Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:12]([NH:23][C:24]([C:26]2[CH:27]=[N:28][CH:29]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:31]=2)=[O:25])[CH:11]=1)([O-])=O>C(Cl)(Cl)Cl.CO.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:12]([NH:23][C:24]([C:26]2[CH:27]=[N:28][CH:29]=[C:30]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:31]=2)=[O:25])[CH:11]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2[N+](=O)[O-])cc1NC(=O)c1cncc(-c2ccccc2)c1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2N)cc1NC(=O)c1cncc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 83.6 %

Procedure:
To a solution mixture of tert-butyl 4-(2-nitrophenyl)-2-(5-phenylpyridine-3-carboxamido)benzoate (0.28 g) in chloroform (3.0 mL) and methanol (2.0 mL), 10% palladium-carbon (0.13 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 5 hours and 40 minutes. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-90% chloroform/methanol] to obtain 0.22 g of tert-butyl 4-(2-aminophenyl)-2-(5-phenylpyridine-3-carboxamido)benzoate as a light yellow solid.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=O)=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)[CH2:7][CH3:8].C(Cl)Cl>CN(C=O)C>[C:25]([C:24]1[CH:28]=[CH:29][C:21]([C@H:18]2[CH2:17][CH2:16][C@H:15]([C@H:12]3[CH2:13][CH2:14][C@H:9]([CH2:6][CH2:7][CH3:8])[CH2:10][CH2:11]3)[CH2:20][CH2:19]2)=[CH:22][CH:23]=1)#[N:27]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C(N)=O)cc3)CC2)CC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C#N)cc3)CC2)CC1

Procedure:
A solution of 32.6 g of p-(trans-4-(trans-4-propyl-cyclohexyl)-cyclohexyl)-acetophenone in 100 ml of dioxane is added dropwise to a solution of 40 g of NaOH and 48 g of bromine in 230 ml of water at 20°, while stirring. Stirring is continued for 1 hour. A solution of 14 g of NaHSO3 in 140 ml of water is added and hydrochloric acid is added until the pH is 5. Customary working up (CH2Cl2) gives p-(trans-4-(trans-4-propylcyclohexyl)-cyclohexyl)-benzoic acid. The crude product is boiled with 60 ml of SOCl2 for 2.5 hours. After evaporation, the resulting crude acid chloride is dissolved in 430 ml of dioxane, 200 ml of 25% aqueous ammonia is added and the mixture is poured onto ice and filtered to give p-(trans-4-(trans-4-propylcyclohexyl)-cyclohexyl)-benzamide. 65 g of POCl3 is added dropwise to a solution of 32.7 g of this amide in 500 ml of DMF at 50°, while stirring. After the mixture has been further stirred for 1 hour, it is poured onto ice and worked up in the customary manner (CH2Cl2) to give trans-1-p-cyanophenyl-4-(trans-4-propyl-cyclohexyl)-cyclohexane, m.p. 55°, c.p. 184°.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[H-].[Na+].Cl[C:13]1[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([N:25]2[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]2)=[O:24])=[CH:15][N:14]=1.[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37]>CN(C)C=O.[Cl-].[Na+].O.C(O)C.O>[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37].[O:32]=[S:28]1(=[O:31])[CH2:29][CH2:30][N:25]([C:23]([C:16]2[C:17]([C:19]([F:22])([F:21])[F:20])=[N:18][C:13]([O:9][CH:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[N:14][CH:15]=2)=[O:24])[CH2:26][CH2:27]1
Reactant: OC1CN2CCC1CC2
Reactant: O=C(c1cnc(Cl)nc1C(F)(F)F)N1CCS(=O)(=O)CC1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Cl-]
Agent: [H-]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cnc(OC2CN3CCC2CC3)nc1C(F)(F)F)N1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50.2 %

Procedure:
To a solution of quinuclidin-3-ol (127 mg) in N,N-dimethylformamide (5 mL) was added 60% sodium hydride (60 mg), and the mixture was stirred at room temperature for 20 minutes. To the reaction mixture was added 4-{[2-chloro-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}thiomorpholine 1,1-dioxide (344 mg), followed by stirring at room temperature for 1 hour, and then at 80° C. for 3 hours. To the reaction mixture were added water and saturated brine, followed by stirring and then extracting with a mixed solvent of chloroform:2-propanol=3:1. The obtained organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol:28% aqueous ammonia=10:1:0.1) to obtain a colorless oily substance (207 mg). This oily substance was dissolved in ethanol (5 mL) and then fumaric acid (58 mg) was added thereto, followed by stirring at an external temperature of 80° C. for 1 hour. The reaction mixture was cooled to room temperature under stirring, and further stirred at room temperature for 1 hour, and then the obtained colorless solid was collected by filtration, washed with ethanol, and dried to obtain 3-({5-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]-4-(trifluoromethyl)pyrimidin-2-yl}oxy)quinuclidine fumarate (138 mg).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([C:8]1[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[CH:10][N:9]=1)[CH3:7].[CH2:17](O)[CH3:18]>O>[CH2:6]([C:8]1[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[CH:10][N:9]=1)[CH3:7]
Reactant: CCc1cc(C(=O)O)ccn1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1ccnc(CC)c1
Reaction time: 64 h

Procedure:
2.35 ml of concentrated sulfuric acid are added to a solution of 5 g of 2-ethylpyridine-4-carboxylic acid in 75 ml of ethanol. The reaction mixture is refluxed with stirring for about 64 hours and then concentrated to dryness under reduced pressure. The residue thus obtained is taken up in 500 ml of water and then extracted with 500 ml of dichloromethane. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. 5.08 g of ethyl 2-ethylpyridine-4-carboxylate are thus obtained in the form of an oil.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][SiH:10]([CH2:12][SiH:13]([Cl:15])[Cl:14])[Cl:11]>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.C1C=CC=CC=1>[Cl:9][Si:10]1([Cl:11])[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[Si:13]([Cl:15])([Cl:14])[CH2:12]1
Reactant: Cl[SiH](Cl)C[SiH](Cl)Cl
Reactant: C#Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: Cl[Si]1(Cl)C=C(c2ccccc2)[Si](Cl)(Cl)C1
Yield: 48.2 %

Procedure:
Hydrosilation of phenylacetylene with bis(dichlorosilyl)methane in the presence of Pd(PPh3)4. Into the same apparatus as described in Example 1 were added 1 g of bis(dichlorosilyl)methane, 0.101 g of Pd(PPh3)4, and 20 ml of dried benzene. The flask content was heated to reflux and 0.52 ml of phenylacetylene was added over a ten minute period. The flask content was refluxed, with stirring, for another hours and then the solvent removed at atmospheric pressure. The products were vacuum distilled at 67 Pa to give a mixture comprising 0.89 g of 1,1,3,3-tetrachloro-4-phenyl-1,3-disilacyclopent-4-ene (TCD-GC area 48.2%) and 3,3,5,5-tetrachloro-1,7-diphenyl-3,5-disilahepta-1,6-diene (TCD-GC area6%).
Reaction SMILES: [OH-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([O:23]CC)=[O:22])[CH2:17][CH2:16]2)=[O:14])=[CH:4]1>C(O)C>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=[O:22])[CH2:17][CH2:16]2)=[O:14])=[CH:4]1
Reactant: CCOC(=O)C1CCN(C(=O)Cc2coc3ccccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCN(C(=O)Cc2coc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 ml of 1N sodium hydroxide solution are added to a solution of 42.1 g of the product obtained in Step A in 200 ml of ethanol. After 8 hours' stirring at room temperature, the ethanol is removed by evaporation, the mixture is washed with ether, and the aqueous phase is rendered acidic with 1N hydrochloric acid. After extraction with dichloromethane, decanting and drying, concentration under reduced pressure enables the expected product to be isolated.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][NH:15][CH:16]2[C:19]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[CH2:22][CH2:21][CH2:20]2)=[CH:11][C:10]=1[O:30][CH3:31])C1C=CC=CC=1.C=O.[C:34]([BH3-])#N.[Na+].Cl.[BrH:39]>CO.CC(O)C>[BrH:39].[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:19]1([CH:16]2[C:17]3[C:12](=[CH:11][C:10]([O:30][CH3:31])=[C:9]([OH:8])[CH:18]=3)[CH2:13][CH2:14][N:15]2[CH3:34])[CH2:22][CH2:21][CH2:20]1
Reactant: [BH3-]C#N
Reactant: COc1cc2c(cc1OCc1ccccc1)C(C1(c3ccccc3Cl)CCC1)NCC2
Agent: Br
Agent: C=O
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: COc1cc2c(cc1O)C(C1(c3ccccc3Cl)CCC1)N(C)CC2
Temperature: 10 °C
Reaction time: 24 h

Procedure:
A mixture of the hydrochloride salt of 7-benzyloxy-1-[1-(2-chlorophenyl)cyclobutyl]-6-methoxy-1,2,3,4-tetrahydroisoquinoline (2.75 g prepared in a similar manner to that described in Example RB25), methanol (50 ml) and 37-40% aqueous formaldehyde solution (3 ml) was cooled to 10° C. and sodium cyanoborohydride (1.52 g) was added. The mixture was stirred for 24 hours and the solvents removed by evaporation. The residue was partitioned between ethyl acetate and dilute aqueous sodium hydroxide solution. The organic layer yielded a gum which was dissolved in methanol (25 ml) and concentrated hydrochloric acid (25 ml) and heated under reflux for 1 hour. The solvents were removed by evaporation and the residue partitioned between ether and saturated aqueous sodium bicarbonate solution. The ether layer yielded a residue which was dissolved in propan-2-ol (100 ml) and 48% aqueous hydrobromic acid (5 ml). The solvent was removed by evaporation and the residue crystallised and then recrystallised from propan-2-ol to give 1-[1-(2-chlorophenyl)cyclobutyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide, m.p. 148°-150° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl.CCOC(C)=O>[C:28]([NH:2][CH2:3][CH:4]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[CH:20][CH:21]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:30])[CH3:29]
Reactant: COC(=O)C(CN)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(CNC(C)=O)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl 4-[1-(aminomethyl)-2-methoxy-2-oxoethyl]benzoate hydrochloride (600 mg, 1.90 mmol) in CH2Cl2 were added pyridine (0.38 mL, 4.75 mmol) and acetyl chloride (0.20 mL, 2.85 mmol). After stirring for 2 h at room temperature, the reaction mixture was diluted with EtOAc, washed (sat. CuSO4, sat. NaHCO3, brine), dried (MgSO4), and concentrated. Flash chromatography on silica gel (50-100% EtOAc/hexanes) afforded tert-butyl 4-{1-[(acetylamino)methyl]-2-methoxy-2-oxoethyl}benzoate as a thick, colorless oil. 1H NMR (CDCl3) δ7.94 (d, J=8.2 Hz, 2H), 7.28 (d, J=8.2 Hz, 2H), 5.87 (t, J=5.5 Hz, 1H), 3.96 (dd, J=8.8, 5.9 Hz, 1H), 3.71-3.60 (m, 2H), 3.67 (s, 3H), 1.93 (s, 3H), 1.57 (s, 9H). MS (ESI) calcd [M+H]+ 322.1, found 322.1.
Reaction SMILES: [CH3:1][O:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([N:6]3C(OC(C)(C)C)=O)[CH2:4]1)[CH2:10]2.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]12[CH2:4][CH:5]3[CH2:11][CH:9]([CH2:8][CH:7]([NH:6]3)[CH2:12]1)[CH2:10]2
Reactant: COC12CC3CC(C1)N(C(=O)OC(C)(C)C)C(C3)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC12CC3CC(C1)NC(C3)C2
Temperature: 0 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer was charged tert-butyl 5-methoxy-2-azatricyclo[3.3.1.13,7]decane-2-carboxylate, Intermediate-17 (0.1 g, 0.037 mmol) in DCM (5 mL). Then reaction mixture was cooled to 0° C. and trifluoroacetic acid (0.22 g, 1.8 mmol) was added and stirred for 4 hours. After completion of the reaction (reaction was monitored by LCMS) reaction mixture was concentrated followed by trituration with mixture of hexane:ether (1:1) to give Intermediate-18 (0.09 g, yield=95%) as an oily mass.
Reaction SMILES: [CH3:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[NH:12][N:11]=[N:10]1.[CH3:15]N(C)C=O.[H-].[Na+].CI>O>[CH3:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH3:15])[N:11]=[N:10]1
Reactant: CN(C)C=O
Reactant: Cc1c(Cl)cccc1-n1nn[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cc1c(Cl)cccc1-n1nnn(C)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of the above-mentioned 1-(2-methyl-3-chlorophenyl)-1,4-dihydrotetrazole-5-one 10.00 g and N,N-dimethylformamide 100 mL was added 55% sodium hydride 2.30 g under ice-cooling. The mixtures were raised to room temperature and were stirred for one hour. To the reaction mixtures was added methyl iodide 3.2 mL under ice-cooling. The mixtures were raised to room temperature and were stirred for fourteen hours. To the reaction mixtures was added water and the mixtures were extracted with ethyl acetate. The organic layers were washed with 10% hydrochloric acid, water and saturated saline, and were dried over anhydrous magnesium sulfate and were then concentrated under reduced pressure. The resulting residues were subjected to a silica gel column chromatography to give 1-(2-methyl-3-chlorophenyl)-4-methyl-1,4-dihydrotetrazole-5-one (hereinafter, referred to as “Intermediate (PRC-P)”) 1.56 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[CH3:36][Mg]Br.S([O-])(O)(=O)=O.[K+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][C:18]([CH:21]([OH:22])[CH3:36])=[CH:19][CH:20]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: C[Mg]Br
Reactant: COC(=O)c1c(-c2ccc(C=O)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccc(C(C)O)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
To a solution (2.6 ml) of 6-chloro-4-(4-formylphenyl)-2-(4-methanesulfonylbenzyl)-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (130 mg) in THF was added a solution (3 mol/l, 0.10 ml) of methyl magnesium bromide in THF at room temperature with stirring, and the mixture was stirred at room temperature for 1 hr. After the completion of the reaction, 5% aqueous potassium hydrogensulfate solution was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane/ethyl acetate=1/2-ethyl acetate) to give the title compound (72 mg) as colorless crystals.
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1.[Cl:29]C1SC2C=CC=C(Cl)C=2N=1>>[Cl:29][C:27]1[C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=[CH:2][CH:28]=1
Reactant: Clc1nc2c(Cl)cccc2s1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(Cl)cccc2s1

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 2,4-dichlorobenzothiazole in place of 2-chloro-6-fluorobenzothiazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.10-2.31 (m, 4H), 3.05-3.19 (m, 2H), 3.33-3.48 (m, 2H), 4.46-4.59 (m, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.71 (d, J=7.3 Hz, 1H), 8.07 (s, 1H), 8.19 (d, J=8.0 Hz, 1H), 8.41 (br. s., 2H), 8.56 (s, 1H). MS (ES+): m/z=411.09/413.08 (3:1) [MH+]. HPLC: tR=2.16 min (ZQ2, polar—5 min).
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])[N:30]=[CH:31][C:24]=12>C1COCC1.C(OCC)(=O)C>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[N:29]1[C:25]2=[N:26][CH:27]=[N:28][C:23]([O:3][C@@H:4]([CH2:15][O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=3)=[O:6])=[C:24]2[CH:31]=[N:30]1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Reactant: COC[C@H](C)OC[C@H](O)C(=O)Nc1ccc(C)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC[C@H](C)OC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1ccc(C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
Sodium hydride (21.24 mg, 0.53 mmol) was added to (S)-2-hydroxy-3-((S)-1-methoxypropan-2-yloxy)-N-(5-methylpyridin-2-yl)propanamide (Intermediate Y5) (95 mg, 0.35 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) (122 mg, 0.46 mmol) in dry THF (2 mL) was added. The reaction was allowed to warm up to room temperature and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), and washed sequentially with water (10 mL) and saturated brine (5 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0-100% ethyl acetate in isohexane to afford the product (160 mg, 91%). 1H NMR (400 MHz, DMSO) δ 1.09 (d, 3H), 2.24 (s, 3H), 3.23 (s, 3H), 3.26-3.38 (m, 2H), 3.77-3.86 (m, 1H), 4.00-4.16 (m, 2H), 5.85-5.91 (m, 1H), 7.55-7.70 (m, 4H), 7.73-7.78 (m, 1H), 7.88 (d, 1H), 8.16-8.19 (m, 1H), 8.54 (s, 1H), 8.59 (s, 1H), 10.79 (s, 1H). m/z (ESI+) (M+H)+=497.20; HPLC tR=2.36 min.
Reaction SMILES: ClCCl.C(N(S(F)(F)[F:10])CC)C.[CH2:13]([C:20]1[C:25]([O:26][CH2:27][O:28][CH3:29])=[CH:24][CH:23]=[C:22]([N:30]2[CH2:34][CH2:33][C@@H:32](O)[C:31]2=[O:36])[N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[CH2:13]([C:20]1[C:25]([O:26][CH2:27][O:28][CH3:29])=[CH:24][CH:23]=[C:22]([N:30]2[CH2:34][CH2:33][C@@H:32]([F:10])[C:31]2=[O:36])[N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: COCOc1ccc(N2CC[C@@H](O)C2=O)nc1Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: COCOc1ccc(N2CC[C@@H](F)C2=O)nc1Cc1ccccc1
Reaction time: 2 h

Procedure:
3 ml of dichloromethane was added to 0.18 ml of diethylaminosulfur trifluoride. Into the mixture was added dropwise a solution of 3 ml of dichloromethane containing 371 mg of 2-benzyl-3-methoxymethyloxy-6-[(3R)-3-hydroxy-2-pyrrolidinone-1-yl]pyridine under cooling in an ethanol/dry ice bath. The mixture was returned to room temperature and stirred for 2 hours. Then, water was added thereto, and the mixture was extracted with ethyl acetate. The organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvents was removed. The residue was subjected to silica gel column chromatography using 17-20% ethyl acetate/hexane as an eluent for separation and purification, to give 116 mg of the target compound.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)=[O:5].[OH2:17].[OH-].[Na+]>CO>[F:15][C:11]1[CH:10]=[C:9]([CH:7]2[CH2:8][CH:6]2[C:4]([OH:17])=[O:5])[CH:14]=[CH:13][CH:12]=1
Reactant: O
Reactant: CON(C)C(=O)C1CC1c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CC1c1cccc(F)c1
Temperature: 25 °C

Procedure:
A mixture of 2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid methoxy-methyl-amide (8.96 g), water (20 mL), and NaOH (3.2 g) in MeOH (40 mL) was refluxed for 3 h. The reaction mixture was cooled down to room temperature and concentrated in vacuo. The residue was acidified by 6 N HCl followed by extraction with CH2Cl2. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (7.1 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][C:8]1[C:9]([CH3:17])=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12].C[N:19](C)C=O>ClCCl>[OH:7][C:8]1[C:9]([CH3:17])=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH2:19])=[O:12]
Reactant: CN(C)C=O
Reactant: Cc1c(O)cccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1c(O)cccc1C(N)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
Oxalyl chloride (4.19 ml, 48 mmol) was added to an ice-cold solution of 3-hydroxy-2-methylbenzoic acid (3.62 g, 24 mmol) in dichloromethane (30 mL). N,N-dimethylformamide (2 mL) was then added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was concentrated in vacuo three times from toluene. The residue was then suspended in tetrahydrofuran (10 mL), added to ice-cold 0.88 ammonia solution (10 mL) and stirred for 2.5 hours, allowing the temperature to rise to ambient. The reaction mixture was then extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo and the residue was concentrated in vacuo from acetone and triturated with diethyl ether to afford the title compound as a solid in 45% yield. LRMS APCI m/z 152 [M+H]+
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=2)=[CH:11][C:10]=1[C:35]1[N:36]([C:41]2[CH:42]=[C:43]3[C:47](=[CH:48][CH:49]=2)[N:46]([CH3:50])[CH:45]=[CH:44]3)[C:37]([OH:40])=[N:38][N:39]=1)C1C=CC=CC=1>[Pd].CO>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][C:12]2[CH:11]=[C:10]([C:35]3[N:36]([C:41]4[CH:42]=[C:43]5[C:47](=[CH:48][CH:49]=4)[N:46]([CH3:50])[CH:45]=[CH:44]5)[C:37]([OH:40])=[N:38][N:39]=3)[C:9]([OH:8])=[CH:14][C:13]=2[OH:15])[CH:30]=[CH:29][C:28]=1[O:31][CH3:32]
Reactant: COc1ccc(C=Cc2cc(-c3nnc(O)n3-c3ccc4c(ccn4C)c3)c(OCc3ccccc3)cc2OCc2ccccc2)cc1OC
Agent: [Pd]
Solvent: CO
Product: COc1ccc(CCc2cc(-c3nnc(O)n3-c3ccc4c(ccn4C)c3)c(O)cc2O)cc1OC
Reaction time: 8 h
Yield: 88 %

Procedure:
A flask was charged with 5-{2,4-bis-benzyloxy-5-[2-(3,4-dimethoxy-phenyl)-vinyl]-phenyl}-4-(1-methyl-1H-indol-5-yl)-4H-[1,2,4]triazol-3-ol (164 mg; 0.25 mmol), 10% palladium on carbon (50 mg); methanol (20 mL), and place under an atmosphere of hydrogen. The reaction was stirred overnight, and then filtered through celite. The solvent was removed to give 4-[2-(3,4-Dimethoxy-phenyl)-ethyl]-6-[5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-[1,2,4]triazol-3-yl]-benzene-1,3-diol (109 mg; 0.22 mmol).