Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH:35]=O)=[CH:15][N:16]3[CH2:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][C:21]=3[O:33][CH3:34])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:37]([CH2:42][CH:43]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:39][CH2:40][CH3:41])=[O:38]>O1CCOCC1>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH:35]=[C:42]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:43])=[CH:15][N:16]3[CH2:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])=[CH:22][C:21]=3[O:33][CH3:34])=[CH:12][CH:11]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(C(=O)OC(C)(C)C)ccc1Cn1cc(C=O)c2ccc(C(=O)NCC3CCCC3)cc21
Solvent: C1COCCO1
Product: CCOC(=O)C(C)=Cc1cn(Cc2ccc(C(=O)OC(C)(C)C)cc2OC)c2cc(C(=O)NCC3CCCC3)ccc12
Yield: 100.6 %

Procedure:
A solution of t-butyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-formylindol-1-ylmethyl]3-methoxybenzoate (Example 1, part(f)) (2.8 g) and (carbethoxyethylidene)triphenylphosphorane (4.6 g) in dioxane (29 ml) was heated at reflux for 18 hours. The solvent was evaporated. The resultant residue was purified by flash chromatography on silica gel (192 ml), eluting with 1:4 ethyl acetate:hexane to give t-butyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-(2-ethoxycarbonyl-1-propenyl)indol-1-ylmethyl]-3-methoxybenzoate (3.3 g, 100%) as a light yellow solid; mp 118°-120°; NMR (80 MHz, CDCl3) 2.15(d, 3H, CCH3), 3.40(dd, 2H, NHCH2), 5.42(s, 2H, NCH2), 6.22(br t, 1H, NH), 6.78(d, 1H, Ar).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]#[N:9])[NH:4][C:3]=1[C:10]([OH:12])=O.S(Cl)([Cl:15])=O>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]#[N:9])[NH:4][C:3]=1[C:10]([Cl:15])=[O:12]
Reactant: N#Cc1[nH]c(C(=O)O)c(Cl)c1Cl
Reactant: O=S(Cl)Cl
Product: N#Cc1[nH]c(C(=O)Cl)c(Cl)c1Cl

Procedure:
3,4-Dichloro-5-cyano-1H-pyrrole-2-carboxylic acid (Intermediate 131, 0.9 g, 0.2 mmol) was dissolved in excess thionyl chloride (5 ml) and heated to reflux for 30 minutes. The reaction mixture was concentrated and the residue was dissolved in THF and concentrated (×2). The solid (0.82 g, 89%) was pumped to dryness and stored under argon.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[CH:17][CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[Br:20][C:21]1[C:22]([NH2:28])=[N:23][CH:24]=[N:25][C:26]=1Cl.[F-].[Cs+].C(N(CC)C(C)C)(C)C>>[NH2:28][C:22]1[N:23]=[CH:24][N:25]=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[CH:17][CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[C:21]=1[Br:20]
Reactant: Nc1ncnc(Cl)c1Br
Reactant: C[C@H](N)c1nn2cccc2c(=O)n1-c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1Br)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 71.1 %

Procedure:
(S)-2-(1-Aminoethyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (1.2 g, 4.72 mmol) was treated 5-bromo-6-chloropyrimidin-4-amine (2 g, 9.6 mmol), cesium fluoride (1.44 g, 9.48 mmol), N,N-diisopropylethylamine (4.2 mL, 24.11 mol) according to Preparation 13. The residue was purified by flash chromatography using Isolera® Purification System (0% to 50%, dichloromethane-ethyl acetate) to give 1.43 g (71% yield) of the title compound as a solid. Purity 100%.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[CH2:12]([O:14][C:15]1[CH:35]=[CH:34][C:18]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][CH:24]([CH:27]3[CH2:32][O:31][C:30](=[O:33])[CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[C:17]([F:36])[C:16]=1[F:37])[CH3:13].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:12]([O:14][C:15]1[CH:35]=[CH:34][C:18]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][CH:24]([CH:27]3[CH2:32][O:31][C:30]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])([OH:33])[CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[C:17]([F:36])[C:16]=1[F:37])[CH3:13]
Reactant: CCOc1ccc(OCC2CCC(C3CCC(=O)OC3)CC2)c(F)c1F
Reactant: C#C[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1ccc(OCC2CCC(C3CCC(O)(C#C[Si](C)(C)C)OC3)CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
2.55 g of trimethylsilylacetylene was dissolved in 20 mL THF, and then 15.7 mL of a 1.66 M hexane solution of n-butyllithium was added dropwise thereto at −70° C., followed by stirring at that temperature for 1 hour. To the resulting solution, a solution containing 9.12 g of 5-[4-(4-ethoxy-2,3-difluorophenoxymethyl)cyclohexyl]tetrahydropyran-2-one obtained in the twelfth step of Example 1 dissolved in 30 mL of THF was added dropwise at −70° C., followed by stirring at that temperature for 1 hour, and then the temperature of the solution was gradually increased to room temperature. The reaction product was poured into 50 mL of a saturated ammonium chloride aqueous solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water and concentrated under reduced pressure. The resulting brown residue was purified by silica gel column chromatography to provide 10.7 g of 5-[4-(4-ethoxy-2,3-difluorophenoxymethyl)cyclohexyl]-2-trimethylsilanylethynyltetrahydropyran-2-ol as a brown solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1.Cl[CH2:21][C:22]1[C:23]([CH3:39])=[N:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:38])([F:37])[F:36])[CH:29]=2)=[CH:26][CH:27]=1.O>CN(C)C=O>[CH3:39][C:23]1[C:22]([CH2:21][O:19][C:6]2[CH:7]=[CH:8][C:9]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[N:15]3)=[C:4]([CH3:3])[CH:5]=2)=[CH:27][CH:26]=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:37])([F:38])[F:36])[CH:29]=2)[N:24]=1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Reactant: Cc1nc(-c2cccc(OC(F)(F)F)c2)ccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(-c3cccc(OC(F)(F)F)c3)nc2C)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
28 mg (0.69 mmol) of 60% sodium hydride were added to at 0° C. to a solution of 153 mg (0.66 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 6.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 200 mg (0.66 mmol) 3-chloromethyl-2-methyl-6-(3-trifluoromethoxy-phenyl)-pyridine were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 16 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, n-heptane, and ether. The residue was dried at 40° C. in vacuum to give 234 mg (72%) of the title compound as slightly yellow powder.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1.[C:17]1([CH3:31])[CH:22]=[CH:21][C:20]([N:23]2[C:27](B(O)O)=[CH:26][CH:25]=[N:24]2)=[CH:19][CH:18]=1>>[C:10]1([N:7]2[C:6]3[CH:16]=[C:2]([C:27]4[N:23]([C:20]5[CH:21]=[CH:22][C:17]([CH3:31])=[CH:18][CH:19]=5)[N:24]=[CH:25][CH:26]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(-n2nccc2B(O)O)cc1
Reactant: Brc1ccc2ncn(-c3ccccc3)c2c1
Product: Cc1ccc(-n2nccc2-c2ccc3ncn(-c4ccccc4)c3c2)cc1

Procedure:
The title compound, off-white foam (36 mg, 28%), MS (ISP) m/z=351.3 [(M+H)+], was prepared in accordance with the general method of example 1 from 6-bromo-1-phenyl-1H-benzo[d]imidazole (intermediate E) (100 mg, 366 μmol) and 1-p-tolyl-1H-pyrazol-5-ylboronic acid (intermediate B) (96.2 mg, 476 μmol).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:21])/[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[S:17])=[C:9]([O:22][CH3:23])[C:8]([CH3:24])=[C:7]2[C:3]=1[C:4](=[O:25])[O:5][CH2:6]2.N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33].Cl>C(#N)C>[C:32]([O:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:21])/[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[S:17])=[C:9]([O:22][CH3:23])[C:8]([CH3:24])=[C:7]2[C:3]=1[C:4](=[O:25])[O:5][CH2:6]2)(=[O:34])[CH3:33]
Reactant: CCOC(=S)CC/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CCOC(=S)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1OC(C)=O)C(=O)OC2
Reaction time: 2 h

Procedure:
To a solution of 1.6 g of ethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-thiohexenoate in 120 ml of acetonitrile at 0° C. was added 0.74 ml of pyridine followed by 1.0 ml of acetyl chloride. After stirring for 2 hours the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic solution was dried over anhydrous magnesium sulfate and evaporated to an oil, which was triturated with ether to give ethyl (E)-6-(1,3-dihydro-4-acetoxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-thiohexenoate, m.p. 81°-84° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9])=O.Cl.[CH3:39][O:40][NH2:41]>N1C=CC=CC=1>[CH3:39][O:40][N:41]=[CH:1][C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9]
Reactant: CON
Reactant: O=Cc1cccc(CN(C(=O)c2cc(C(=O)O)c(C(=O)O)cc2C(=O)O)[C@H]2CCCc3ccccc32)c1
Agent: Cl
Solvent: c1ccncc1
Product: CON=Cc1cccc(CN(C(=O)c2cc(C(=O)O)c(C(=O)O)cc2C(=O)O)[C@H]2CCCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.2 %

Procedure:
The product from Example 76E (132 mg, 0.26 mmol) in pyridine (5 mL) was treated with O-methylhydroxylamine hydrochloride (26 mg, 0.32 mmol). After stirring for 1 hour at room temperature, the volatiles were evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 1N HCl, water, brine, dried (Na2SO4), filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 100:1:1 ethyl acetate:formic acid:water) to provide the title compound as a white solid (43 mg, 31%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[F:7][C:8]([F:14])([F:13])[C:9](OC)=[O:10]>CO>[F:7][C:8]([F:14])([F:13])[C:9]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6])=[O:10]
Reactant: COC(=O)C(F)(F)F
Reactant: NCCCCO
Solvent: CO
Product: O=C(NCCCCO)C(F)(F)F
Yield: 85.4 %

Procedure:
4-amino-1-butanol (15.0 g, 168.27 mmol) and methyl trifluoroacetate (82.96 mL, 824.55 mmol) were combined in methanol (250 mL) and heated at reflux for 2 hours. The reaction was concentrated to yield the title compound (26.6 g, 85.4%) as a clear oil which had the following properties: 1H NMR CDCl3 δ: 7.08 (brd s, 1H), 3.71 (t, J=5.4 Hz, 2H), 3.40 (q, J=6.2 and 6.2 Hz, 2H), 1.75-1.61 (m, 4H).
Reaction SMILES: CC(C)([O-])C.[K+].C1COCC1.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([N:25]3[CH:34]([CH3:35])[CH2:33][C:32]4[C:27](=[CH:28][C:29]([C:36]5[CH:40]=[CH:39][NH:38][N:37]=5)=[CH:30][CH:31]=4)[CH2:26]3)[N:22]=[C:21]([NH2:41])[N:20]=2)[CH2:15][CH2:14]1.Br[CH2:43][C:44]#[N:45]>CN(C=O)C>[NH2:41][C:21]1[N:22]=[C:23]([N:25]2[CH:34]([CH3:35])[CH2:33][C:32]3[C:27](=[CH:28][C:29]([C:36]4[CH:40]=[CH:39][N:38]([CH2:43][C:44]#[N:45])[N:37]=4)=[CH:30][CH:31]=3)[CH2:26]2)[CH:24]=[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]2)[N:20]=1
Reactant: CC1Cc2ccc(-c3cc[nH]n3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: N#CCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC1Cc2ccc(-c3ccn(CC#N)n3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Potassium tert-butoxide in THF (1.0 M, 74.2 uL, 0.0742 mmol) was added to a solution of 4-(4-methylpiperazin-1-yl)-6-[3-methyl-7-(1H-pyrazol-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine (15.0 mg, 0.0371 mmol) in DMF (0.3 mL) and stirred at r.t. for 10 min, and then bromoacetonitrile (3.71 uL, 0.0556 mmol) was added. The mixture was stirred at r.t. for 1 h. LCMS showed the reaction was complete. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=444.2.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH2:7][C:8](=[C:13]1[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([C:27]#[N:28])[C:21]=3[O:20][C:19]3[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[O:4].Cl.[NH2:32][OH:33].C(N(CC)CC)C>C(O)C>[OH:33][NH:32][C:27]([C:22]1[C:21]2[O:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[C:8]3[CH2:9][CH:10]4[N:5]([C:3](=[O:4])[C:2]([F:30])([F:29])[F:1])[CH:6]([CH2:12][CH2:11]4)[CH2:7]3)[C:26]=2[CH:25]=[CH:24][CH:23]=1)=[NH:28]
Reactant: NO
Reactant: N#Cc1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: N=C(NO)c1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F

Procedure:
A solution of 9-[8-(2,2,2-trifluoroacetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-4-carbonitrile in ethanol (0.1 to 2 M solution) may be treated with hydroxylamine hydrochloride (1 to 2 equiv) and triethylamine (2 to 3 equiv) and may be heated to reflux for a period of 1 to 10 hr. After cooling, the mixture may be evaporated under reduced pressure, and the residue may be partitioned between equal amounts of water and an organic solvent such as ethyl acetate. The organic layer may be separated, dried over an appropriate drying agent such as magnesium sulfate, filtered, and evaporated. The residue may be purified via column chromatography to yield Compound 1f.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[OH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:23][OH:24].[OH-].[K+]>O.O1CCCC1>[OH:24][CH2:23][C:10]1[C:9](=[O:8])[C:18]2[C:13](=[CH:14][C:15]([C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=2)[N:12]([CH3:5])[CH:11]=1
Reactant: OCc1cnc2cc(C(F)(F)F)ccc2c1O
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(CO)c(=O)c2ccc(C(F)(F)F)cc21
Reaction time: 3 h

Procedure:
Dimethyl sulphate (24.4 g.) was added over 5 minutes to a stirring solution of 4-hydroxy-3-hydroxymethyl-7-trifluoromethylquinoline (23.6 g.) and potassium hydroxide (16.3 g.) in a mixture of water (50 ml.) and tetrahydrofuran (50 ml.) at room temperature. After stirring for a further 3 hours at this temperature the solid product was collected. The filtrate was extracted with dichloromethane (3×200 ml.). The combined extracts were dried over anhydrous magnesium sulphate and evaporated to give a second crop of the solid. The combined solids were purified by high pressure liquid chromatography over silica gel, eluting with isopropanol: dichloromethane 10:90 at a flow rate of 200 ml. per minute. The same solvent was used for applying the product to silica gel. This procedure gave the novel 3-hydroxymethyl-1-methyl-7-trifluoromethyl-4-quinolone, m.p. 172°-175°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][OH:16])[N:14]=1)=[O:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH:15]=[O:16])[N:14]=1)=[O:8]
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CO)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1csc(NC(=O)NCc2cccc(F)c2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The 1-(3-fluorobenzyl)-3-(4-(hydroxymethyl)thiazol-2-yl) urea is taken up in DCM and cooled to 0° C. and Dess-Martin oxidant (1.1 equiv) was added. Stirred at ambient temperature for 1 hour. Washed with dilute Na2SO3. Removed solvent in vacuo to give 1-(3-fluorobenzyl)-3-(4-formylthiazol-2-yl)urea (used directly in next step).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:18]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[N:19]3)[O:11][C:12]=2[CH2:13][CH2:14][C:15](O)=[O:16])=[CH:4][CH:3]=1.ON1C2N=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[CH3:46][N:47]1[CH2:52][CH2:51][CH:50]([CH2:53][N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:49][CH2:48]1>O.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:18]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[N:19]3)[O:11][C:12]=2[CH2:13][CH2:14][C:15]([N:57]2[CH2:56][CH2:55][N:54]([CH2:53][CH:50]3[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]3)[CH2:59][CH2:58]2)=[O:16])=[CH:4][CH:3]=1
Reactant: Cc1cc(C)n(-c2nc(-c3ccc(Cl)cc3)c(CCC(=O)O)o2)n1
Reactant: CN1CCC(CN2CCNCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)n(-c2nc(-c3ccc(Cl)cc3)c(CCC(=O)N3CCN(CC4CCN(C)CC4)CC3)o2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
A mixture of 3-[4-(4-chlorophenyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-oxazolyl]propionic acid (51.5 mg), 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (41 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (46 mg), 4-[(1-methyl-4-piperidinyl)methyl]piperazine (60 mg) and N,N-dimethylformamide (0.5 ml) was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was concentrated, introduced into preparative HPLC and purified. Ethyl acetate was added to the obtained oil and the mixture was washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated to give 1-{3-[4-(4-chlorophenyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-oxazolyl]propanoyl}-4-[(1-methyl-4-piperidinyl)methyl]piperazine (54.5 mg, yield 72%). Recrystallization from ethanol-isopropyl ether gave colorless prism crystals. melting point: 126–127° c.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:10]=[C:9]([NH:11][C:12]([NH:14][C:15]2[N:16]=[C:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[S:18][CH:19]=2)=[O:13])[CH:8]=[CH:7][CH:6]=1)=[N+]=[N-]>CCO.[OH-].[OH-].[Pd+2]>[NH2:1][CH2:4][C:5]1[N:10]=[C:9]([NH:11][C:12]([NH:14][C:15]2[N:16]=[C:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[S:18][CH:19]=2)=[O:13])[CH:8]=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=NCc1cccc(NC(=O)Nc2csc(-c3ccncc3)n2)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: NCc1cccc(NC(=O)Nc2csc(-c3ccncc3)n2)n1
Temperature: 45 °C

Procedure:
Pd(OH)2 (70 mg, 0.5 mmol) was suspended in EtOH (5 mL) followed by adding N-(6-azidomethyl-2-pyridyl)-N′-[2-(4-pyridinyl)-4-thiazolyl]urea (70 mg, 0.198 mmol, Example 69) in EtOH (8 mL). The resulting mixture was heated at 45° C. under H2 balloon for 3 h. After cooling to RT, the mixture was filtered by passing through 2 layers of pleated filtered papers. Solvent was removed in vacuo to yield the final compound as a yellow solid. MS m/z: 327.3 (M+H). Calc'd. for C15H14N6OS-326.38.
Reaction SMILES: BrBr.[S-:3][C:4]#[N:5].[Na+].[NH2:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[Cl:23])[N:11]=[C:10]([C:24]#[N:25])[CH:9]=1.O>CO>[NH2:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][C:14]=2[Cl:23])[N:11]=[C:10]([C:24]#[N:25])[C:9]=1[S:3][C:4]#[N:5]
Reactant: N#C[S-]
Reactant: N#Cc1cc(N)n(-c2ccc(C(F)(F)F)cc2Cl)n1
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#CSc1c(C#N)nn(-c2ccc(C(F)(F)F)cc2Cl)c1N
Temperature: 20 °C
Yield: 91.2 %

Procedure:
Bromine (0.5 ml) was added over 10 minutes to a stirred solution of sodium thiocyanate (1.7 g) in anhydrous methanol at −65° C. A solution of 5-amino-1-(2-chloro-4-(trifluoromethyl)phenyl]-1-H-pyrazole-3-carbonitrile (1.5 g) in anhydrous methanol was added over 10-minutes and the stirred mixture allowed to warm to 20° C. over 16-hours. After pouring into water the precipitate was collected and dried to give 5-amino-1-[2-chloro-4-(trifluoromethyl)phenyl]-4-thiocyanato-1H-pyrazole-3-carbonitrile (1.64 g). HPLC (C-18 column, eluting with 3:1 CH3CN/H2O at 1.0 ml/min.) showed the compound as a peak of 86.6% area at 5.11 minutes.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][CH:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[S:8]1.O>C1(C)C=CC=CC=1>[Br:2][CH2:6][CH:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[S:8]1
Reactant: BrP(Br)Br
Reactant: CC1(C)CC(CO)Sc2ccccc21
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CC(CBr)Sc2ccccc21
Reaction time: 1 h
Yield: 88 %

Procedure:
Phosphorus tribromide (1 ml, 10.7 mmol) is added drop by drop with a syringe at between 20 and 25° C. to a solution of the previous 6-(hydroxymethyl-4,4-dimethyl-3,4-dihydro-2H-1-benzothiopyrane (1.85 g, 8.9 mmol) in 6.2 ml of anhydrous toluene. The mixture was left to agitate for 1 hour and then hydrolysed at 0° C. by ice and then by water. This was then extracted with ethyl ether, dried over MgSO4, filtered and the solvents evaporated. 2.14 g of 6-(bromomethyl-4,4-dimethyl-3,4-dihydro-2H-1-benzothiopyrane is obtained (gross yield=88%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH:26][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: Nc1cccc(OCc2ccccc2)c1
Product: Cc1cc(Nc2cccc(OCc3ccccc3)c2)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) and 3-benzyloxyaniline (97 mg, 0.486 mmol) similar to Example 13 and isolated as a yellow oil (161 mg, 90%). 1H NMR (CDCl3): 8.78–8.76 (m, 1H), 8.48–8.45 (m, 1H), 7.79–7.74 (m, 1H), 7.68 (s, 1H), 7.42–7.29 (m, 6H), 7.24 (t, J=8.1 Hz, 1H), 7.10 (s, 1H), 6.92 (dd, J=0.8, 8.0 Hz, 1H), 6.77–6.74 (m, 1H), 6.58 (s, 1H), 5.04 (s, 2H), 2.42 (s, 3H).
Reaction SMILES: [CH:1](=O)[CH3:2].ClC(Cl)C.[C:8]1([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][C:18]([C:24]4[N:25]=[C:26]([CH2:34][CH:35]5[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]5)[N:27]5[CH:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=45)=[CH:19][CH:20]=3)[N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([N:38]1[CH2:39][CH2:40][CH:35]([CH2:34][C:26]2[N:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]3=[C:24]([C:18]3[CH:17]=[C:16]4[C:21]([CH:22]=[CH:23][C:14]([C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)=[N:15]4)=[CH:20][CH:19]=3)[N:25]=2)[CH2:36][CH2:37]1)[CH3:2]
Reactant: CC=O
Reactant: Nc1nccn2c(CC3CCNCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCN1CCC(Cc2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetaldehyde (6.76 mg, 0.15 mmol) in dichloroethane (5 mL, 2 equiv) was added to 1-(2-Phenyl-quinolin-7-yl)-3-piperidin-4-ylmethyl-imidazo[1,5-a]pyrazin-8-ylamine (100.00 mg, 0.23 mmol) and sodium triacetoxyborohydride (65.0 mg, 306.8 mmol). The reaction mixture was stirred at rt overnight. The crude product was purified by a 5 g Jones silica gel (dry loaded with silica, wetted with 100% CH2Cl2, eluted with 100% CH2Cl2 h 3% (7N NH3) in MeOH/CH2Cl2→6% (7N NH3) in MeOH/CH2Cl2) and afforded the desired product. 1H NMR (400 MHz, METHANOL-D) δ 8.38 (1H, d, J=8.66), 8.25 (1H, s), 8.08 (2H, dd, J=1.64 Hz, J=1.08), 8.00 (2H, m), 7.79 (1H, dd, J=2.06, J=1.70), 7.51 (1H, d, J=5.15), 7.44 (3H, m), 7.00 (1H, d, J=5.12), 3.06 (2H, d, J=10.88), 2.97 (2H, d, J=7.08), 2.54 (2H, d, J=5.80), 2.18 (2H, m), 1.98 (1H, m), 1.75 (2H, d, J=13.12), 1.43 (2H, m), 1.07 (3H, t); MS (ES+): m/z 435.12/436.10 (15/5) [MH+]; HPLC: tR=1.71 min (OpenLynx, polar—5 min).