Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[N:13]([CH3:15])[C:12]1[CH2:11][CH2:10][C:9](=[CH:16][C:17]3[N:18]=[CH:19][NH:20][C:21]=3[CH3:22])[C:8](=[O:23])[C:7]2=1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[N:13]([CH3:15])[C:12]1[CH2:11][CH2:10][CH:9]([CH2:16][C:17]3[N:18]=[CH:19][NH:20][C:21]=3[CH3:22])[C:8](=[O:23])[C:7]2=1
Reactant: Cc1[nH]cnc1C=C1CCc2c(c3cccc(F)c3n2C)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1[nH]cnc1CC1CCc2c(c3cccc(F)c3n2C)C1=O
Yield: 99.4 %

Procedure:
8-Fluoro-1,2,3,9-tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4-yl)methylene]-4H-carbazol-4-one (1.5 g) was dissolved in ethanol (50 ml) and added to a suspension of 5% palladium on charcoal (200 mg) in ethanol (ca. 50 ml), and the resulting mixture was hydrogenated at room temperature and atmospheric pressure until hydrogen uptake had ceased. The mixture was filtered, and the filtrate was evaporated in vacuo to give the title compound (1.5 g), m.p. 189°-191° (decomp.), t.l.c. (System A 100:8:1), Rf 0.43.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].CN(C)C=O.[H-].[Na+].Br[CH:34]([CH2:36][CH3:37])[CH3:35]>C(OCC)(=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[N:7]([CH:34]([CH2:36][CH3:37])[CH3:35])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCC(C)Br
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nn(C(C)CC)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
To a mixture of 4′-[(3-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile (1.00 g) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.60 g), and the mixture was stirred at room temperature for 30 min. To the mixture was added 2-bromobutane (1.64 g), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.61 g, 53%).
Reaction SMILES: [Na+].[CH:2]1([N:5]2[C:9]([C:10]([O-])=[O:11])=[C:8]([C:13]3[CH:14]=[N:15][C:16]([N:19]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:17][CH:18]=3)[N:7]=[C:6]2[C:34]2[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:36][CH:35]=2)[CH2:4][CH2:3]1.[N:45]1([CH:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH2:49][CH2:48][CH2:47][CH2:46]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:2]1([N:5]2[C:9]([C:10]([N:53]3[CH2:54][CH2:55][CH:50]([N:45]4[CH2:49][CH2:48][CH2:47][CH2:46]4)[CH2:51][CH2:52]3)=[O:11])=[C:8]([C:13]3[CH:14]=[N:15][C:16]([N:19]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:17][CH:18]=3)[N:7]=[C:6]2[C:34]2[CH:35]=[CH:36][C:37]([O:40][C:41]([F:44])([F:42])[F:43])=[CH:38][CH:39]=2)[CH2:3][CH2:4]1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: O=C([O-])c1c(-c2ccc(N(Cc3ccccc3)Cc3ccccc3)nc2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1c(-c2ccc(N(Cc3ccccc3)Cc3ccccc3)nc2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1)N1CCC(N2CCCC2)CC1
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of 0.12 g (0.2 mmol) of 3-cyclopropyl-5-(6-dibenzylamino-pyridin-3-yl)-2-(4-trifluoromethoxy-phenyl)-3H-imidazole-4-carboxylic acid sodium salt and 0.03 g (0.2 mmol) of 4-pyrrolidin-1-yl-piperidine in 1 ml of DMF was added 83 microliters (0.6 mmol) of triethylamine and 0.08 g (0.2 mmol) of HATU. The mixture was stirred for 1 h after which time it was evaporated to dryness, the residue was partitioned between CH2Cl2 and saturated sodium hydrogen carbonate solution, the organic phase was dried with sodium sulfate and concentrated. Purification by flash column chromatography [MeOH/CH2Cl2 5:95] afforded 0.1 g (79%) of the title compound as a colorless solid. MS: 721.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[C:21]1([C:27](=O)[CH2:28][CH2:29][C:30](=O)[CH3:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[CH3:31][C:30]1[N:1]([C:2]2[C:3](=[O:20])[N:4]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:7]=2)[C:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:28][CH:29]=1
Reactant: Nc1cc(-c2ccccn2)cn(-c2ccccc2)c1=O
Reactant: CC(=O)CCC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2)n1-c1cc(-c2ccccn2)cn(-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 31.3 %

Procedure:
25 mg of 3-amino-1-phenyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one was dissolved in 10 ml of toluene. To the mixture were added 20 mg of 1-phenyl-1,4-pentandione and 0.2 mg of p-toluenesulfonate (hydrate), followed by heating under reflux for 1 hour. After cooling to room temperature, the reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate, followed by extracting with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 12 mg of the title compound.
Reaction SMILES: [CH2:1]([S:8][C:9](=[S:15])[NH:10][CH2:11][C:12](Cl)=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].S(Cl)[Cl:22]>ClCCl>[CH2:1]([S:8][C:9]1[S:15][C:12]([CH2:13][Cl:22])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClSCl
Reactant: C=C(Cl)CNC(=S)SCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1cnc(SCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.0 g of (2-chloro-allyl)-dithiocarbamic acid benzyl ester and 4.1 g of sodium hydrogen carbonate are placed in 100 ml of dichloromethane and cooled in an ice bath. In the course of 3 minutes, a solution of 3.2 g of sulfur chloride in 10 ml of dichloromethane is added, and when the addition is complete the ice bath is removed. The mixture is stirred at room temperature for 2 hours and filtered off with suction, and the filtrate is concentrated by evaporation. The residue crystallises after the addition of diethyl ether. Filtration yields 2-benzylsulfanyl-5-chloromethyl-thiazole having a melting point of 129-131° C. in the form of the hydrochloride. Extraction of the mother liquor with semi-saturated aqueous sodium hydrogen carbonate solution and removal of the ether by distillation yield 2-benzylsulfanyl-5-chloromethyl-thiazole having a melting point of 57-61° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Li+].CC([N-]C(C)C)C.[Br:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:24]([F:36])[CH:23]=1.CN([CH:40]=[O:41])C>C1COCC1>[Br:21][C:22]1[CH:23]=[C:24]([F:36])[C:25]([O:29][C:30](=[O:35])[C:31]([CH3:32])([CH3:33])[CH3:34])=[C:26]([F:28])[C:27]=1[CH:40]=[O:41]
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(=O)Oc1c(F)cc(Br)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)C(=O)Oc1c(F)cc(Br)c(C=O)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
Add n-butyl lithium 1.6N (23 ml, 36.8 mmol) to diisopropylamine (5.0 ml, 35.6 mmol) in anhydrous THF (7 ml) at 0° C. Stir the resulting yellow solution for 30 min at 0° C. Add this LDA solution dropwise via canula to a solution of 2,2-Dimethyl-propionic acid 4-bromo-2,6-difluoro-phenyl ester (8.01 g, 27.33 mmol) in anhydrous THF (40 ml) at −78° C. over 40 min. Stir the resulting bright yellow solution for 1 h at −78° C. Add anhydrous DMF (2.8 ml, 35.0 mmol) and stir the mixture for 1.5 h at −78° C. Quench the mixture with dilute sulfuric acid and extract the product with EtOAc (×3). Wash the combined organic layers with water (×3), saturated aq. sodium chloride and dry over anhydrous sodium sulfate. Filter and concentrate to yield the crude product. Purification by flash chromatography (Silica gel-hexane/EtOAc) yields 8.35 g of the title compound (95% yield).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[C:31]([CH3:38])[CH:30]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1>C(O)C.C1COCC1.[Pd]>[NH2:35][C:32]1[CH:33]=[CH:34][C:29]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19]([NH:21][CH3:22])=[O:20])=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:30][C:31]=1[CH3:38]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(C)c3)S(C)(=O)=O)c(C3CC3)cc12
Reaction time: 12 h
Yield: 86 %

Procedure:
To 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-methyl-4-nitrophenyl)methylsulfonamido)benzofuran-3-carboxamide (2.0 g, 3.72 mmol) in Ethanol (10 mL) and THF (2 mL), Pd/C (0.396 g) was added and subjected to hydrogenation at RT for 12 h. The reaction mixture was filtered through Celite. The solvent was evaporated under reduced pressure to afford the title compound in 86% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.85-7.95 (m, 1H), 7.67-7.73 (m, 1H), 7.37-7.42 (m, 1H), 7.11-7.26 (m, 1H), 6.59-6.68 (m, 1H), 5.86 (br. s., 1H), 3.18 (s, 1H), 2.99 (s, 2H), 2.10-2.17 (m, 1H), 1.37-1.51 (m, 1H), 1.08-1.19 (m, 1H), 0.91-1.06 (m, 1H), 0.45-0.92 (m, 1H). LCMS (m/z, ES+)=508 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[CH3:16][O:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>ClCCl.CO>[CH3:16][O:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=2[O:14][CH3:15])[CH2:20][CH2:19]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Reactant: COC1CCNCC1
Solvent: ClCCl
Solvent: CO
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCC(OC)CC1

Procedure:
Prepared analogously to Example 1.1.c. from 1 g (3.62 mmol) of 1-(2-bromoethoxy)-2-methoxy-4-nitrobenzene and 1.25 g (10.87 mmol) of 4-methoxypiperidine. Yield: 1 g (89% of theory); C15H22N2O5 (M=310.35); calc.: molecular ion peak (M+H)+: 311; found: molecular ion peak (M+H)+: 311; Rf value: 0.5 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([CH:14]=1)[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[H][H]>C(OCC)(=O)C.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:14]=1
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1cc(Cl)ccc1OCCc1ccccc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(Cl)ccc1OCCc1ccccc1
Yield: 93.9 %

Procedure:
570 mg of platinum dioxide was suspended in a solution of 11.39 g of the crude ethyl 5-chloro-2-(2-phenylethoxy)cinnamate in 80 ml of ethyl acetate and stirred in a hydrogen gas stream at room temperature for 4.5 hours. Filtering through Celite and evaporating under reduced pressure gave 10.76 g of crude ethyl 3-[5-chloro-2-(2-phenylethoxy)phenyl]propionate. This compound was not purified any more but used in the subsequent reaction as such.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]2[C:19]=1[C:20]1[CH:21]=[CH:22][C:23]2[O:28][CH2:27][CH2:26][CH2:25][C:24]=2[CH:29]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C(O)C.O>[C:1]([O:5][CH:6]([C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]2[C:19]=1[C:20]1[CH:21]=[CH:22][C:23]2[O:28][CH2:27][CH2:26][CH2:25][C:24]=2[CH:29]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1nc2ccccn2c1-c1ccc2c(c1)CCCO2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(C(=O)O)c1nc2ccccn2c1-c1ccc2c(c1)CCCO2
Yield: 55.7 %

Procedure:
A mixture of methyl 2-(tert-butoxy)-2-[3-(3,4-dihydro-2H-1-benzopyran-6-yl)imidazo[1,2-a]pyridin-2-yl]acetate (25e) (31 mg, 0.079 mmol) and potassium hydroxide (18 mg, 0.37 mmol) in a mixture of ethanol (3 mL) and water (1 mL) was refluxed for 1 hour. The mixture was concentrated in vacuo. Water (1 mL) was added to the residue and the aqueous layer was extracted with ethyl acetate (5 mL). The aqueous layer was acidified with 1M hydrochloric acid until pH 7 and extracted with dichloromethane (2×5 mL). The organic layer was concentrated in vacuo to provide the desired acid (17 mg, 0.044 mmol, 56%) as a beige solid.
Reaction SMILES: [ClH:1].C(O)(C(F)(F)F)=O.C(OC([N:16]1[CH2:20][C@@H:19]([CH3:21])[CH2:18][C@H:17]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[CH:33]=[C:32]([C:37]#[C:38][C:39]2[NH:43][C:42]([C@@H:44]4[CH2:49][C@@H:48]5[C@@H:46]([CH2:47]5)[N:45]4C(OC(C)(C)C)=O)=[N:41][CH:40]=2)[CH:31]=[CH:30]3)[N:26]=1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[CH3:21][C@@H:19]1[CH2:20][NH:16][C@H:17]([C:22]2[NH:23][CH:24]=[C:25]([C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][CH:36]=3)[CH:33]=[C:32]([C:37]#[C:38][C:39]3[N:43]=[C:42]([C@@H:44]5[CH2:49][C@@H:48]6[C@@H:46]([CH2:47]6)[NH:45]5)[NH:41][CH:40]=3)[CH:31]=[CH:30]4)[N:26]=2)[CH2:18]1
Reactant: C[C@H]1C[C@@H](c2nc(-c3ccc4cc(C#Cc5cnc([C@@H]6C[C@H]7C[C@H]7N6C(=O)OC(C)(C)C)[nH]5)ccc4c3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: C[C@@H]1CN[C@H](c2nc(-c3ccc4cc(C#Cc5c[nH]c([C@@H]6C[C@H]7C[C@H]7N6)n5)ccc4c3)c[nH]2)C1
Reaction time: 8 h
Yield: 148.1 %

Procedure:
2M HCl (0.33 mL, 0.66 mmol) in dioxane was added to a solution of a TFA salt of (1R,3S,5R)-tert-butyl 3-(5-((6-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (115 mg, 0.131 mmol) in dioxane (2 mL) and the reaction was stirred vigorously overnight. The reaction was concentrated to yield an HCl salt of (1R,3S,5R)-3-(4-((6-(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (87 mg) which was used without further purification. LC-MS retention time 2.793 min; m/z 449.41 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([S:25]([CH:28]=[CH:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)(=[O:27])=[O:26])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][N:22]([S:25]([CH:28]=[CH:29][CH:30]3[CH2:35][CH2:34][N:33]([C:9]([CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:10])[CH2:32][CH2:31]3)(=[O:26])=[O:27])[CH2:21][CH2:20]2)=[CH:17][CH:18]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: O=S(=O)(C=CC1CCNCC1)N1CCN(c2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)N1CCC(C=CS(=O)(=O)N2CCN(c3ccc(F)cc3)CC2)CC1
Reaction time: 3 h

Procedure:
3-Phenylpropionyl chloride (0.21 ml) was added dropwise to a solution of 4-(4-fluorophenyl)-1-[2-(piperidin-4-yl)-ethenylsulphonyl]-piperazine (0.5 g) in dichloromethane containing triethylamine (0.2 ml). The mixture was stirred for 3 hours, evaporated to dryness, diluted with water and extracted with ethyl acetate (2×15 ml). The ethyl acetate extracts were combined and washed with aqueous sodium bicarbonate, water and dried. Removal of the solvent gave 4-(4-fluorophenyl)-1-[2-(1-phenethylcarbonylpiperidin-4-yl)-ethenylsulphonyl]-piperazine as a gum, M+H=486 (485).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[CH3:15]O>[Pd]>[CH3:15][C:11]1[C:2]([CH3:1])=[C:3]([CH:8]=[C:9]([NH2:12])[CH:10]=1)[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1C
Reactant: CO
Agent: [Pd]
Product: Cc1cc(N)cc(C(=O)O)c1C
Reaction time: 18 h

Procedure:
Combine methyl 2-methyl-5-nitrobenzoate (5.32 g, 27.2 mmol) and methanol (100 mL). Add 5% palladium-on-carbon (0.27 g). Hydrogenate on a pressure apparatus at 50 psi. After 18 hours, filter through celite to remove the catalyst and evaporate the filtrate in vacuo to give methyl 2-methyl-5-aminobenzoic acid: Rf=0.34 (silica gel, ethyl acetate/hexane 1/4).
Reaction SMILES: COC1C=CC(CO)=CC=1OCC1C=CC(C(F)(F)F)=CC=1.C[O:24][C:25](=[O:59])[CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:34]([S:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=3)[CH:40]=2)=[C:33]2[C:29]=1[CH2:30][CH2:31][CH2:32]2>>[CH3:46][O:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][S:37][C:34]2[CH:35]=[CH:36][C:28]([O:27][CH2:26][C:25]([OH:59])=[O:24])=[C:29]3[C:33]=2[CH2:32][CH2:31][CH2:30]3)=[CH:40][C:41]=1[O:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:56])[F:57])=[CH:51][CH:50]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OC)c(OCc3ccc(C(F)(F)F)cc3)c2)c2c1CCC2
Agent: COc1ccc(CO)cc1OCc1ccc(C(F)(F)F)cc1
Product: COc1ccc(CSc2ccc(OCC(=O)O)c3c2CCC3)cc1OCc1ccc(C(F)(F)F)cc1

Procedure:
Preparation of [4-Methoxy-3-(4-trifluoromethyl-benzyloxy)-phenyl]-methanol (compound 78A) The title compound was prepared in the manner analogous to Example 14A using 1-bromomethyl-4-trifluoromethyl-benzene and 5-hydroxymethyl-2-methoxy-phenol. MS m/z 295 (M-OH). Step 2. Preparation of 4-Chloromethyl-1-methoxy-2-(4-trifluoromethyl-benzyloxy)-benzene (compound 78B) The title compound was prepared in the manner analogous to Example 3B using 78A. MS m/z 295 (M-Cl). Step 3. Preparation of {7-[4-Methoxy-3-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acid methyl ester (compound 78C) The title compound was prepared in the manner analogous to Example 1F using 78B and 12C. MS m/z 373 (M−159). Step 4. Preparation of {7-[4-Methoxy-3-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acid (compound 78) The title compound was prepared in the manner analogous to Example 1 using 78C. mp 150-151° C.; IR (KBr) cm−1: 3046, 1722, 1515, 1328, 1232, 1106; 400 MHz 1H NMR (DMSO-d6): δ 12.95 (br(s), 1H), 7.71 (d, 2H, J=8.1 Hz), 7.58 (d, 2H, J=8.1 Hz), 7.03 (d, 1H, J=8.5 Hz), 6.70-6.86 (m, 3H), 6.57 (d, 1H, J=8.5 Hz), 5.01 (s, 2H), 4.61 (s, 2H), 3.89 (s, 2H), 3.69 (s, 3H), 2.75 (t, 2H, J=7.3 Hz), 2.62 (t, 2H, J=7.3 Hz), 1.87 (pentet, 2H); MS m/z 517 (M−1). Anal. Calc'd for C27 H25F3O3S: C, 62.54; H, 4.86; found: C, 62.54; H, 4.71.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH2:18][CH2:19][CH3:20].[BrH:21].N([O-])=O.[Na+]>O1CCOCC1.O.[Cu]Br>[Br:21][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH2:18][CH2:19][CH3:20]
Reactant: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
2-(4-Amino-3-propylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (33.2 mmol, 10 g) was dissolved in dioxane (15 mL) and water (30 mL) was added. The suspension was heated to reflux then hydrobromic acid (48% weight in water, 149 mmol, 17 mL) was added drop wise via an addition funnel over a 20 minute period. The mixture was heated for a further 20 minutes before cooling to 0° C. A solution of sodium nitrite (33.2 mmol, 2.290 g) in water (30 mL) was added to the mixture over a 30 minute period and the mixture stirred at 0° C. for 30 minutes. A solution of copper (I) bromide (38.2 mmol, 5.48 g) in water (30 mL) and hydrobromic acid (48% weight in water, 149 mmol, 17 mL) was added drop wise to the mixture over a 20 minute period at 0° C. and the mixture was allowed to stir at 0° C. for 20 minutes. The mixture was warmed to 60° C. for 20 minutes then allowed to stir at room temperature overnight. The reaction mixture was extracted with diethyl ether (3×100 mL), the organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (eluting with 10% ethyl acetate/90% heptane) to afford the title compound (6.1 g). MS (ESI) m/z 365.5 [M−H]
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=1.[CH2:18]([O:22][C:23]1[C:28]([CH:29]=[CH:30][C:31](O)=[O:32])=[CH:27][CH:26]=[C:25]([C:34]([F:37])([F:36])[F:35])[N:24]=1)[CH2:19][CH2:20][CH3:21]>>[CH2:18]([O:22][C:23]1[C:28]([CH:29]=[CH:30][C:31]([NH:2][CH2:3][C:4]2[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=2)=[O:32])=[CH:27][CH:26]=[C:25]([C:34]([F:37])([F:35])[F:36])[N:24]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCOc1nc(C(F)(F)F)ccc1C=CC(=O)O
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Agent: Cl
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2OCCCC)cc(F)c1NS(C)(=O)=O
Yield: 53.7 %

Procedure:
N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide HCl salt (25 mg, 0.087 mmol) was reacted with 3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (21 mg, 0.73 mmol) to give the title compound (24 mg, 54%).
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[OH:14])[CH:9]=[O:10])[CH3:4]>O.[N+]([O-])([O-])=O.[Ag+]>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[OH:14])[C:9]([OH:1])=[O:10])[CH3:4]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOc1cc(C(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 26.4 %

Procedure:
A solution of silver nitrate (45.0 g, 265.0 mmol, 1.0 equiv) in water (230 mL) was treated with NaOH (10.6 g, 265 mmol, 1.0 equiv) and stirred for 20 min at rt. The formed precipitate was filtered off, washed with water (3×200 mL) and directly suspended in water (260 mL). To this suspension was added 3-ethoxy-4-hydroxy-benzaldehyde (20.0 g, 120.4 mmol, 0.45 equiv) and NaOH (26.5 g, 662.5 mmol, 2.5 equiv) the reaction mixture heated to reflux for 2 h. The reaction mixture was filtered, acidified to pH 2 by addition of sulfuric acid and the solution extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, the solvent removed by evaporation under reduced pressure and the crude material purified over a plug of silica eluting with dichloromethane/methanol/acetic acid (97:2:1) to give 5.8 g (27%) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.32 (t, J=7.0 Hz, 3H), 4.04 (q, J=7.0 Hz, 2H), 6.88 (d, J=8.0 Hz, 1H), 7.46 (s, 1H), 7.48 (d, J=8.0 Hz, 1H), 9.67 (br s, 1H), 12.42 (br s, 1H). 13C NMR (75 MHz, DMSO): δ 14.52, 63.93, 114.09, 115.11, 121.68, 123.49, 146.29, 151.32, 167.22. MS (ISN): 181.0 [M−H]−.