Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:52]=[O:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:54]=[O:55].[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][C:48]([F:50])([F:51])[F:49])=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@:10]1([CH2:54][OH:55])[CH:52]=[O:53])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)O[C@H](C=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)O[C@@](C=O)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
(2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 6n (1.21 g, 1.63 mmol) was dissolved in 12 mL 1,4-dioxane, followed by addition of 2.65 mL 37% formaldehyde solution and dropwise addition of 4.89 mL 1 M sodium hydroxide. The reaction mixture was stirred for 16 hours at 70° C. Thereafter, the reaction mixture was concentrated under reduced pressure and was partitioned after 30 mL of saturated sodium chloride solution were added. The aqueous phase was extracted with ethyl acetate (30 mL×3) and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydro-pyran-2-carbaldehyde 6p (1.27 g, pale yellow grease), which was used directly in the next step without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][C:21]([CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:22][CH:23]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[N:20][C:21]([CH2:24][N:25]4[CH2:26][CH2:27][CH2:28][CH2:29]4)=[CH:22][CH:23]=2)=[CH:3][C:2]([C:35]2[CH:36]=[C:31]([Cl:30])[C:32]([OH:47])=[C:33]([Cl:46])[CH:34]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Nc1ccc(CN2CCCC2)nc1)C1CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: O=C(c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(CN2CCCC2)nc1)C1CC1
Yield: 63.7 %

Procedure:
Following general procedure F, {6-Bromo-4-[6-(pyrrolidin-1-ylmethyl)pyridin-3-ylamino]quinolin-3-yl}(cyclopropyl)methanone (45 mg, 0.100 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.150 mmol) to afford the desired product (34 mg, 64%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.40 (s, 1H), 8.72 (d, J=2.5 Hz, 1H), 8.30 (dd, J=8.8, 2.0 Hz, 1H), 8.16-8.06 (m, 2H), 7.96 (dd, J=8.3, 2.5 Hz, 1H), 7.65 (d, J=8.3 Hz, 1H), 7.46 (s, 2H), 4.65 (s, 2H), 3.63-3.59 (m, 2H), 3.21-3.12 (m, 2H), 2.85-2.76 (m, 1H), 2.20-2.16 (m, 2H), 2.09-2.01 (m, 2H), 1.20-1.10 (m, 4H); ESI MS m/z 533 [C29H26Cl2N4O2+H]+; HPLC 98.8% (AUC), tR=10.76 min.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[C:5]([Br:11])=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].[CH3:17][N:18](C)C=O>>[Br:11][C:5]1[C:6]([CH2:8][CH2:9][CH3:10])=[CH:7][C:2]([C:17]#[N:18])=[N:3][CH:4]=1
Reactant: CCCc1cc(Br)ncc1Br
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCc1cc(C#N)ncc1Br
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
To a solution of 2,5-dibromo-4-propylpyridine (100 mg, 0.444 mmol) in N,N-dimethylformamide (0.9 mL), dinitrile zinc (57 mg, 0.449 mmol) and tetrakistriphenylphosphine palladium (25 mg, 0.0222 mmol) were added at room temperature, and the mixture was stirred under microwave irradiation at 100° C. for 20 minutes. The reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, and extracted with hexane/ethyl acetate (4/1). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (60 mg (yield 60%)) was obtained as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:22]=O)=[N:11][CH:12]=[C:13]([N:15]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[N:16]3)[N:14]=2)=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:22]=[N:25][OH:26])=[N:11][CH:12]=[C:13]([N:15]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[N:16]3)[N:14]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1cc(C)n(-c2cnc(C=O)c(Nc3ccc(Cl)cc3)n2)n1
Agent: Cl
Solvent: CCO
Product: Cc1cc(C)n(-c2cnc(C=NO)c(Nc3ccc(Cl)cc3)n2)n1
Reaction time: 0.25 h
Yield: 76.7 %

Procedure:
3-(4-Chloro-phenylamino)-5-(3,5-dimethyl-pyrazol-1-yl) -pyrazine-2-carbaldehyde (100 mg, 0.27 mmol) was dissolved in ethanol (99%, 10 mL) and hydroxylamine, hydrochloride (20 mg, 0.27 mmol) was added. The mixture was heated to reflux for 3 hours and concentrated in vacuo. Ethyl acetate (30 mL) and aqeuous sodium carbonate (20 mL) were added and stirred for 15 minutes. The layers were separated and the organic phase was washed with brine, dried over sodium sulphate, filtrated and concentrated in vacuo to give 3-(4-chloro-phenylamino)-5-(3,5-dimethyl-pyrazol-1-yl)-pyrazine-2-carbaldehyde oxime (71 mg, 76%) as an orange solid.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[CH2:3][CH2:4][C:5]([O-:7])=[O:6].[Na+].[H-].[Na+].[C:18]([C:20]1[CH:42]=[CH:41][C:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2CCC(OC(C)(C)C)=O)=[CH:22][C:21]=1F)#[N:19]>O1CCCC1>[C:5]([CH2:4][CH2:3][C:30]1[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=1)[CH2:25][O:24][C:23]1[CH:41]=[CH:42][C:20]([C:18]#[N:19])=[C:21]([CH:22]=1)[O:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])([OH:7])=[O:6]
Reactant: Cc1ccccc1C(O)CCC(=O)[O-]
Reactant: CC(C)(C)OC(=O)CCc1ccccc1COc1ccc(C#N)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(CCC(=O)O)Oc1cc(OCc2cccc(CCC(=O)O)c2)ccc1C#N
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 60.9 %

Procedure:
A solution of dry sodium (RS)-4-hydroxy-4-(2-methylphenyl)butanoate (0.18 g) in dry tetrahydrofuran (50 mL) is treated with sodium hydride and stirred at 60° C. for 15 minutes. tert-Butyl 3-[(4-cyano-3-fluoro-phenoxymethyl)phenyl]propionate (0.2 g) is added and the mixture heated at reflux for 4 hours. After standing at room temperature for 18 hours the reaction mixture is filtered. Ethyl acetate (50 mL) and 1 N hydrochloric acid (50 mL) are added to the filtrate and the organic phase is separated. The organic phase is washed with water (10 mL), dried over magnesium sulphate, evaporated and the residue purified by flash chromatography on silica eluting with a mixture of dichloromethane and methanol (95:5 v/v). Fractions homogeneous in the required product are combined and evaporated. The residue is dissolved in ether and the solution washed with 1% sodium bicarbonate solution, 0.5 N hydrochloric acid, water, dried over magnesium sulphate and evaporated. The resulting colourless gum is crystallised from a mixture of cyclohexane and ethyl acetate to give (RS)-4-{5-[3-(2-carboxyethyl)benzyloxy]-2-cyano-phenoxy}-4-(2-methylphenyl)butanoic acid (0.12 g) m.p. 136-137° C. [Elemental analysis:- C,71.4; H,6.23; N,2.91%. Calculated:- C,71.0; H,5.75; N,2.96%].
Reaction SMILES: N1C=CC=CC=1NC1C=CC=CC=1N.[Cl:15]C1C=C(C=CC=1)/C=C/C(Cl)=O.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1/[CH:42]=[CH:43]/[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[ClH:50]>CO>[ClH:15].[Cl:50][C:46]1[CH:45]=[C:44]([CH:49]=[CH:48][CH:47]=1)/[CH:43]=[CH:42]/[C:34]1[N:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=1
Reactant: O=C(Cl)/C=C/c1cccc(Cl)c1
Reactant: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Agent: Nc1ccccc1Nc1ccccn1
Solvent: CO
Product: Clc1cccc(/C=C/c2nc3ccccc3n2-c2ccccn2)c1

Procedure:
Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-3-chlorocinnamoyl chloride (Amino, Y.; Kawada, K.; Toi, K.; Kumashiro, I.; Fukushima, K. Chem. Pharm. Bull., 1988, 36, 4426) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([O:24][CH:25]([CH3:27])[CH3:26])[CH:23]=1)[C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:12].[N:28]1([C:32]([C:34]2[CH:35]=[C:36]([Cl:41])[C:37](Cl)=[N:38][CH:39]=2)=[O:33])[CH2:31][CH2:30][CH2:29]1>C(#N)C>[N:28]1([C:32]([C:34]2[CH:35]=[C:36]([Cl:41])[C:37]([O:7][C:8]3[CH:9]=[C:10]([CH:21]=[C:22]([O:24][CH:25]([CH3:27])[CH3:26])[CH:23]=3)[C:11]([NH:13][C:14]3[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=3)=[O:12])=[N:38][CH:39]=2)=[O:33])[CH2:31][CH2:30][CH2:29]1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(OC(C)C)c2)cn1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1cnc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCC4)cc3Cl)cc(OC(C)C)c2)cn1
Temperature: 120 °C
Yield: 69.3 %

Procedure:
Cesium carbonate (489 mg, 1.5 mmol) was added to a solution of 3-hydroxy-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide (144 mg, 0.5 mmol) and 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (173 mg, 0.75 mmol) in acetonitrile (5 mL) and the stirred mixture heated at 120° C. in a microwave reactor for 1 hour. The mixture was cooled to RT and ambient pressure, the acetonitrile evaporated in vacuo, the residue partitioned between water (25 mL) and ethyl acetate (50 mL). The organic layer was washed with brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with 75% ethyl acetate in isohexane, to give the desired compound (167 mg). 1H NMR δ (CDCl3): 1.3 (d, 6H), 2.3 (m, 2H), 2.5 (s, 3H), 4.1-4.3 (m, 4H), 4.55 (m, 1H), 6.85 (d, 1H), 7.2 (d, 1H), 7.3 (s, 1H), 8.05 (s, 1H), 8.1 (s, 1H), 8.2 (s, 1H) 8.3 (s, 1H) and 9.45 (s, 1H). m/z 482 (M+H)+.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([S:23][C:24]4[CH:44]=[CH:43][C:27]5[N:28]=[C:29]([NH:31][C:32]([NH:34][CH2:35][CH2:36][N:37]6[CH2:42][CH2:41][O:40][CH2:39][CH2:38]6)=[O:33])[S:30][C:26]=5[CH:25]=4)=[N:21][N:22]=3)[N:19]=2)=[CH:10][CH:9]=1.I([O-])(=O)(=O)=[O:46].[Na+]>O.C(O)(=O)C>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([S:23][C:24]4[CH:44]=[CH:43][C:27]5[N:28]=[C:29]([NH:31][C:32]([NH:34][CH2:35][CH2:36][N+:37]6([O-:46])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]6)=[O:33])[S:30][C:26]=5[CH:25]=4)=[N:21][N:22]=3)[N:19]=2)=[CH:10][CH:9]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=C(NCCN1CCOCC1)Nc1nc2ccc(Sc3nnc4ccc(-c5ccc(F)cc5)nn34)cc2s1
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: O=C(NCC[N+]1([O-])CCOCC1)Nc1nc2ccc(Sc3nnc4ccc(-c5ccc(F)cc5)nn34)cc2s1
Temperature: 20 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
116 mg of periodate of sodium in 0.5 cm3 of water are added to a mixture of 200 mg of 1-(6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea in 5 cm3 of acetic acid at 20° C. After an overnight period, the precipitate is filtered off. The white powder obtained is a mixture containing oxidized product and starting product. This mixture is taken up in 10 cm3 of acetic acid with 155 mg of sodium periodate dissolved in 1 cm3 of water. The mixture is left to stir overnight at 20° C. The precipitate is then filtered off and then washed successively with diisopropyl ether and with diethyl ether. 155 mg of white powder of 1-(6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)-3-[2-(4-oxidomorpholin-4-yl)ethyl]urea are obtained, the characteristics of which are as follows:
Reaction SMILES: Cl.[CH:2]([C@H:5]1[NH:10][CH2:9][CH2:8][NH:7][C:6]1=[O:11])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.Cl[C:22]1[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=1.[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[CH:2]([C@H:5]1[N:10]([C:22]2[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=2)[CH2:9][CH2:8][NH:7][C:6]1=[O:11])([CH3:4])[CH3:3]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CC(C)[C@H]1NCCNC1=O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)[C@@H]1C(=O)NCCN1c1nccc(C(F)(F)F)n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a solution of (R)-3-isopropylpiperazin-2-one hydrochloride (2.61 g, 14.62 mmol) and iPr2NEt (7.60 mL, 43.86 mmol) in DMF (20 mL) was added a solution of 2-chloro-4-(trifluoromethyl)pyrimidine (3.47 g, 19.00 mmol) in DMF (2 mL). The resulting solution was stirred at 100° C. under N2 for 3 h at which point the reaction was deemed complete by LC-MS. Sat. aq. NH4Cl (30 mL) was added to quench the reaction, followed by addition of EtOAc (30 mL). The EtOAc layer was separated and the aqueous layer was extracted with EtOAc (3×20 mL). The EtOAc layers were combined, dried using Na2SO4 and evaporated to give nearly pure crude product. Purification on a silica cartridge using ISCO FCC eluting with 100% EtOAc gave 4.03 grams of (R)-3-isopropyl-4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (96%) as a slightly orange thick oil. LC-MS m/z 289.17 [M+H]+. 1H NMR (CDCl3, 400 MHz): δ 8.52 (d, J=4.8 Hz, 1H), 6.82 (d, J=4.4 Hz, 1H), 6.56 (br, 1H), 5.20 (d, J=6.8 Hz, 1H), 4.83-4.77 (m, 1H), 3.55-3.37 (m, 3H), 2.49-2.41 (m, 1H), 1.15 (d, J=6.8 Hz, 3H), 1.04 (d, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[NH:11][C:12]=2C2C=CN=CC=2)=[CH:4][CH:3]=1.FC1C=CC(C2N=C(C3C=CC(C#N)=CC=3)NC=2[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=3)[NH:11][C:12]=2[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccccn3)[nH]2)cc1
Reactant: O=C(O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Product: O=C(O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccccn3)[nH]2)cc1

Procedure:
The title compound was prepared using the procedure in U.S. Pat. No. 5,656,644 (Example 9) to prepare 4- [4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2yl]benzoic acid except using 4-[4-(4-fluorophenyl)-5-(2-pyridyl)-1H-imidazol-2yl]benzonitrile. ESMS (M+H)+=360.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[N:15]=[C:14](F)[CH:13]=[CH:12][C:8]=2[N:9]=[CH:10][N:11]=1.[NH3:20]>C(O)C>[NH2:20][C:14]1[CH:13]=[CH:12][C:8]2[N:9]=[CH:10][N:11]=[C:6]([NH:5][C:4]3[CH:17]=[CH:18][CH:19]=[C:2]([Br:1])[CH:3]=3)[C:7]=2[N:15]=1
Reactant: Fc1ccc2ncnc(Nc3cccc(Br)c3)c2n1
Reactant: N
Solvent: CCO
Product: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2n1
Yield: 72 %

Procedure:
Reaction of 4-(3-bromoanilino)-6-fluoropyrido[3,2-d]pyrimidine (0.12 g, 0.38 mmol)(described in a previous experimental) with a saturated solution of ammonia in ethanol in a pressure vessel at 100° C. for 18 h gives 6-amino-4-(3-bromoanilino)pyrido[3,2-d]pyrimidine, (87 mg, 72%). 1H NMR (CDCl3) δ 8.76 (1H, brs), 8.64 (1H, s), 8.23 (1H, brs), 7.93 (1H, d, J=9.0 Hz), 7.81 (1H, dt, Jd=7.7 Hz, Jt=1.8 Hz), 7.28-7.22 (2H, m), 7.00 (1H, d, J=9.0 Hz), 4.90 (2H, brs).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:30][C:29]([CH2:31][OH:32])=[N:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+]>C(#N)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:30][C:29]([CH:31]=[O:32])=[N:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3nnc(CO)s3)[nH]2)cc1)C1CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=Cc1nnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
To a solution of [5-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl]methanol (700 mg) in acetonitrile (10 mL) was added Dess-Martin reagent (752 mg), and the mixture was stirred at 80° C. for 30 min. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was stirred for 20 min. The insoluble material was removed by filtration through celite, and the filtrate was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give the title compound (700 mg, yield 100%) as a yellow amorphous solid.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([OH:10])=O)#[N:2].C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[F:20][C:21]([F:33])([F:32])[C:22]1[CH:23]=[CH:24][C:25]([C:28](=[N:30]O)[NH2:29])=[N:26][CH:27]=1>CN(C)C=O.N1C=CC=CC=1>[C:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[O:10][N:30]=[C:28]([C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:33])([F:20])[F:32])=[CH:27][N:26]=2)[N:29]=1)#[N:2]
Reactant: NC(=NO)c1ccc(C(F)(F)F)cn1
Reactant: N#Cc1ccsc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccsc1-c1nc(-c2ccc(C(F)(F)F)cn2)no1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.2 %

Procedure:
To a stirred solution of 3-cyano-thiophene-2-carboxylic acid (42.5 mg, 0.278 mmol) and methylene chloride (1.5 mL) in an ice bath under argon, was added oxalyl chloride (205 μL, 0.410 mmol) over 2 min and then 2 drops of dimethylformamide. The solution was stirred for 5 min, the ice bath was removed, and the solution was stirred for 1 h. The solution was concentrated to dryness to yield a white solid. To the solid was added 5-trifluoromethyl-pyridine-2-amidoxime (56.4 mg, 0.275 mmol) and pyridine (1.6 mL), and the resultant solution was stirred for 10 min at ambient temperature. The solution was then refluxed for 21 h. The solution was cooled to room temperature and the product was precipitated by addition of 5 mL of deionized water. The precipitate was filtered, washed with deionized water, and dried under vacuum to yield 38.3 mg (43%) of the title compound as a pink solid. 1H NMR (CDCl3): 9.09 (m, 1H), 8.40 (d, J=8.25 Hz, 1H), 8.16 (dd, J=8.24, 2.20 Hz, 1H), 7.80 (d, J=5.22 Hz, 1H), 7.52 (d, J=5.22 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]2[N:12]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:11]=[CH:10][C:9]=2[CH:21]([CH3:23])[CH3:22])=[CH:4][C:3]=1[CH3:26].C([Li])CCC.CN(C)[CH:34]=[O:35].[Cl-].[NH4+]>C1COCC1>[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[N:12]1[C:8]([CH2:7][O:6][C:5]2[CH:24]=[CH:25][C:2]([CH:34]=[O:35])=[C:3]([CH3:26])[CH:4]=2)=[C:9]([CH:21]([CH3:23])[CH3:22])[CH:10]=[N:11]1
Reactant: CN(C)C=O
Reactant: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1C=O
Reaction time: 0.5 h
Yield: 14 %

Procedure:
To a −78° C. solution of 5-(4-Bromo-3-methyl-phenoxymethyl)-1-(2,6-dichloro-phenyl)-4-isopropyl-1H-pyrazole (906 mg, 2.0 mmol) in anhydrous THF is added 1.6 M n-butyllithium (1.35 mL). After 30 minutes, N,N-dimethylformamide is added (0.5 mL, 6.4 mmol). After 30 minutes, saturated aqueous ammonium chloride is added. The mixture is extracted with ethyl acetate (2×). The combined ethyl acetate layers are dried (MgSO4) and concentrated under reduced pressure. The crude residue is purified via flash chromatography (ethyl acetate/heptane gradient) to afford the title compound (110 mg, 14%). LC-ES/MS m/e 403.0 (M+1).
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([S:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:6][C:5]=2[N:26]=1.C(ON=O)CC(C)C.C(Br)(Br)[Br:36]>C(#N)C>[C:20]1([CH2:19][S:18][C:7]2[N:8]=[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])[C:4]3[S:3][C:2]([Br:36])=[N:26][C:5]=3[N:6]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)C[C@H](CO)Nc1nc(SCc2ccccc2)nc2nc(N)sc12
Reactant: BrC(Br)Br
Agent: CC(C)CCON=O
Solvent: CC#N
Product: CC(C)C[C@H](CO)Nc1nc(SCc2ccccc2)nc2nc(Br)sc12
Temperature: 60 °C
Yield: 40 %

Procedure:
To a suspension of (R)-2-(2-amino-5-phenylmethylthio-thiazolo[4,5-d]pyrimidin-7-ylamino)-4-methyl-pentan-1-ol (WO 00/09511) (131 mg, 0.34 mmol) in bromoform (6 mL) and anhydrous acetonitrile (2.5 mL), isoamylnitrite (158 μL, 1.2 mmol) was added. The mixture was heated at 60° C. under a nitrogen atmosphere for 30 minutes followed by evaporation of the solvent. The crude, red solid was flash chromatographed on silica (eluent—ethyl acetate:dichloromethane, 10:90) and the product was dried in vacuo at 50° C. overnight, resulting in 61 mg (40% yield) of the title compound as a brown solid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Br:5][C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][NH:12][C:9]2=[N:10][CH:11]=1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[Br:5][C:6]1[CH:7]=[C:8]2[C:14]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:22])=[CH:13][NH:12][C:9]2=[N:10][CH:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1c[nH]c2ncc(Br)cc12
Reaction time: 0.75 h
Yield: 40 %

Procedure:
To a suspension of AlCl3 (338 mg, 2.54 mmol) in dichloromethane (10 mL) was added 5-bromo-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.507 mmol). After stirring for 45 min, benzoyl chloride (0.3 mL, 2.54 mmol) was added and the reaction mixture was stirred for 3 h, before quenching with MeOH at 0° C. The mixture was concentrated in vacuum, the pH was changed to 4 by addition of 1N aqueous NaOH, and the aqueous layer was extracted twice with EtOAc. The organic layer was dried over MgSO4, filtered and adsorbed on silica gel. Purification on silica gel with a gradient of EtOAc/hexanes afforded (5-bromo-1H-pyrrolo[2,3-b]pyridine-3-yl)-phenyl-methanone as a white solid (61 mg, 40% yield).