Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1OC.[Cl-].[Al+3].[Cl-].[Cl-].CO[C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20]>ClCCl>[C:19]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:20])[C:18]1[CH:22]=[CH:23][CH:24]=[CH:16][CH:17]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: COc1ccccc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
60.6 g (324.2 mmol) of 2-bromoanisole was added dropwise to a dichloromethane (350 ml) solution containing 51.8 g (388.6 mmol) of aluminum chloride and 55.31 g (324.3 mmol) of 3-methoxybenzoyl chloride which was cooled to 0° C. After addition, the resulting mixture was stirred for 2 hours. After a reaction, the reaction solution was washed with water, the solvent was removed, and the obtained product was purified by column chromatography to obtain a benzophenone derivative represented by the following formula (47) as 67.7 g (210.7 mmol, yield of 65%) of a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([OH:18])=[CH:13][C:12]=2[OH:19])=[O:10])=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=O)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:10])[C:11]3[C:12](=[CH:13][C:14]([OH:18])=[C:15]([Cl:17])[CH:16]=3)[O:19][C:20]=2[CH3:21])=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccc(Br)cc1)c1cc(Cl)c(O)cc1O
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1oc2cc(O)c(Cl)cc2c(=O)c1-c1ccc(Br)cc1

Procedure:
This compounds was synthesised in the same manner as described above. 2-(4-Bromo-phenyl)-1-(5-chloro-2,4-dihydroxy-phenyl)-ethanone (1.5 g, 4.4 mmol), Acetic anhydride (2.0 ml), Potassium carbonate (2.1 g 15.2 mmol). 3-(4-Bromo-phenyl)-6-chloro-7-hydroxy-2-methyl-chromen-4-one was obtained an off white solid (1.2 g, 74.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:7][C:4]=1[CH:5]=[O:6].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:7][C:4]=1[CH2:5][OH:6]
Reactant: COc1ccc(Oc2ccccc2Cl)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Oc2ccccc2Cl)cc1CO
Yield: 99.2 %

Procedure:
A solution of 2-methoxy-5-(2-chlorophenoxy)benzaldehyde (8 g) in methanol (50 ml) and sodium borohydride (685 mg) were treated in a similar manner to that of Example 3-(5) to give oily 2-methoxy-5-(2-chlorophenoxy)benzyl alcohol (8 g).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(N(C)C)=O>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.O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Nc1nc2cccc(Br)n2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(-c2cccc3nc(N)nn23)cc1
Temperature: 150 °C

Procedure:
5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (2 g, 9.4 mmol), 4-methoxybenzeneboronic acid (1.71 g, 11.26 mmol), potassium phosphate (3.98 g, 18.77 mmol) and tetrakis(triphenylphosphine)palladium (0.54 g, 0.47 mmol) were added to a microwave tube containing a stirrer bar. Dimethylacetamide (12 mL) and water (4 mL) were then added and the reaction was heated to 150° C. for 10 min. The reaction was filtered through silica and washed through with methanol and concentrated under reduced pressure. The crude was suspended in diethyl ether and the solid collected and was used without further purification. Yield: 1.70 g, 71%; LCMS method: 1, RT: 3.43 min, MI: 241 [M+1]. NMR 1H (DMSO): 3.82 (s, 3H), 6.16 (brs, 2H), 6.96 (d, 1H), 7.06 (d, 2H), 7.29 (d, 1H), 7.46 (t, 1H), 7.92 (d, 2H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[C:4]#[N:5].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>O1CCOCC1>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:2]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=2[C:4]#[N:5])=[CH:18][CH:17]=1
Reactant: COc1ccc(CN)cc1
Reactant: N#Cc1c(F)cccc1C(F)(F)F
Solvent: C1COCCO1
Product: COc1ccc(CNc2cccc(C(F)(F)F)c2C#N)cc1
Temperature: 180 °C
Yield: 93.9 %

Procedure:
2-Fluoro-6-(trifluoromethyl)benzonitrile (2.44 g, 12.9 mmol) and 4-methoxybenzylamine (7.09 g, 51.7 mmol) were suspended in 1,4-dioxane (10 mL) and heated in a microwave at 180° C. for 30 min. The 1,4-dioxane was removed under vacuum, and the crude material was purified by chromatography on silica gel eluting with CH2Cl2 to give 3.71 g of 2-(4-methoxybenzylamino)-6-(trifluoromethyl)benzonitrile (94%) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ 3.71 (s, 3H), 4.42 (d, J=5.6 Hz, 2H), 6.89 (m, 2H), 6.97 (m, 2H), 7.29 (m, 3H), 7.48 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:25])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:6]=2[CH:24]=1.[ClH:26]>ClCCl.C(OCC)C.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[C:3]([F:25])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[C:6]=2[CH:24]=1.[ClH:26]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(F)c(Cl)cc32)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=c1[nH]c2cc(F)c(Cl)cc2n1C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl 4-(6-chloro-5-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinecarboxylate (D4) (0.460 mmol, 170 mg) was dissolved in dichloromethane-diethyl ether, and HCl (5 ml of a 4M solution in 1,4-dioxane) was added at room temperature; the mixture was shaken at room temperature overnight. Solvent was evaporated to afford the title compound, mono hydrochloride salt, complete conversion, M++H=270.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:8])=[N:4][NH:5][C:6]=1[CH3:7].[H-].[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([C:19]([NH:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([CH2:28]OS(C)(=O)=O)[CH2:24][CH2:23]2)=[O:20])[C:15]([CH3:18])=[N:16][CH:17]=1>C(#N)C.O>[Cl:11][C:12]1[CH:17]=[N:16][C:15]([CH3:18])=[C:14]([CH:13]=1)[C:19]([NH:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([CH2:28][N:4]2[C:3]([CH3:8])=[C:2]([Cl:1])[C:6]([CH3:7])=[N:5]2)[CH2:24][CH2:23]1)=[O:20]
Reactant: Cc1n[nH]c(C)c1Cl
Reactant: Cc1ncc(Cl)cc1C(=O)N[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1ncc(Cl)cc1C(=O)N[C@H]1CC[C@H](Cn2nc(C)c(Cl)c2C)CC1
Temperature: 120 °C

Procedure:
To a solution of 4-chloro-3,5-dimethyl-1H-pyrazole (step 5a) (37 mg, 0.283 mmol) in dry acetonitrile (4.5 mL) at room temp is added sodium hydride (14 mg of a 60% dispersion in mineral oil, 0.353 mmol). The mixture is stirred at room temp for 10 minutes before trans-methanesulfonic acid 4-[(5-chloro-2-methyl-pyridine-3-carbonyl)-amino]-cyclohexylmethyl ester (step 4) (85 mg, 0.236 mmol) is added in one portion. The mixture is heated at 120° C. for 30 minutes using microwave radiation. After cooling to RT, the reaction mixture is diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The EtOAc extracts are combined, washed with saturated brine (10 mL), dried (MgSO4), filtered and evaporated to give a colourless foam. Purification by chromatography on silica gel using a 12 g pre-packed column eluting with 0-100% EtOAc affords the title compound as a colourless solid. MS m/z 395.3/397.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (1H, d), 8.39 (1H, d), 7.78 (1H, d), 3.83 (2H, d), 3.67 (1H, m), 2.47 (3H, s), 2.20 (3H, s), 2.09 (3H, s), 1.89 (2H, m), 1.73 (1H, m), 1.57 (2H, m), 1.16 (4H, m).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:36]=[CH:35][C:9]([CH2:10][N:11]2[C:15](=[O:16])[C:14]3([CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[N:13]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:12]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[ClH:37]>O1CCOCC1>[ClH:37].[O:16]=[C:15]1[C:14]2([CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)[N:13]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:12][N:11]1[CH2:10][C:9]1[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1ccc(NS(C)(=O)=O)cc1)CN2c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1ccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)cc1

Procedure:
tert-Butyl 3-(4-(methylsulfonamido)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (2.30 g, 4.47 mmol) and 4M hydrochloric acid in 1,4-dioxane (25 mL) were stirred at room temperature for 2 hours. The reaction was evaporated and dried under vacuum to give product as a light yellow solid (2.02 g, quant.); MS for C21H26N4O3S m/z 415 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:12][C:13]3[CH:30]=[CH:29][CH:28]=[CH:27][C:14]=3[C:15]=2[NH:16][C:17](=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[O:10])=[N:6][CH:7]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:12][C:13]3[CH:30]=[CH:29][CH:28]=[CH:27][C:14]=3[C:15]=2[NH:16][C:17](=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:10])=[N:6][CH:7]=1
Reactant: COC(=O)CCCCC(=O)Nc1c(C(=O)Nc2ccc(Cl)cn2)oc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCC(=O)Nc1c(C(=O)Nc2ccc(Cl)cn2)oc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.1 %

Procedure:
Methyl 6-[(2-{[(5-chloropyridin-2-yl)amino]-carbonyl}benzofuran-3-yl)amino]-6-oxohexanoate (4.30 g) obtained in Example 10(1) is suspended in methanol (5 m), and thereto is added at room temperature 2N aqueous sodium hydroxide solution (30 ml). The mixture is stirred at room temperature for 4 hours, and at 50° C. for 2 hours. The reaction solution is diluted with water and acidified by addition of 10% hydrochloric acid under ice-cooling, and the precipitates are collected by filtration and dried to give the title compound (3.54 g). ESI-MS M/Z:414/416[M−H]−
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]2[N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:12]=[CH:13][C:3]=12.[Cl-].C1(N(C2C=CC=CC=2)C([N+]2C=CC=CC=2)=O)C=CC=CC=1.[CH2:41]([O:43][NH2:44])[CH3:42].C[O-].[Na+].Cl.C(ON)C>CO.C(N(CC)CC)C>[NH2:1][C:2]1[C:7]([C:8]([NH:44][O:43][CH2:41][CH3:42])=[O:10])=[CH:6][N:5]=[C:4]2[N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:12]=[CH:13][C:3]=12
Reactant: CCCCCn1ncc2c(N)c(C(=O)O)cnc21
Reactant: CCON
Agent: C[O-]
Agent: Cl
Agent: O=C(N(c1ccccc1)c1ccccc1)[n+]1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCCn1ncc2c(N)c(C(=O)NOCC)cnc21
Reaction time: 0.33 h

Procedure:
To a stirred solution of 1.1 g of 4-amino-1-n-pentyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid and 0.56 g of triethylamine in 35 ml of MeOH was added a solution of 1.43 g of diphenylcarbamylpyridinium chloride in 5.6 ml of MeOH. After stirring for 20 min., the reaction mixture was cooled in an ice bath and added to a cold stirred solution of ethoxyamine which was prepared by adding 3.32 ml of a 25% methanolic sodium methoxide solution to a solution of 1.42 g of ethoxyamine hydrochloride in 10 ml of MeOH. The resulting mixture was stirred at room temperature for 1.5 hr. and then concentrated. The residue was diluted with 60 ml of water and the resulting mixture extracted with ether. The combined extracts were dried (MgSO4), filtered, and concentrated to give 1.98 g of an amber oil which was chromatographed over silica gel using ether as the eluant. The fractions containing the product were combined and concentrated to leave 0.92 g of a white foam. The foam was induced to crystallize by dissolving it in hot toluene containing a small amount of chloroform and cooling, whereupon crystals precipitated. These were collected, washed with cold toluene and hexane, and air-dried to give 0.69 g (53%) of the title compound as white crystals, m.p. 142.3°-144.2°.
Reaction SMILES: [C:1]([C:5]1[C:6]([CH3:29])([CH3:28])[CH2:7][O:8][C:9]=1[C:10]1[CH:26]=[C:25]([OH:27])[C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[O:16][C:12]=2[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[Na].[O:31]=[O:32]>C(Cl)Cl>[C:1]([C:5]12[O:32][O:31][C:9]1([C:10]1[CH:26]=[C:25]([OH:27])[C:13]3[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[O:16][C:12]=3[CH:11]=1)[O:8][CH2:7][C:6]2([CH3:29])[CH3:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(-c2nc3c(O)cc(C4=C(C(C)(C)C)C(C)(C)CO4)cc3o2)cc1
Reactant: O=O
Agent: [Na]
Solvent: ClCCl
Product: COc1ccc(-c2nc3c(O)cc(C45OCC(C)(C)C4(C(C)(C)C)OO5)cc3o2)cc1
Yield: 93.1 %

Procedure:
To 5 mL of methylene chloride were added 1.0 mg of TPP and 95.1 mg (0.24 mmol) of 4-t-butyl-5-(4-hydroxy-2-(p-methoxyphenyl)benzo[d]oxazol-6-yl)-3,3-dimethyl-2,3-dihydrofuran (Compound [67]), and the mixture was externally irradiated with a 940 W sodium lamp in an oxygen atmosphere for30 minutes. After the resulting mixture was concentrated, the concentrate was applied to a silica gel column and the elution was carried out with the mixture of hexane and ethyl acetate (hexane:ethyl acetate=3:1), and then followed by recrystallization from the mixture of methylene chloride and hexane to obtain 95.8 mg of 5-t-butyl-1-(4-hydroxy-2-(p-methoxyphenyl)benzo[d]oxazol-6-yl)-4,4-dimethyl-2,6,7-trioxabicyclo[3.2.0]heptane (Compound [68]) as colorless granular micro-crystal. Yield 93.1%.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][CH:51]=1)[N:48]=[C:47]([CH2:52][CH2:53][N:54]1[CH2:58][CH2:57][CH2:56][C@H:55]1[CH3:59])[CH:46]=[CH:45]2>COCCOC.O.C(OCC)(=O)C.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]>[CH3:59][C@@H:55]1[CH2:56][CH2:57][CH2:58][N:54]1[CH2:53][CH2:52][C:47]1[CH:46]=[CH:45][C:44]2[C:49](=[CH:50][CH:51]=[C:42]([C:28]3[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=3)[CH:43]=2)[N:48]=1
Reactant: C[C@@H]1CCCN1CCc1ccc2cc(Br)ccc2n1
Reactant: OB(O)c1cccnc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: C[C@@H]1CCCN1CCc1ccc2cc(-c3cccnc3)ccc2n1
Temperature: 80 °C

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (28.8 mg, 0.025 mmol), 2-(dicyclohexylphosphino)biphenyl (35.0 mg, 0.10 mmol), 3-pyridinylboronic acid (0.375 mmol), and sodium carbonate (40.0 mg, 0.375 mmol) were combined in 1,2-dimethoxyethane (4 mL) and water (1.5 mL). The mixture was then treated with the product from Example 42D (80 mg, 0.25 mmol) and heated at 80° C. for 24 hours. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate (20 mL). The organic layer was separated, washed with 5% NaHCO3 (25 mL×3), 25% brine (25 mL), dried over Na2SO4, filtered, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (heptane:acetone:CH2Cl2:TEA (60:40:5:1) to provide the title compound. The title compound was treated with HCl in IPA:ethyl acetate to give the trihydrochloride salt. mp 205-207° C.; MS (ESI) 318 (M+H)+; 1H NMR (DMSO-d6) δ 9.48 (1H, br, s), 9.05 (1H, d), 8.96 (1H, d), 9.00 (1H, d), 8.86 (1H, br, s), 8.60 (1H, d), 8.59 (1H, d), 8.32 (1H, dd), 8.23 (1H, d), 4.08 (1H, br, m), 3.90 (2H, br, m), 3.65 (2H, br, m), 3.46 (1H, q), 2.40 (1H, m), 2.19 (2H, m), 1.84 (1H, m), 1.58 (3H, d).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:15]=2)=[CH:9][C:8]=1[Cl:30])[CH3:2].[N:32]1([CH2:38][CH2:39][CH2:40]O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:40][CH2:39][CH2:38][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:17]=[C:16]([C:21]#[C:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[CH:15]=2)=[CH:9][C:8]=1[Cl:30])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(O)cc(C#Cc3ccc(Cl)cc3)c2)cc1Cl
Reactant: OCCCN1CCCCC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(Cl)cc3)cc(OCCCN3CCCCC3)c2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (0.4 g; 0.85 mmol), 3-piperidin-1-yl-propan-1-ol (0.12 g; 0.85 mmol) and tributylphosphine (0.37 mL; 1.5 mmol) were dissolved in THF (50 mL) in a dried reaction flask under an atmosphere of nitrogen. 1,1′-(Azodicarbonyl)dipiperidine (0.38 g; 1.5 mmol) dissolved in THF (25 mL) was added to the reaction mixture, which was stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness and 5% aqueous citric acid and ethyl acetate was added. The organic phase was separated, dried, evaporated to dryness, and purified by prep HPLC (method A). Yield: 275 mg. HPLC-MS: m/z: 598.0 (M+); Rt: 2.3 min.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10](Br)=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([C:16]#[N:17])[C:3]=1[S:18][C:19]([F:22])([F:21])[F:20].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+].COCCOCCOC>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].O>[Cl:15][C:8]1[CH:9]=[C:10]([C:28]2[CH:29]=[CH:30][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:26][CH:27]=2)[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]([NH2:1])=[C:3]([S:18][C:19]([F:22])([F:21])[F:20])[C:4]([C:16]#[N:17])=[N:5]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1nn(-c2c(Cl)cc(Br)cc2Cl)c(N)c1SC(F)(F)F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOCCOC
Product: N#Cc1nn(-c2c(Cl)cc(-c3ccc(C(F)(F)F)cc3)cc2Cl)c(N)c1SC(F)(F)F
Temperature: 20 °C
Yield: 56.5 %

Procedure:
A mixture of 6 g of 5-amino-3-cyano-1-(2,6-dichloro-4-bromophenyl)4-trifluoromethylthiopyrazole (prepared according to procedures reported in U.S. Pat. No. 5,232,940), 4-trifluoromethylphenylboronic acid (5.3 g), K2CO3 (5.8 g), tris(dibenzylidene acetone)dipalladium (0.6 g) and diglyme was heated at 130° C. for 25 hours. After cooling to 20° C., the mixture was poured into water and extracted with diethyl ether. The ether solutions were combined, dried, filtered and the filtrate concentrated and purified by chromatography. The desired product as a solid (3.9 g, mp 181-184° C.) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([S:12][C:13]#N)=[CH:8][NH:9]2)=[CH:5][CH:4]=1.CI.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([S:12][CH3:13])=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(SC#N)c[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: CO
Product: COc1ccc2c(SC)c[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.9 %

Procedure:
To a solution of 6-methoxy-3-thiocyanato-1H-indole (0.336 g, 1.64 mmole) and methyl iodide (0.700 g, 4.93 mmole) in methanol (10 ml) was added potassium hydroxide solution (0.164 ml, 10N) at 0° C. The reaction mixture was stirred for 1 h at room temperature. Silica gel (5 g) was added to the reaction mixture and the solvent was removed under reduced pressure. The residue was purified on a column of silica gel, eluting the product with mixtures of ethyl acetate:hexane (1:9 to 1:1). The first product which was eluted was the desired 6-methoxy-3-methylsulfanyl-1H-indole (0.120 g, 37% yield) followed by 6-methoxy-1H-indole-3-thiol (0.126 g). Step 3
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[CH2:6][CH2:5]2.CI.[CH3:16]C(C)([O-])C.[K+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]([CH3:16])[C:7](=[O:13])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)c(F)cc2N1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Product: CN1C(=O)CCc2cc(Br)c(F)cc21

Procedure:
In analogy to the procedure described for the preparation of intermediates A-1 [A], 6-bromo-7-fluoro-3,4-dihydro-1H-quinolin-2-one was reacted with methyl iodide in presence of potassium tert-butoxide to give the title compound as a white foam. MS: 258.0, 259.9 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18]CC)=[O:17].[OH-].[Na+]>CO>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:13])[F:14])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc2cc(C(F)(F)F)ccc2c1O
Temperature: 25 °C
Yield: 28.7 %

Procedure:
A mixture of ethyl 4-hydroxy-7-(trifluoromethyl)-3-quinolinecarboxylate (43.4 g, 0.521 mol) and 10% sodium hydroxide (150 mL) was heated to reflux. Most of the ester did not dissolve so methanol (150 mL) was added over the course of an hour to facilitate dissolution. After refluxing for 2 hours a solution was obtained. The solution was refluxed for an additional 2 hours and then allowed to cool to ambient temperature overnight. The methanol was removed under reduced pressure and the resulting aqueous solution was acidified with concentrated hydrochloric acid. The resulting precipitate was isolated by filtration, washed with water and then dried in a vacuum oven at 120° C. for 24 hours to provide 38.5 g of 4-hydroxy-7-(trifluoromethyl)-3-quinolinecarboxylic acid as a white solid.
Reaction SMILES: C(O[C:6](=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14](=[O:16])[NH2:15])(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+].[Cl:30][C:31]1[N:36]=C(Cl)[C:34]([Cl:38])=[CH:33][N:32]=1>C(Cl)Cl.O.CO>[Cl:30][C:31]1[N:36]=[C:6]([NH:7][C@@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[C:14]([NH2:15])=[O:16])[C:34]([Cl:38])=[CH:33][N:32]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1C(N)=O
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reaction time: 2 h

Procedure:
trans-(2-Carbamoyl-cyclohexyl)-carbamic acid tert-butyl ester (246.5 mg, 1.02 mmol, J. Molec. Cat. B: Enzymatic, 2004, 29, 115-121) was dissolved in DCM and treated with TFA (5 mL). After 2 h, solvent was removed by rotary evaporation and the residue was repeated evaporated from CHCl3 to remove any trace of TFA. To this residue was sequentially added MeOH (3 mL), water (1.5 mL), NaHCO3 (171.2 mg, 2.04 mmol) and 2,4,5-trichloropyrimidine (224 mg, 1.22 mmol). After stirring for 40 h, addition of water (3 mL) gave a precipitate that was removed by filtration and washed with water (5×2 mL) and ether (2×2 mL) to afford 2-(2,5-dichloro-pyrimidin-4-ylamino)-trans-cyclohexanecarboxylic acid amide as a white solid that was used without further purification in the subsequent step.