Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:15]3[O:16][CH2:17][CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[N:13]4[C:14]=3[C:10]([C:11](=[O:25])[NH:12]4)=[CH:9][CH:8]=2)=[C:5]([CH3:26])[O:4][N:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:1][C:2]1[C:6]([C:7]2[C:15]3[O:16][CH2:17][CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[N:13]4[C:14]=3[C:10]([C:11]([O:25][CH3:27])=[N:12]4)=[CH:9][CH:8]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2c(=O)[nH]n3c2c1OCC3c1ccccn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1nn2c3c(c(-c4c(C)noc4C)ccc13)OCC2c1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 9-(3,5-dimethylisoxazol-4-yl)-3-pyridin-2-yl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-6(5H)-one (0.03 g, 0.086 mmol) in N,N-dimethylformamide (0.24 mL) at 0° C. was treated with potassium carbonate (0.024 g, 0.172 mmol) followed by dropwise addition of 0.2 M methyl iodide in N,N-dimethylformamide (0.517 mL, 0.103 mmol) and stirred at 0° C. for 30 min. The ice bath was removed and the reaction mixture was stirred for 1 h. The reaction mixture was treated with water (20 mL) and extracted with EtOAc (30 mL). The organic layer was separated and washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated to give a colorless residue. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) gave Example 6 (10 mg, 30%, first peak to elute) and Example 7 (8 mg, 20%, second peak to elute). Example 6: 1H NMR (500 MHz, DMSO-d6) δ 8.47 (d, J=4.4 Hz, 1H), 7.86-7.71 (m, 1H), 7.38-7.29 (m, 1H), 7.29-7.21 (m, 2H), 7.00 (d, J=8.0 Hz, 1H), 5.14 (dd, J=3.4 Hz, 1H), 4.93 (d, J=3.5 Hz, 2H), 3.08 (s, 3H), 2.30 (s, 3H), 2.13 (s, 3H); LCMS calculated for C20H19N4O3 (M+H)+: m/z=363.1. found: 363.1. Example 7: 1H NMR (500 MHz, DMSO-d6) δ 8.55 (d, J=4.1 Hz, 1H), 7.82-7.68 (m, 1H), 7.33 (dd, J=7.0, 5.2 Hz, 1H), 7.27 (d, J=8.3 Hz, 1H), 6.91 (d, J=8.3 Hz, 1H), 6.82 (d, J=7.9 Hz, 1H), 5.76-5.66 (m, 1H), 4.93-4.73 (m, 2H), 3.99 (s, 3H), 2.27 (s, 3H), 2.11 (s, 3H); LCMS calculated for C20H19N4O3 (M+H)+: m/z=363.1. found: 363.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N=C=NCCCN(C)C)C.[NH2:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([OH:35])=[O:34].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([NH:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([OH:35])=[O:34])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: Nc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)Nc1ccccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of commercially available (R)-tert-butoxycarbonylamino-phenyl-acetic acid (1.00 g, 3.98 mmol), dimethyl-pyridin-4-yl-amine (0.49 g, 3.98 mmol) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (0.84 g, 4.38 mmol) in anhydrous dichloromethane (30 mL), a solution of 2-aminobenzoic acid (0.55 g, 3.98 mmol) and triethylamine (0.56 mL, 4.38 mmol) in anhydrous dichloromethane (6 mL) was added drop wise at 0-5° C. The reaction was stirred at room temperature for 4 h, then the resulting solution was washed with 1N HCl solution, water and brine After drying over Na2SO4, the solvent was removed to give the intermediate 2-((R)-2-tert-butoxycarbonylamino-2-phenyl-acetylamino)-benzoic acid. To a solution of this intermediate in dry dichloromethane (20 mL), dimethyl-pyridin-4-yl-amine (0.19 g, 1.59 mmol) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (0.84 g, 4.38 mmol) were added. The mixture was stirred at room temperature for 2 h, then washed with 1N HCl solution, then with water and brine, dried over Na2SO4 and evaporated to dryiness. The intermediate [(R)-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-phenyl-methyl]-carbamic acid tert-butyl ester was dissolved in dry pyridine (5 mL) and aminoguanidine hydrogencarbonate (0.60 g, 4.38 mmol) was added. The mixture was heated under microwave condition at 180° C. for 30 minutes, the solvent was then evaporated and the crude purified by flash column chromatography on silica gel eluting with DCM/CH3OH 96/4, to afford title compound (0.16 g, 10% yield).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([CH:9](Br)[CH:10](Br)[C:11]#[N:12])=[CH:5][CH:4]=1.C[O-].[Na+].C[CH2:21][O:22]CC>CO>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:22][CH3:21])=[CH:10][C:11]#[N:12])=[CH:5][CH:4]=1
Reactant: CCOCC
Reactant: N#CC(Br)C(Br)c1ccc(C(F)(F)F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=CC#N)c1ccc(C(F)(F)F)cc1
Temperature: 5 °C
Reaction time: 33 h

Procedure:
3-(4-(Trifluoromethyl)phenyl)-2,3-dibromopropionitrile (2098 grams) was dissolved in methanol and chilled to 5° C. in an ice-bath. Next, over a 2 hour period, sodium methylate (95%) was added keeping the temperature between 5°-10° C. The reaction mixture was then allowed to warm to room temperature, was stirred for 33 hours, and was stripped to near dryness. Upon the addition of 8 l. ether the organic-inorganic mixture was slurried, slowly filtered, and the filtrate stripped again, resulting in a brown oil. NMR analysis confirmed that the oil was the desired mixture of products.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:16]=4[N:15]=[CH:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[N-:24]=[N+:25]=[N-:26].[Na+].[Cl-].[NH4+]>CN(C=O)C>[N:23]1[NH:24][N:25]=[N:26][C:22]=1[C:20]1[CH:19]=[CH:18][C:17]2[N:13]([CH2:12][C:10]3[CH:9]=[CH:8][C:6]4[N:7]=[C:3]([S:2][CH3:1])[S:4][C:5]=4[CH:11]=3)[CH:14]=[N:15][C:16]=2[CH:21]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CSc1nc2ccc(Cn3cnc4cc(C#N)ccc43)cc2s1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Cn3cnc4cc(-c5nn[nH]n5)ccc43)cc2s1
Temperature: 125 °C
Yield: 99.9 %

Procedure:
A suspension of 1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (694 mg, 2.1 mmol), sodium azide (403 mg, 6.3 mmol), and ammonium chloride (331 mg, 6.3 mmol) in DMF (3 mL) was heated in a sealed tube at 125° C. for 15 h. The mixture was cooled to rt and a precipitate formed. The solid was collected by filtration to afford 6-((5-(2H-tetrazol-5-yl)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (796 mg, 100%) as a yellow solid that did not require further purification. 1H NMR (500 MHz, DMSO-d6) δ 8.41 (s, 1H), 8.19 (s, 1H), 8.02 (s, 1H), 7.88 (dd, J=1.0, 8.4 Hz, 1H), 7.81 (d, J=8.6 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.45 (dd, J=1.4, 8.5 Hz, 1H), 7.15-7.30 (br s, 2H), 5.60 (s, 2H), 2.76 (s, 3H); LCMS (ESI) m/z 380 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH3:18])[C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[CH:10][C:5]=2[O:4][N:3]=1.[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH3:18])[C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:22]([C:21]4[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=4[Cl:19])=[O:23])=[N:15][CH:16]=3)=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Cc1cc2c(C)noc2cc1-c1ccc(N)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc2c(C)noc2cc1-c1ccc(NC(=O)c2ccccc2Cl)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a solution of 5-(3,5-dimethylbenzo[d]isoxazol-6-yl)-2-pyridylamine (105) (14.5 mg, 0.06 mmol) in 1 ml DCM was added 2-chlorobenzoyl chloride (16 μl, 0.12 mmol) followed by addition of DIEA (63 μl). The resulting solution was stirred at r.t. for 2 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (120 μl) at r.t. for 1 h before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished N-[5-(3,5-dimethylbenzo[d]isoxazol-6-yl)(2-pyridyl)](2-chlorophenyl)carboxamide (106) (17.1 mg, yield: 75.4%, purity>95%) as off-white solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:10](=[O:11])[CH2:9][N:8]([CH2:12][C:13]2[S:14][C:15]([C:18](=[N:24][OH:25])[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:16][CH:17]=2)[S:7]1(=[O:27])=[O:26].C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:25]/[N:24]=[C:18](/[C:15]1[S:14][C:13]([CH2:12][N:8]2[S:7](=[O:27])(=[O:26])[NH:6][C:10](=[O:11])[CH2:9]2)=[CH:17][CH:16]=1)\[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: COc1ccc(CN2C(=O)CN(Cc3ccc(C(CCC(C)C)=NO)s3)S2(=O)=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CC/C(=N\O)c1ccc(CN2CC(=O)NS2(=O)=O)s1
Reaction time: 0.25 h

Procedure:
The title E compound, 2-(2,4-dimethoxy-benzyl)-5-(5-{1-[-hydroxyimino]-4-methyl-pentyl}-thiophen-2-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (40 mg, 0.08 mmol) is stirred in equal volumes of CH2Cl2 and TFA (4 mL) at RT for 3 h. The volatiles are evaporated and the residue is stirred in equal volumes of MeCN/water (5 mL) for 15 min. The mixture is filtered through a 0.2, Acrodisc and the solvents are evaporated to dryness. The residue is triturated from hexane/Et2O (4:1) to afford 5-(5-{1-[(E)-hydroxyimino]-4-methyl-pentyl}-thiophen-2-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a light pink solid: [M+1]+=346.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:12][CH2:11][N:10]([C:13](=[O:24])[C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[O:22][CH3:23])[CH2:9]1)(=O)=O.[C:33]1([N:39]2[C:43]3([CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)[C:42](=[O:49])[NH:41][CH2:40]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[Cl:32][C:27]1[CH:26]=[C:25]([C:8]2([CH2:7][CH2:6][N:46]3[CH2:45][CH2:44][C:43]4([N:39]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH2:40][NH:41][C:42]4=[O:49])[CH2:48][CH2:47]3)[CH2:12][CH2:11][N:10]([C:13](=[O:24])[C:14]3[C:15]([O:22][CH3:23])=[CH:16][CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[CH2:9]2)[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: COc1cccc(OC)c1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccc(Cl)c(Cl)c2)C1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(OC)c1C(=O)N1CCC(CCN2CCC3(CC2)C(=O)NCN3c2ccccc2)(c2ccc(Cl)c(Cl)c2)C1
Yield: 51.2 %

Procedure:
2-[1-(2,6-Dimethoxy-benzoyl)-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl methanesulfonate (200 mg, 0.398 mmol), and 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (100 mg, 0.432 mmol) were dissolved in THF/H2O (4 mL/1 mL) and treated with potassium carbonate (110 mg, 0.796 mmol, 2 eq.) at reflux for 22 hours. The solution was concentrated in vacuo and the aqueous phase was extracted (3x) with dichloromethane. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (40 g) with a gradient from ethyl acetate to 10% methanol in dichloromethane to give 130 mg (51%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH:9](S(C3C=CC=CC=3)=O)[C:8]2=[O:21])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]=[CH:9][C:8]2=[O:21])=[CH:22][CH:23]=1
Reactant: O=C1C(S(=O)c2ccccc2)CCCN1Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1C=CCCN1Cc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 1-(4-fluorobenzyl)-3-(phenylsulfinyl)piperidin-2-one one (25 g, 74 mmol) in toluene (200 mL) was added anhydrous sodium carbonate (20 g, 190 mmol). The mixture was heated to reflux for 1.5 hours. The reaction mixture was cooled to ambient temperature and the solids were removed by filtration. The filtrate solvent was removed under vacuum and the residue was purified using silica gel column chromatography eluting with 3:1 EtOAc:hexanes. Appropriate fractions were combined and removal of the solvents under vacuum gave the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.26 (m, 2H), 7.01 (m, 2H), 6.56 (dt, J=9.9, 4.2 Hz, 1H), 6.00 (dt, J=9.7, 1.8 Hz, 1H), 4.59 (s, 2H), 3.32 (t, J=7.2 Hz, 2H), 2.33 (m, 2H).
Reaction SMILES: [C:1]1([CH:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([NH:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3C2CCCCO2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(O)C>[C:36]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([NH:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(NCCN1CCCCC1)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Agent: Cl
Solvent: CCO
Product: O=C(NCCN1CCCCC1)c1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
A solution of 6-[(2,2-diphenylethyl)amino]-N-[2-(1-piperidinyl)ethyl]-9-tetrahydro-2H-pyran-2-yl-9H-purine-2-carboxamide (Preparation 10) (420 mg, 0.76 mmol) in ethanol (20 ml) was treated with 2 M aqueous hydrochloric acid (0.9 ml). The mixture was heated under reflux for 30 minutes after which time a white precipitate had formed. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane and 10% weight by volume aqueous ammonia. The organic phase was separated, dried (anhydrous magnesium sulphate), filtered and evaporated under reduced pressure to afford the title compound as a white solid (319 mg).
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=1.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][Si:21]([CH3:23])([CH3:22])[C:24]#[C:25][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=1
Reactant: C#C[Si](C)(C)C
Reactant: FC(F)(F)Oc1cccc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
Add copper (I) iodide (45.0 mg, 0.24 mmol), bis(triphenylphosphine)palladium (II) dichloride (147.4 m g, 0.21 mmol) and triethylamine (2.37 mL, 16.8 mmol), to a solution of 1-bromo-3-trifluoromethoxybenzene (0.62 mL, 4.15 mmol) and trimethylsilylacetylene (0.78 mL, 5.4 mmol), in ethyl acetate (4 mL) and stir at 50° C. for 18h. Cool the reaction mixture to room temperature, concentrate and purify by silica gel chromatography, eluting with hexanes to give the title compound (1.07 g, 100%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:12]=1>>[CH3:27][C:25]1[NH:24][N:23]=[C:22]([NH:21][C:13]2[N:12]=[C:11]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:20]3[C:15]([CH:14]=2)=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:26]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: OCCN1CCCCC1
Product: Cc1cc(Nc2cc3ccccc3c(OCCN3CCCCC3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 2-piperidin-1-yl-ethanol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5-methyl-1H-pyrazol-3-yl)-[1-(2-piperidin-1-yl-ethoxy)-isoquinolin-3-yl]-amine. LC-MS m/e 352(MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:32][CH2:31][N:30]([C:33](=[O:35])C)[CH2:29][CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH2:36]([N:38]=C=O)[CH3:37]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:28][CH2:29][N:30]([C:33]([NH:38][CH2:36][CH3:37])=[O:35])[CH2:31][CH2:32]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CCN=C=O
Reactant: CC(=O)N1CCC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1
Product: CCNC(=O)N1CCC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1

Procedure:
4-(8-Amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl)-N-ethylpiperidine-1-carboxamide was synthesized using the same procedure as 1-{4-[8-amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]piperidin-1-yl}ethanone except ethylisocyanate was used instead of acetic anhydride; yellow powder; MS (ES+): m/z 492.10 (70) [MH+], 493.11 (45) [MH+2], 211.41 (100) [MH-280]; HPLC: tR=2.08 min (polar—5 min/openlynx).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][N:2]2[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:19])[CH:15]=2)[N:10]=1.[F:20][C:21]([F:34])([F:33])[C:22]1[N:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](O)=[O:31])=[CH:24][CH:23]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH2:3][N:2]2[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:19][C:30](=[O:31])[CH2:29][CH2:28][C:25]3[CH:26]=[N:27][C:22]([C:21]([F:20])([F:33])[F:34])=[CH:23][CH:24]=3)[CH:15]=2)[N:10]=1
Reactant: O=C(O)CCc1ccc(C(F)(F)F)nc1
Reactant: Nc1ccc2nc(N3CC4CCC3CC4)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccc(C(F)(F)F)nc1)Nc1ccc2nc(N3CC4CCC3CC4)ccc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of the product of Step B (307 mg, 1.2 mmol), the product of Step E (404 mg, 1.2 mmol) and triethylamine (0.17 mL, 1.2 mmol) in 10 mL methylene chloride was added 4-dimethylaminopyridine (222 mg, 1.8 mmol) followed by 1-(3-dimethylaminopropyl)3-ethylcarbodiimide HCl (349 mg, 1.82 mmol). The resulting mixture was stirred at r.t. for 3 days. The solvent was removed under vacuum and residue was purified by preparative thin layer chromatography eluting with hexane/ethyl acetate/triethylamine (1:7:0.1) to afford the product, MS: m/z 455 (MH+), as an off-white solid.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[N-:13]=[N+:14]=[N-:15].[Na+]>CS(C)=O>[N:13]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)=[N+:14]=[N-:15]
Reactant: CC(=O)c1ccc(CCBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)c1ccc(CCN=[N+]=[N-])cc1

Procedure:
p-(2-Bromoethyl)-acetophenone (J.A.C.S. 62, 1940, 1435) was reacted with sodium azide in dimethyl sulphoxide to give p-(2-azidoethyl)acetophenone. Oxidation with sodium hypobromide gave p-(2-azidoethyl)benzoic acid (melting point 130°-131°, from acetone/hexane) which was converted with thionyl chloride into the corresponding acid chloride. Treatment of the acid chloride with ammonia gave p-(2-azidoethyl)benzamide. Treatment with triphenylphosphine and hydrolysis gave p-(2-aminoethyl)benzamide of melting point 132°-133° (from ethanol).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].N1C=CC=CC=1.[CH2:22]([O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([C:43](Cl)=[O:44])=[CH:39][CH:38]=2)=[CH:33][CH:32]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C([O-])(O)=O.[Na+].CCOC(C)=O>CCOC(C)=O>[CH2:6]([O:5][P:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:43]([C:40]1[CH:39]=[CH:38][C:37]([C:34]2[CH:35]=[CH:36][C:31]([O:30][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:32][CH:33]=2)=[CH:42][CH:41]=1)=[O:44])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Reactant: CCOP(=O)(OCC)c1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Nc3ccccc3P(=O)(OCC)OCC)cc2)cc1
Reaction time: 0.42 h

Procedure:
At rt, to a solution of (2-Amino-phenyl)-phosphonic acid diethyl ester in EtOAc are added 10 equivaltents of pyridine followed by 1 equivalent of 4′-octyloxy-biphenyl-4-carbonylchloride (VAW132) and the mixture obtained is stirred for ca. 25 minutes. The mixture obtained is subjected to an aqueous work-up (NaHCO3/EtOAc), the organic phase obtained is dried, solvent is evaporated and the evaporation residue is subjected to column chromatography. {2-[(4′-Octyloxy-biphenyl-4-carbonyl)-amino]-phenyl}-phosphonic acid diethyl ester is obtained.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]2[S:18][C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:16][C:15]2=[O:25])=[CH:9][C:8]=1[O:26][CH3:27].C(Cl)(Cl)Cl.[C:42](Cl)(=[O:44])[CH3:43]>CCOC(C)=O>[C:42]([N:22]1[CH2:21][CH2:20][N:19]([C:17]2[S:18][C:14](=[CH:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]4[CH:28]=[CH:29][C:30]([C:32]([F:35])([F:33])[F:34])=[CH:31][C:3]=4[C:2]([F:36])([F:1])[F:37])=[C:8]([O:26][CH3:27])[CH:9]=3)[C:15](=[O:25])[N:16]=2)[CH2:24][CH2:23]1)(=[O:44])[CH3:43]
Reactant: CC(=O)Cl
Reactant: COc1cc(C=C2SC(N3CCNCC3)=NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1cc(C=C2SC(N3CCN(C(C)=O)CC3)=NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 40 %

Procedure:
To a flask was added 5-[1-[4-(2,4-bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-methylidene]-2-piperazin-1-yl-thiazol-4-one (51, mg, 94 μL) from Example 23, chloroform (5 mL), acetyl chloride (1.5 equiv, 10 μL) and TEA (3 equiv, 40 μL). The reaction solution was stirred at 45° C. for 1.5 hours. The solution was then diluted with EtOAc (75 mL) and filtered through a Buchner funnel to remove excess K2CO3. The solution was washed with aq NH4Cl (50 ml×2), dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was chromatographed (SiO2, DCM/MeOH 100:0 to 94:06) to provide the title compound (19 mg, 40% yield). 1H NMR (CDCl3) δ 7.95-7.97 (2H, m), 7.84 (2H, d, J=7.7 Hz), 7.77 (1H, s), 7.08-7.11 (2H, m), 6.87 (1H, d, J=8.2 Hz), 5.44 (2H, s), 4.09-4.11 (2H, m), 3.97 (3H, s), 3.79-3.81 (2H, m), 3.61-3.66 (4H, m), 2.17 (3H, s), 1.60 (3H, s); MS (ESI) 588 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:15][C:16](=[O:30])[C:17]2[CH:22]=[C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:20]=[C:19]([F:29])[CH:18]=2)=[CH:7][CH:6]=1.[C:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])[CH3:32]>>[C:31]([N:34]1[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][O:4][C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]([NH:15][C:16](=[O:30])[C:17]3[CH:22]=[C:21]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:20]=[C:19]([F:29])[CH:18]=3)=[CH:7][CH:6]=2)[CH2:36][CH2:35]1)(=[O:33])[CH3:32]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(Nc1ccc(OCCCl)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Product: CC(=O)N1CCN(CCOc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)CC1

Procedure:
Compound is prepared from N-[4-(2-chloroethoxy)-naphthalen-1-yl]-3-fluoro-5-piperidin-1-yl-benzamide and 4-acetylpiperizine according to conditions described in general procedure N. 1H NMR 300 MHz (CDCl3) 8.3(dd, 1H, J=1.8 and 8.7 Hz), 7.9(s, 1H), 7.84(d, 1H, J=7.5 Hz), 7.74(d, 1H, J=8.7 Hz), 7.54(m, 2H), 7.31(s, 1H), 6.99(d, 1H, J=7.5 Hz), 6.84(d, 1H, J=8.1 Hz), 6.76(d, 1H, J=11.7 Hz), 4.32(t, 2H, J=5.7 Hz), 3.66(t, 2H, J=5.4), 3.5(t, 2H, J=5.4 Hz), 3.28(m, 4H), 3.0 (t, 2H, J=5.7 Hz), 2.65(m, 4H), 2.05(s, 3H), 1.62-1.8(m, 6H).