Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[S:5][C:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:8]=1.C(=O)([O-])O.[Na+].Cl.CN(C)CCCN=C=NCC.Cl.[N:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][C:50](O)=[O:51])[CH:44]=1>CN(C)C=O.O.ClCCl>[ClH:1].[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]2[N:8]=[C:4]([CH2:3][NH:2][C:50](=[O:51])[CH2:49][C:45]3[CH:44]=[N:43][CH:48]=[CH:47][CH:46]=3)[S:5][C:6]=2[C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(-c2nc(CN)sc2-c2ccc(OC)cc2)cc1
Reactant: O=C(O)Cc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(CNC(=O)Cc3cccnc3)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
2-Aminomethyl-4,5-bis(4-methoxyphenyl)thiazole hydrochloride (1.00 g) was added to a mixture of dichloromethane and saturated aqueous solution of sodium hydrogencarbonate, and was extracted with dichloromethane. The organic layer was washed with water, and brine, and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and resulting residue was dissolved in dimethylformamide (25 ml). To the resulting mixture was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.64 g) and 3-pyridylacetic acid hydrochloride (0.52 g), and stirred at ambient temperature for 2 hours and stirred at 60° C. for 5 hours. After allowing to cool to ambient temperature, the mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium hydrogencarbonate, water, and brine, and dried over magnesium sulfate and treated with activated charcoal. After filtration, the filtrate was evaporated in vacuo. The residue was subjected to column chromatography on silica gel (50 g) and eluted with a mixture of methanol and chloroform. The fractions containing the object compound were combined and evaporated in vacuo, and the resulting residue was dissolved in ethanol, and added an ethanol solution of hydrogen chloride. The mixture was evaporated in vacuo, and the resulting precipitate was collected by filtration and washed with diethyl ether, to give 4,5-bis(4-methoxyphenyl)-2-(3-pyridylacetylaminomethyl)thiazole hydrochloride (0.52 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1C=O.[CH:14](OC)([O:17][CH3:18])[O:15][CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:16][O:15][CH:14]([O:17][CH3:18])[C:3]1[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:2]=1[F:1]
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(OC)c1ccc(C(F)(F)F)cc1F
Reaction time: 0.25 h
Yield: 97.7 %

Procedure:
A solution of 2-fluoro-4-trifluoromethylbenzaldehyde (10.0 g, 52.0 mmol), trimethyl orthoformate (55.0 g, 520 mmol) and a catalytic amount of p-toluene sulfonic acid (5 mol %) was stirred at room temperature for 24 hours. The resulting solution was saturated with the addition of solid Na2CO3 and stirred for 15 minutes. The mixture was then filtered and the solution was evaporated. The residue was diluted with ether and evaporated yielding 12.1 g (98%) of the desired product as an oil.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:9])[CH2:5][CH2:6][CH2:7][OH:8].[Cl:10][C:11]1[C:16]([C:17]2[C:22]([F:23])=[CH:21][C:20](F)=[CH:19][C:18]=2[F:25])=[C:15]([NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:14]=[C:13]([N:32]([CH3:35])[C:33]#[N:34])[N:12]=1>CS(C)=O.C(OCC)(=O)C>[Cl:10][C:11]1[C:16]([C:17]2[C:18]([F:25])=[CH:19][C:20]([O:8][CH2:7][CH2:6][CH2:5][N:4]([CH3:9])[CH3:3])=[CH:21][C:22]=2[F:23])=[C:15]([NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:14]=[C:13]([N:32]([CH3:35])[C:33]#[N:34])[N:12]=1
Reactant: CN(C#N)c1nc(Cl)c(-c2c(F)cc(F)cc2F)c(NCC(F)(F)F)n1
Reactant: CN(C)CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN(C)CCCOc1cc(F)c(-c2c(Cl)nc(N(C)C#N)nc2NCC(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of sodium hydride (60% in mineral oil, 12 mg, 0.30 mmol) in 2 mL of dimethylsulfoxide is added 3-dimethylamino-1-propanol (27 μL, 0.23 mmol). The mixture is then stirred at room temperature for 1 h. 4-Chloro-6-[(2,2,2-trifluoroethyl)amino]-5-(2,4,6-trifluorophenyl)pyrimidin-2-yl(methyl)cyanamide (60 mg, 0.152 mmol) is then added, and the reaction mixture is heated at 60° C. for 4 h, and diluted with ethyl acetate. The organic layer is washed with water and saturated sodium chloride, dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with a gradient of ethyl acetate to 50% methyl alcohol in ethyl acetate to methyl alcohol. Concentration provides 4-chloro-5-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-6-[(2,2,2-trifluoroethyl)amino]pyrimidin-2-yl(methyl)cyanamide as a light yellow semisolid solid (20 mg). MS: m/z 479.3(M+H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]1[CH:22]=[CH:21][C:16]([O:17][CH2:18][CH:19]=O)=[CH:15][C:14]=1[C:23]([F:26])([F:25])[F:24]>>[CH2:1]([C:3]1[N:4]2[CH2:9][CH2:10][NH:11][CH:19]([CH2:18][O:17][C:16]3[CH:21]=[CH:22][C:13]([F:12])=[C:14]([C:23]([F:26])([F:24])[F:25])[CH:15]=3)[C:5]2=[C:6]([I:8])[N:7]=1)[CH3:2]
Reactant: CCc1nc(I)cn1CCN
Reactant: O=CCOc1ccc(F)c(C(F)(F)F)c1
Product: CCc1nc(I)c2n1CCNC2COc1ccc(F)c(C(F)(F)F)c1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (1.540 mmol) and (4-fluoro-3-trifluoromethyl-phenoxy)-acetaldehyde (0.342 g; 1.540 mmol) afforded 3-ethyl-8-(4-fluoro-3-trifluoromethyl-phenoxymethyl)-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. Subsequent protection of the secondary amine, and purification by FC (DCM/MeOH=60/1) allowed the isolation of the pure product 3-ethyl-8-(4-fluoro-3-trifluoromethyl-phenoxymethyl)-1-iodo-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (0.412 g; 47%). LC-MS: tR=0.93 min.; [M+H]+=570.37 g/mol.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[N:23]=[CH:24][CH:25]=[C:26]4[CH:30]=[CH:29][S:28][C:27]=34)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:32].CCOCC>CCOC(C)=O.CO>[ClH:32].[ClH:32].[ClH:32].[S:28]1[C:27]2=[C:22]([N:19]3[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][C@H:11]4[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]4)[CH2:17][CH2:18]3)[N:23]=[CH:24][CH:25]=[C:26]2[CH:30]=[CH:29]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4ccsc34)CC2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CO
Product: N[C@H]1CC[C@H](CCN2CCN(c3nccc4ccsc34)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Trans-{4-[2-(4-thieno[2,3-c]pyridin-7-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester (605 mg, 1.36 mmol) was dissolved in a mixture of EtOAc (10 ml) and MeOH (1 ml) and treated with 2 N HCl in Et2O (10 ml, 20 mmol). The resulting mixture was stirred 5 h at room temperature. A white precipitate was formed that was collected by filtration and washed with EtOAc. The solid was dried over night under high vacuum to yield trans-4-[2-(4-thieno[2,3-c]pyridin-7-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride as a white solid (365 mg, 59%), MS (ISP) m/z=345.2 [(M+H)+].
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][C@H:14]([CH2:19][C@@H:20]([CH3:25])[CH2:21][CH2:22][CH2:23][CH3:24])[C:15](OC)=[O:16]>C(OCC)C>[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][C@H:14]([CH2:19][C@@H:20]([CH3:25])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:15][OH:16]
Reactant: CCCC[C@H](C)C[C@@H](OC1CCCCO1)C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCC[C@H](C)C[C@H](CO)OC1CCCCO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A mixture of 0.6 g of lithium aluminum hydride and 60 ml of diethyl ether was kept at -5° to -10° C., and a solution of the ester derivative (2.12 g) obtained in Step 8 in 50 ml of diethyl ether was added thereto dropwise, followed by stirring at that temperature for 2 hours. The reaction mixture was poured into ice-water and extracted with diethyl ether. The extract was washed with water and distilled to remove the solvent to obtain 1.51 g (70.01%) of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH2:15])=[CH:5][CH:4]=1.[C:16](Cl)(=[O:18])[CH3:17]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(CCN)c2c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc2cccc(CCNC(C)=O)c2c1

Procedure:
0.01 ml of 2-(7-methoxynaphth-1-yl)ethylamine is dissolved in 6 ml of pyridine. The mixture is cooled in an ice bath with agitation, and 0.012 mol of acetyl chloride is added dropwise.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].CO[CH:13]1[CH2:17][CH2:16][CH:15](OC)O1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]2[CH:13]=[CH:17][CH:16]=[CH:15]2)[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: COC1CCC(OC)O1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(-n2cccc2)c1

Procedure:
A mixture of 3-nitroaniline (15 g, 0.11 mmol), 2,5-dimethoxytetrahydrofuran (42 ml, 0.33 mol) and a catalytic amount of pTSA in dry toluene (150 ml) is heated to reflux for 2 hours. After cooling the mixture is concentrated under reduced pressure and the residue is purified by column-chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (1:1) as the eluent. Yield: 16 g (78%). Mp 65-70° C.
Reaction SMILES: Cl.[N:2]1([C:8]2[C:19]3=[C:20]4[N:15]([CH:16]([CH3:21])[CH2:17][CH2:18]3)[CH:14]=[C:13]([C:22]([OH:24])=[O:23])[C:12](=O)[C:11]4=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[OH-].[Na+].Cl>O>[N:2]1([C:8]2[C:19]3=[C:20]4[N:15]([CH:16]([CH3:21])[CH2:17][CH2:18]3)[CH:14]=[C:13]([C:22]([OH:24])=[O:23])[CH2:12][C:11]4=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: CC1CCc2c(N3CCNCC3)ccc3c(=O)c(C(=O)O)cn1c23
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1CCc2c(N3CCNCC3)ccc3c2N1C=C(C(=O)O)C3
Yield: 94.7 %

Procedure:
3.8 g of 8-(1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride was added to 100 ml of water and 1 N aqueous sodium hydroxide solution was added thereto followed by heating the mixture to form a uniform solution. The solution was rendered alkaline (pH=8) with dilute hydrochloric acid to obtain 3.1 g of 8-(1-piperazinyl)-5-methyl-6,7-dihydro-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as colorless needles having a melting point of 264° to 265° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([C:9]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:30]=[CH:29][C:24]3[B:25]([OH:28])[O:26][CH2:27][C:23]=3[CH:22]=2)=[CH:16][C:10]=1[O:11][CH2:12][C:13](O)=[O:14])#[N:8]>>[OH:28][B:25]1[C:24]2[CH:29]=[CH:30][C:21]([O:20][C:17]3[CH:18]=[CH:19][C:9]([C:7]#[N:8])=[C:10]([O:11][CH2:12][C:13]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:14])[CH:16]=3)=[CH:22][C:23]=2[CH2:27][O:26]1
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1OCC(=O)O
Reactant: C1COCCN1
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1OCC(=O)N1CCOCC1

Procedure:
Following the general procedure, morpholine (80 μL, 0.93 mmol) was coupled with [2-cyano-5-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenoxy]-acetic acid ((D39), 150 mg, 0.46 mmol) to give a crude oil containing (D41). Purification by reverse phase HPLC followed by lyophilization gave a white solid of (D41) (38 mg, 21%). 1H NMR 400 MHz (d6-DMSO) δ: 9.32 (br s, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.21 (br s, 1H), 7.15 (dd, J=9.0, 1.5 Hz, 1H), 6.90 (d, J=1.5 Hz, 1H), 6.65 (dd, J=8.5, 1.5 Hz, 1H), 5.17 (s, 2H), 5.03 (s, 2H), 3.65-3.55 (m, 4H), 3.49-3.40 (m, 4H); MS (ES) m/z: 395 (M+H)+; HPLC purity 96.02% (Maxplot), 97.64% (220 nm) and 97.18% (254 nm).
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4]1[C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]2[C:13](O[C:16](=[O:17])[C:6]=2[CH:5]=1)=[O:14]>CC(O)=O>[O:17]=[C:16]1[C:6]2[C:7](=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:4][CH:5]=2)[C:13](=[O:14])[NH:3][NH:2]1
Reactant: NN
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc2c(=O)[nH][nH]c(=O)c2c1
Temperature: 120 °C
Yield: 84.9 %

Procedure:
Hydrazine hydrate (26 g, 0.52 mol) was added in one portion to a stirred mixture of 1,2,4-benzenetricarboxylic anhydride (100 g, 0.52 mol), in HOAc (1.0 L) at RT. The mixture was heated to 120° C. for 2 hours and then allowed to cool to RT. The solid was filtered, washed with water (250 ml) and dried in the vacuum oven at 50° C. for 20 hours to give the title compound (91 g, 85% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[C:23]([O:24][C:25]3[CH:26]=[N:27][C:28]([S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])=[CH:29][CH:30]=3)=[CH:22][C:12]3[NH:13][C:14]([C:16]4[CH:21]=C[CH:19]=[CH:18][N:17]=4)=[N:15][C:11]=3[CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[N:36]1C=CN=CC=1C(O)=O>>[Cl:1][C:2]1[C:7]([O:8][C:9]2[C:23]([O:24][C:25]3[CH:26]=[N:27][C:28]([S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])=[CH:29][CH:30]=3)=[CH:22][C:12]3[NH:13][C:14]([C:16]4[CH:21]=[N:36][CH:19]=[CH:18][N:17]=4)=[N:15][C:11]=3[CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2cccnc2Cl)cn1
Reactant: O=C(O)c1cnccn1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2cccnc2Cl)cn1

Procedure:
The entitled compound was obtained as a colorless solid in the same method as in Example 197 or in accordance with the method or by combining it with an ordinary method but using 4-(2-chloropyridin-3-yloxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 242 and pyrazine-2-carboxylic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:15]=2)[CH2:9]1)=O)(C)(C)C.[ClH:27]>>[ClH:27].[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[N:15]=[C:14]([CH:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)[O:18][N:17]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(-c2noc(C3CCCN(C(=O)OC(C)(C)C)C3)n2)cc1
Agent: Cl
Product: COc1ccc(-c2noc(C3CCCNC3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
3-[3-(4-Methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.39 g, 1.08 mmol) was dissolved in 2 ml of 4N HCl (dioxane solution). The resulting reaction mixture was stirred at R.T. for 1 h and concentrated to afford 0.320 g (100%) of 3-[3-(4-Methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidine hydrochloride as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[I-].[K+].[Cl-].[Cl-].[Cl-].[Al+3]>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(F)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [I-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(O)cc1F
Temperature: 40 °C
Reaction time: 3 h
Yield: 28.6 %

Procedure:
2-Fluoro-4-methoxy-benzaldehyde (1 g, 6.49 mmol) was added to a suspension of anhydrous potassium iodide (2.15 g, 13 mmol) and aluminum trichloride (1.04 g, 7.8 mmol) in anhydrous toluene (10 mL), and the mixture was stirred at 40° C. for 3 hours. Aluminum trichloride (2.15 g, 13 mmol) and anhydrous potassium iodide (0.86 g, 6.49 mmol) were added, and the mixture was stirred for 3 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (5×20 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (silica gel, hexanes/ethyl acetate 4:1) to give 2-fluoro-4-hydroxy-benzaldehyde as a white solid (260 mg, 29%). 1H NMR (200 MHz, Acetone-d6): δ 10.08 (s, 1H), 9.77 (b, 1H), 7.69 (t, 1H, J=8.4), 6.78 (dd, 1H, J=8.8, 2.6), 6.65 (dd, 1H, J=12.5, 2.2)ppm.
Reaction SMILES: N([CH:4]([C@@H:6]([C@@H:8](/[CH:10]=[CH:11]/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[OH:9])[NH2:7])[OH:5])=[N+]=[N-].S>N1C=CC=CC=1>[CH3:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]/[CH:11]=[CH:10]/[C@H:8]([OH:9])[C@@H:6]([NH2:7])[CH2:4][OH:5]
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@@H](N)C(O)N=[N+]=[N-]
Agent: S
Solvent: c1ccncc1
Product: CCCCCCCCCCCCC/C=C/[C@H](O)[C@@H](N)CO

Procedure:
The azidosphingosine was then reacted with hydrogen sulfide in pyridine (see Schmidt, Liebigs. Ann. Chem., 663-667 (1988) and U.S. Pat. No. 4,937,328, incorporated herein by reference) to yield L-threo-sphingosine. ##STR10##
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[Br-].[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([Zn+])=[N:25][CH:26]=1.[K+].[K+].[K+].C(N(CC([O-])=O)CC(O)=O)CN(CC([O-])=O)CC([O-])=O.ClCCl>O1CCCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([C:2]2[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]([CH:14]=2)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[N:25][CH:26]=1
Reactant: Cc1ccc([Zn+])nc1
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC(C)(C)C)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)[O-]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)OC(C)(C)C)cc(-c2ccc(C)cn2)c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl methyl 5-bromoisophthalate (10.6 g, 33.6 mmol) and bis(tri-tert-butylphosphine)palladium(0) (0.31 g, 0.61 mmol) in tetrahydrofuran (160 mL) was added 5-methyl-2-pyridylzinc bromide (0.5 M in THF; 121 mL, 60.5 mmol). The reaction mixture was heated to 60° C. After 18 h, the reaction was cooled to ambient temperature. Aqueous ethylenediaminetetraacetic acid tripotassium salt (0.4 M, 100 mL) and dichloromethane (100 mL) were added. The mixture was stirred for 15 min and the organic solvent was evaporated. The mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (99% hexanes/ethyl acetate→50% hexanes/ethyl acetate) gave the title compound. MS 328.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](F)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[N:12]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>CC(O)C>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([N:15]3[CH2:16][CH2:17][CH2:18][N:12]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][CH2:14]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: Fc1ccc2ncc(Br)n2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc3ncc(Br)n3n2)CC1
Yield: 195.9 %

Procedure:
A stirred solution of 3-bromo-6-fluoroimidazo[1,2-b]pyridazine (1.6 g, 7.6 mmol), tert-butyl 1,4-diazepane-1-carboxylate [112275-50-0] (4.4 mL, 22.6 mmol), and Hunig's base [7087-68-5] (5.3 mL, 30.4 mmol) in 2-propanol (25 mL) was heated to 65° C. for 3d then partitioned between brine and ethyl acetate. The extract was dried (CaSO4) and evaporated to provide 5.9 g of clear orange liquid which was flash chromatographed (silica gel eluted with 10% (v/v) methanol/ethyl acetate) and crystallized from ethyl acetate/heptane to afford 2.0 g of white powder, mp. 101-102° C. 1H NMR (400 MHz, DMSO-d6) δ ppm (rotomers present) 1.03 (s, 5H) 1.17 (s, 4H) 1.73 (br. s., 1H) 1.85 (br. s., 1H) 2.43-2.47 (m, 1H) 3.20-3.29 (m, 3H) 3.49 (d, J=5.51 Hz, 1H) 3.55-3.66 (m, 3H) 3.70-3.79 (m, 2H) 7.05 (d, J=9.92 Hz, 1H) 7.49 (d, J=7.28 Hz, 1H) 7.78 (d, J=9.70 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm (rotomers present) 24.50, 24.83, 27.45, 27.61, 44.10, 44.78, 44.83, 45.33, 47.58, 47.74, 48.01, 48.09, 78.11, 78.27, 98.80, 109.23, 109.61, 125.65, 125.77, 130.81, 130.89, 136.07, 153.01, 153.18, 153.90, 154.19. LRMS (ESI) m/z 396.1/398.1 [(M+H)]+, calc'd for C16H22BrN5O2: 396.29.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:16]=[CH:15][O:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[C:19]([CH:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)[S:20][C:21]=1[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[N:23]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[C:3]([C:17]2[N:18]=[C:19]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[N:23]=2)=[CH:4][CH:5]=[CH:6][C:7]=1[NH:8][S:9]([C:12]1[CH:16]=[CH:15][O:14][CH:13]=1)(=[O:10])=[O:11]
Reactant: Cc1nccc(-c2sc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nccc(-c2sc(C3CCNCC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1
Reaction time: 1 h
Yield: 64.6 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate (115 mg, 0.192 mmol) in dichloromethane (2 mL) was added TFA (0.015 mL, 0.192 mmol), and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated and the residue was purified using RP-HPLC. The TFA salt was neutralized to give 62 mg of the title compound. MS (ESI): 500.3 [M+1]+.
Reaction SMILES: C1(C)C=CC=CC=1.[O:8]([C:15]1[CH:16]=[C:17]([N:21]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32](Br)[CH:31]=2)[CH2:22][CH:23]([OH:28])[C:24]([F:27])([F:26])[F:25])[CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:37][C:38]([F:49])([F:48])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CCO.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.CN(C=O)C>[O:8]([C:15]1[CH:16]=[C:17]([N:21]([CH2:29][C:30]2[CH:31]=[C:32]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[C:38]([F:49])([F:48])[F:37])[CH:33]=[CH:34][CH:35]=2)[CH2:22][CH:23]([OH:28])[C:24]([F:27])([F:26])[F:25])[CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: OC(CN(Cc1cccc(Br)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: OC(CN(Cc1cccc(-c2ccccc2C(F)(F)F)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F

Procedure:
To a toluene (8 mL) solution of 3-[(3-phenoxyphenyl)[[3-bromophenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol (0.51 g, 1.1 mmol) from EX-595B was added 2-(tri-fluoromethyl)phenylboronic acid (0.33 g, 1.7 mmol) and DMF (3 mL). To the resulting solution was added K2CO3 (0.31 g, 2.2 mmol) and Pd(PPh3)4 (0.060 g, 0.05 mmol). The slurry was heated to reflux under argon for 18 h. The cooled mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0.32 g (55%) of the desired 3-[(3-phenoxyphenyl)[[(2′-(trifluoromethyl)[1,140 -biphenyl]-3-yl]methyl]amino]-1,1,1-tri-fluoro-2-propanol product as a colorless oil. Anal. calcd. for C29H23NO2F6.0.8 EtOH: C, 64.67; H, 4.93; N, 2.46. Found: C, 64.53; H, 4.69; N, 2.49. HRMS calcd. 532.1711 [M+H]+, found: 532.1708. 1H NMR (C6D6) δ1.72 (d, 1H), 3.17 (dd, 1H), 3.46 (dd, 1H), 3.72 (m, 1H), 4.23 (s, 2H), 6.33 (dd, 1H), 6.43 (dd, 1H), 6.52 (t, 1H) 6.82 (m, 2H), 6.9-7.1 (m, 11H), 7.43 (d, 1H).