (100 mL) and the organic layer was further washed with sat. aqueous NaHCO3 (30 mL), brine (30 mL), dried (MgSO4), filtered and evaporated. The residue was triturated with refluxing Et2O (10 mL) and after cooling the solid was filtered and dried to afford the title compound (325 mg, 77%) a white solid.
Reaction SMILES: [O:1]=[C:2]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)[CH2:3][N:4]([CH3:8])[CH2:5][CH2:6]O.S(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[Cl:21][CH2:6][CH2:5][N:4]([CH3:8])[CH2:3][C:2](=[O:1])[N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1
Reactant: CN(CCO)CC(=O)N1CCc2ccccc2C1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CN(CCCl)CC(=O)N1CCc2ccccc2C1

Procedure:
The procedure is similar to that described in Example 6b), treating 5.6 g of 2-{N-[2-oxo-2-(1,2,3,4-tetrahydro-2-isoquinolyl) ethyl]methylamino}ethanol with an excess of thionyl chloride in chloroform.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:11][C:12]1[N:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1.F[C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28].[NH4+].[Cl-]>C1COCC1>[F:26][C:24]1[CH:23]=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[C:20]([NH:18][C:15]2[CH:16]=[N:17][C:12]([F:11])=[CH:13][CH:14]=2)[CH:25]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Nc1ccc(F)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1Nc1ccc(F)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
LiHMDS (1.0M in THF, 5.0 mL, 5.0 mmol) was added dropwise to a stirred solution of 6-fluoropyridin-3-ylamine (294 mg, 2.63 mmol) in anhydrous THF (5 mL) under a nitrogen atmosphere at −78° C. After 30 min stirring at −78° C., a solution of 2,4-difluoro-1-nitrobenzene (275 μL, 2.50 mmol) in THF (5 mL) was added and stirring at −78° C. continued for 1 h. The solution was poured into an aqueous solution of NH4Cl and extracted with EtOAc (×3). The combined organic fractions were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-100% DCM in cyclohexane) to afford the title compound as a yellow solid (571 mg, 91%). LCMS (Method C): RT 3.33 min [M+H]+ 252.1.
Reaction SMILES: [CH2:1]=[CH2:2].[C:3]1([CH3:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(=O)C>[CH2:1]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:9])[CH3:2]
Reactant: C=C
Reactant: Cc1ccccc1
Solvent: CC(=O)O
Product: CCc1ccccc1C
Reaction time: 16 h

Procedure:
The catalyst from Example II is then soaked in glacial acetic acid for 15 minutes at ambient temperature. The catalyst is then dried and calcined at 500° C. for 16 hours. Using the same reaction conditions as in Example II, toluene is reacted with ethylene in the presence of such an acetic acid-treated catalyst. Ethylation of toluene gives 7.1% conversion of toluene to produce an ethyltoluene product which contains 92.3% of the para-ethyltoluene isomer.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][C:16]([CH:19]3[N:23]([CH2:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:22](=[O:30])[C@H:21]([CH2:31][C:32](O)=[O:33])[S:20]3)=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[NH:58]1[CH2:63][CH2:62][CH:61]([N:64]2[CH2:70][CH2:69][C:68]3[CH:71]=[CH:72][CH:73]=[CH:74][C:67]=3[NH:66][C:65]2=[O:75])[CH2:60][CH2:59]1>C(Cl)Cl>[CH3:29][C:26]([CH3:28])([CH3:27])[CH2:25][CH2:24][N:23]1[C:22](=[O:30])[C@H:21]([CH2:31][C:32](=[O:33])[N:58]2[CH2:59][CH2:60][CH:61]([N:64]3[CH2:70][CH2:69][C:68]4[CH:71]=[CH:72][CH:73]=[CH:74][C:67]=4[NH:66][C:65]3=[O:75])[CH2:62][CH2:63]2)[S:20][CH:19]1[C:16]1[S:15][C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[N:18][CH:17]=1
Reactant: CC(C)(C)CCN1C(=O)[C@H](CC(=O)O)SC1c1cnc(C2CCN(C(=O)OC(C)(C)C)CC2)s1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CCN1C(=O)[C@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)SC1c1cnc(C2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
To a solution of 2-((5S)-2-(2-(1-(tert-Butoxycarbonyl)piperidin-4-yl)thiazol-5-yl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetic acid (360 mg, 0.7 mmol, 1 eq) in DCM (8 mL) was added HOBt (162 mg, 1.06 mmol, 1.5 eq), EDC (202 mg, 1.06 mmol, 1.5 eq), DIEA (364 mg, 2.8 mmol, 4 eq) and 3-(piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one (207 mg, 0.84 mmol, 1.2 eq). The resulting mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with DCM (10 mL) and washed with water (5 mL), brine (5 mL), dried (MgSO4) then concentrated in vacuo. The residue was purified by column chromatography over silica gel eluted with 0 to 10% MeOH in DCM to afford 390 mg of compound I-492 in 75% yield. (M+1) 739. 1H NMR (CDCl3) δ 7.19-6.91 (m, 5H), 6.75 (d, J=7.8 Hz, 1H), 5.68 (m, 1H), 4.75 (m, 1H), 4.47 (m, 1H), 4.18 (m, 1H), 3.93 (m, 1H), 3.46-2.67 (m, 11H), 2.08 (m, 6H), 1.71 (m, 6H), 1.47 (m, 9H), 0.85 (m, 9H) ppm.