Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C:13]1[S:14][C:15]([CH2:19]O)=[C:16]([CH3:18])[N:17]=1.S(Cl)([Cl:23])=O.C(=O)(O)[O-].[Na+].Cl.O>C(Cl)(Cl)Cl>[Cl:23][CH2:19][C:15]1[S:14][C:13]([C:3]2[CH:4]=[CH:5][C:6]([C:9]([F:12])([F:11])[F:10])=[C:7]([F:8])[C:2]=2[F:1])=[N:17][C:16]=1[CH3:18]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)c(F)c2F)sc1CO
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1nc(-c2ccc(C(F)(F)F)c(F)c2F)sc1CCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
To a solution of [2-(2,3-difluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-yl]-methanol (45 mg, 150 μmol) in chloroform (3 ml) was added thionyl chloride (20 μl, 290 μmol) at −10° C. under an argon atmosphere. The reaction mixture was stirred for 30 min, saturated aqueous sodium bicarbonate solution/ice water 1/1 was added and the layers were separated. The aqueous layer was extracted two times with dichloromethane. The combined organic layers were washed with ice water/brine 1/1 and dried over sodium sulfate. The solvent was evaporated in vacuo to give the title compound (44 mg, 134 μmol, 90%) as yellow oil which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6](=[O:7])[C:5]2[CH:8]=[C:9]([CH2:12][NH:13]C(=O)C(F)(F)F)[CH:10]=[CH:11][C:4]=2[O:3]1>N.CO>[CH3:1][C:2]1([CH3:20])[C:6](=[O:7])[C:5]2[CH:8]=[C:9]([CH2:12][NH2:13])[CH:10]=[CH:11][C:4]=2[O:3]1
Reactant: CC1(C)Oc2ccc(CNC(=O)C(F)(F)F)cc2C1=O
Agent: N
Solvent: CO
Product: CC1(C)Oc2ccc(CN)cc2C1=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 26.1 %

Procedure:
Dissolve N-(2,2-dimethyl-3-oxo-2,3-dihydro-benzofuran-5-ylmethyl)-2,2,2-trifluoro-acetamide (253 mg, 0.88 mmol) in 7M ammonia in methanol and stir at ambient temperature for 5 days. Remove volatiles in vacuo, purify by chromatography on silica gel eluting with DCM/2M ammonia in methanol (92:8) to give the title compound (44 mg, 26%). MS (ES+) m/z: 175 M+H−NH3)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7]O.[CH2:9]([O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH2:19][CH2:20][CH2:21][CH:22]2[C:27]([N:29]([C:36]1[CH:37]=[N:38][C:39]([CH:42]([CH3:44])[CH3:43])=[CH:40][CH:41]=1)[CH2:30][C:31]1[CH:32]=[N:33][NH:34][CH:35]=1)=[O:28])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH2:19][CH2:20][CH2:21][CH:22]2[C:27]([N:29]([C:36]1[CH:37]=[N:38][C:39]([CH:42]([CH3:44])[CH3:43])=[CH:40][CH:41]=1)[CH2:30][C:31]1[CH:32]=[N:33][N:34]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:35]=1)=[O:28])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: COCCOCCO
Product: COCCOCCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 394 using diethylene glycol monomethyl ether (1 mL) and 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.0 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[2-(2-methoxyethoxy)ethyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.76 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]3[NH:15][C:16]4[C:21]([C:13]=3[CH2:12][CH2:11][NH:10]2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:5][CH:4]=1.Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]2[NH:29][N:30]=[CH:31][C:24]=12>CS(C)=O.C(N(CC)C(C)C)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]3[NH:15][C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:13]=3[CH2:12][CH2:11][N:10]2[C:23]2[N:28]=[CH:27][N:26]=[C:25]3[NH:29][N:30]=[CH:31][C:24]=23)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Reactant: Clc1ncnc2[nH]ncc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1ccc(C2c3[nH]c4ccccc4c3CCN2c2ncnc3[nH]ncc23)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole from step 1 in dimethylsulfoxide (2.4 ml) and N,N-diisopropylethylamine (175 μl) was added a 0.25 M solution of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine in dimethylsulfoxide (800 μl). The mixture was shaken at room temperature for 24 hours. The mixture was evaporated to dryness and the residue shaken at 50° C. in a mixture of ethyl acetate (3 ml) and water (2 ml) for 30 minutes. The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (2 ml). The combined organic layers were evaporated to dryness and the residue dissolved in dimethylsulfoxide (1.6 ml) at 50° C. then purified by reverse phase chromatography on a preparative LC/UV/MS system using a mass triggered fractionation. Compounds were eluted from the HPLC column (Maccel 120-10-C18 SH 10 μm 20 mmID×50 mm) at 88 ml/min with 5-95acetonitrile/water gradient using 0.1% TFA as modifier to yield 1-(4-methoxyphenyl)-2-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2,3,4,9-tetrahydro-1H-beta-carboline. LCMS m/e 397 (M+1).
Reaction SMILES: [F-:1].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.[Br:24][C:25]1[CH:26]=[C:27]([O:34][CH3:35])[C:28]([N+]([O-])=O)=[N:29][CH:30]=1>O>[Br:24][C:25]1[CH:30]=[N:29][C:28]([F:1])=[C:27]([O:34][CH3:35])[CH:26]=1
Reactant: [F-]
Reactant: COc1cc(Br)cnc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Br)cnc1F
Temperature: 70 °C
Reaction time: 72 h

Procedure:
Tetrabutyl ammonium fluoride (1.0 M THF solution: 3.9 ml) was added to a DMF (5 ml) solution of 5-bromo-3-methoxy-2-nitropyridine (CAS No. 152684-26-9) (450 mg), and the obtained mixture was stirred at 70° C. for 72 hours. The reaction solution was cooled to room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=10:1 to 2:1), so as to obtain the title compound (258 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2([CH:21]=[CH:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1>[CH2:1]([N:8]1[C:16]2([CH:17]=[CH:18][NH:19][CH2:20][CH2:21]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C=CC2(CC1)c1ccccc1C(=O)N2Cc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1c2ccccc2C2(C=CNCC2)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To solution of tert-butyl 2-benzyl-3-oxo-2,2′,3,3′-tetrahydro-1′H-spiro[isoindole-1,4′-pyridine]-1′-carboxylate (4 mmol) in dioxane (10 ml) is added HCl solution in dioxane (4N, 15 ml, 60 mmol) and the mixture is stirred at rt overnight. The solvent is removed and to the residue is added aqueous NaHCO3 solution (30 ml) and EtOAc (30 ml). The layers are separated and the aqueous layer is extracted with EtOAc (30 ml). The combined extracts are washed with brine (30 ml), dried over Na2SO4 and evaporated. The residue is purified by flash column to give the title compound as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].[N:34]1([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36][CH2:35]1.O>CN(C)C=O>[OH:16][CH:15]([CH2:17][N:42]1[CH2:43][CH2:44][CH:39]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:40][CH2:41]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCC1CO1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCC(O)CN1CCC(N2CCCC2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
(2-{[6-Methoxy-7-(2-oxiranylmethoxy)-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (39 mg) and 4-(1-pyrrolidinyl)piperidine (41 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (38 mg, yield 73%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C@H:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([NH:38][O:39][CH3:40])=[O:37])=[C:32]([F:41])[CH:31]=2)[CH2:25]1)=[N+]=[N-].O>C1COCC1>[NH2:20][CH2:23][C@@H:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([NH:38][O:39][CH3:40])=[O:37])=[C:32]([F:41])[CH:31]=2)[CH2:25]1
Reactant: CONC(=O)c1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CONC(=O)c1ccc(N2C[C@H](CN)OC2=O)cc1F
Temperature: 40 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
Triphenylphosphine (317 mg, 1.2 mmol) was added to a solution of 5-(S)-azidomethyl-3-[4′-(N-methoxyamino)carbonyl-3′-fluorophenyl]-oxazolidine-2-one. (0.335 g, 1.1 mmol) in THF (8 ml) under nitrogen atmosphere. The solution was stirred at 40° C. for 2 h, water (0.24 ml) was added, and the reaction mixture stirred at 40° C. overnight. Solvent was removed under vacuum, and the resulting solid was triturated with ether. Precipitated material was filtered, washed with ether and ethanol and dried under vacuum to afford the product as white crystals (120 mg, 42%). HPLC Rt=3.5 min. MS (m/z): [M+H]+=284.
Reaction SMILES: IC.[Cl:3][C:4]1[CH:25]=[CH:24][C:7]([CH2:8][NH:9][C:10]([C:12]2[C:13](=[O:23])[C:14]3[CH:21]=[C:20]([I:22])[CH:19]=[N:18][C:15]=3[NH:16][N:17]=2)=[O:11])=[CH:6][CH:5]=1.[CH2:26](N(CC)CC)C>C(#N)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C:12]2[C:13](=[O:23])[C:14]3[CH:21]=[C:20]([I:22])[CH:19]=[N:18][C:15]=3[N:16]([CH3:26])[N:17]=2)=[O:11])=[CH:24][CH:25]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1n[nH]c2ncc(I)cc2c1=O
Reactant: CCN(CC)CC
Solvent: CI
Solvent: CC#N
Product: Cn1nc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)cnc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Iodomethane (0.6 mL) is added to a mixture of N-(4-chlorobenzyl)-6-iodo-4-oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxamide (Preparation 22, 0.196 g) and triethyl-amine (70 μL) in acetonitrile (10 mL) and the mixture is stirred at room temperature for 48 h. The reaction mixture is concentrated, and the residue is dissolved in chloroform and water. The organic phase is dried (Na2SO4) and concentrated in vacuo. The crude product is purified by flash chromatography on silica gel (240-400 mesh, 7 g) eluting with 2% methanol/chloroform. The product fractions are pooled and concentrated in vacuo to give 0.16 g of the title compound as a yellow solid. Physical characteristics: mp 207-208° C.; 1H NMR (400 MHz, CDCl3) δ4.39, 4.70, 7.33, 9.0, 9.1, 10.0; IR (drift) 1676, 1608, 1574, 1550, 1493, 1470, 1397, 1393, 1370, 1320, 1267, 1257, 812, 673, 666 cm−1; MS (EI) m/z 454 (M+, 61); HRMS (FAB) m/z 454.9767 (C16H12ClIN4O2+H). Anal. Found: C, 42.10; H, 2.61; N, 12.22.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([NH2:45])[CH:40]=1>>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:45][C:41]3[CH:40]=[N:39][CH:44]=[CH:43][CH:42]=3)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Cl)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1
Reactant: Nc1cccnc1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4cccnc4)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1

Procedure:
A solution of the product from Example 43D and Pyridin-3-ylamine was reacted to provide 4-(4-Benzyloxy-phenoxy)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-N-pyridin-3-yl-benzamide using the procedure from Example 43E. The material was then deprotected using the procedure from Example 43F to provide the crude title compound which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (23 mg, 47%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J=6.99 Hz, 6 H) 3.29 (m, 1 H) 6.78 (m, 2 H) 6.95 (m, 3 H) 7.54 (dd, J=8.27, 4.96 Hz, 1 H) 7.90 (d, J=8.82 Hz, 1 H) 8.02 (dd, J=8.82, 2.21 Hz, 1 H) 8.16 (d, J=2.21 Hz, 1 H) 8.29 (m, 1 H) 8.39 (dd, J=4.78, 1.47 Hz, 1 H) 8.94 (s, 1 H) 9.04 (m, 2 H) 9.48 (s, 1 H) 10.59 (s, 1 H) 11.59 (s, 1 H); MS (ESI+) m/z 493 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:25]=[CH:26][C:27]([CH3:34])=[C:28]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[CH3:34][C:27]1[CH:26]=[CH:25][C:24]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C@@H:3]([CH3:14])[C@H:2]([OH:1])[CH2:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:7]=2)=[CH:29][C:28]=1[S:30]([NH2:33])(=[O:32])=[O:31]
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: Cc1ccc(Br)cc1S(N)(=O)=O
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: [Na+]
Solvent: CCO
Product: Cc1ccc(-c2ccc(O[C@@H](C)[C@H](O)CCc3cccnc3)cc2)cc1S(N)(=O)=O
Temperature: 80 °C
Yield: 35.3 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.2g, Example 33), 5-bromo-2-methylbenzenesulfonic acid amide (1.7 g, Example 78a), ethanol (3 ml), 2M aqueous sodium carbonate (0.7 ml) and tetrakis(triphenylphosphine)palladium (0) (0.03 g) with heating at 80° C. for 3 hours. After work-up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give the title compound as a foam (0.10 g).
Reaction SMILES: C[Al](C)C.[CH:5]1([CH2:8][NH:9][CH2:10][CH2:11][CH3:12])[CH2:7][CH2:6]1.C(O[C:16]([C:18]1[N:22]2[CH2:23][CH2:24][N:25]([C:26]3[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=3[CH3:34])[C:21]2=[N:20][C:19]=1[CH3:35])=[O:17])C.[OH-].[Na+]>C1C=CC=CC=1>[CH:5]1([CH2:8][N:9]([CH2:10][CH2:11][CH3:12])[C:16]([C:18]2[N:22]3[CH2:23][CH2:24][N:25]([C:26]4[C:27]([CH3:34])=[CH:28][C:29]([CH3:33])=[CH:30][C:31]=4[CH3:32])[C:21]3=[N:20][C:19]=2[CH3:35])=[O:17])[CH2:7][CH2:6]1
Reactant: CCOC(=O)c1c(C)nc2n1CCN2c1c(C)cc(C)cc1C
Reactant: CCCNCC1CC1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CCCN(CC1CC1)C(=O)c1c(C)nc2n1CCN2c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A solution of trimethyl aluminum (2.0 M in heptane, 2.2 mL, 4.4 mmol) was added to a solution of N-cyclopropylmethyl-N-propylamine (0.63 mL, 4.4 mmol) in benzene (3 mL) at 0° C. The mixture was warmed up to room temperature and stirred at this temperature for 1.5 h, and then added to a stirred solution of 2-methyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-carboxylic acid ethyl ester (0.172 g, 0.55 mmol) in benzene (8.0 mL). The mixture was refluxed for 12 h. Upon cooling at 0° C., 1 N sodium hydroxide (25 mL) was added dropwise to the above mixture. The mixture was extracted with dicholoromethane (40 mL), and the organic layer was dried over anhydrous sodium sulfate. Solvents were removed in vacuo and the residue was subjected to chromatography using ethyl acetate/hexanes (1:1) as eluent to afford the title compound as a light yellow oil which solidified upon cooling (0.209 g, 100% yield). 1H NMR (CDCl3, 300 MHz) δ; 13C NMR (CDCl3, 75 MHz) δ 163.1, 156.0, 141.0, 136.5, 136.1, 132.7, 128.7, 115.8, 52.6, 50.3, 47.1, 42.1, 20.1, 19.9, 17.3, 14.6, 10.3, 9.2, 2.8. Mass spec.: 381.26 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[CH:6][N:7]=1.Cl.O.[NH:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[N:4]=[N:3][C:2]([N:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)=[N:7][CH:6]=1
Reactant: Clc1ncc(-c2ccccc2Cl)nn1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1CCN(c2ncc(-c3ccccc3Cl)nn2)CC1

Procedure:
1.5 g of 3-chloro-6-(2-chlorophenyl)-1,2,4-triazine, 3.05 g of piperidin-4-one monohydrate hydrochloride and 3.1 g of sodium carbonate are heated under reflux in 100 ml of ethanol for 4 hours.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][CH:8]([C:12]([NH2:14])=[O:13])[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.[CH:17](OCC)(OCC)OCC.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[OH:13][C:12]1[N:14]=[CH:17][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:16][CH:15]=2)[C:8]=1[C:9]([NH2:11])=[O:10]
Reactant: NC(=O)C(NCc1ccc(F)cc1)C(N)=O
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: NC(=O)c1c(O)ncn1Cc1ccc(F)cc1

Procedure:
16.05 g (71.04 mmol) of 2-(4-fluorobenzylamino)malonamide are refluxed with 71 ml of triethyl orthoformate, i.e. 6 equivalents, and a catalytic amount of PTSA (250 mg) in 535 ml of absolute ethanol, in a round-bottomed flask placed under argon.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10]CC1C=CC=CN=1>>[CH:1]1[N:7]=[C:8]([SH:9])[N:10]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=12
Reactant: NCc1ccccn1
Reactant: S=C=Nc1ccccc1
Product: Sc1ncc2ccccn12
Temperature: 25 °C

Procedure:
Phenyl Isothiocyanate (22 mL, 0.184 mol) is added slowly to a solution of 2-(aminomethyl)-pyridine (19 mL, 0.184 mol) in xylenes (180 mL) with cooling on ice. The resulting solution is heated at reflux for 3 h, and then allowed to cool to RT overnight. The resulting suspension is cooled to 0° C. and the solid is collected by filtration. The solid is washed with toluene and ether, and dried under vacuum to yield imidazo[1,5-a]pyridine-3-thiol as a green solid: 1H-NMR (CDCl3) δ 12.9 (br s, 1H), 8.25 (dd, J=7.5, 0.9, 1H), 7.21 (d, J=9.3, 1H), 7.06 (s, 1H), 6.75 (dd, J=9.3, 6.3, 1H), 6.59 (dt, J=7.5, 0.9); MS (M+1)+ 151.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[CH2:7][NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][NH:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl[CH2:26]OCC1C=CC=CC=1>O1CCCC1>[CH3:3][O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[CH2:7][N:8]1[CH2:26][N:11]2[CH:10]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:9]1[CH2:14][CH2:13][CH2:12]2
Reactant: ClCOCc1ccccc1
Reactant: COc1ccccc1CN[C@H]1CCCN[C@H]1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1CN1CN2CCCC1C2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (1.47 g, 36.8 mmol of a 60% dispersion in oil) was added to a round-bottomed flask fitted with an N2 inlet, condenser, stirrer and washed with hexane to remove the oil. Anhydrous tetrahydrofuran (THF), 50 mL, was added followed by 6.30 grams (18.9 mmol) of (2S, 3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine in 50 mL of tetrahydrofuran. After heating to reflux for two hours, the mixture was allowed to cool to room temperature and was treated dropwise with benzyl chloromethyl ether (5.1 mL, 36.8 mmol). The mixture was stirred overnight and the excess sodium hydride quenched with water. After being stirred an additional hour, the organic layer was separated and the aqueous layer was extracted with methylene chloride. The organic layers were combined and washed with saturated aqueous sodium chloride before drying over magnesium sulfate. Concentration in vacuo gave a solid which recrystallized from methanol/methylene chloride to a white solid, 2.36 grams (40%), mp 105-107° C. Mass Spectrum (m/e): 309 (M+1, 100%), 159 (12%). 1H-NMR (CDCl3)δ 1.45-2.20 (m, 5H), 3.15 (m, 2H), 3.5 (d, 1H), 3.65-3.85 (m, 2H), 3.75 (s, 3H), 3.95 d,1H), 4.10 (d, 1H), 6.8 (d, 1H), 6.95 (t, 1H), 7.15-7.6 (m, 7H). Anal. Calc'd for C20H24N2O; C, 77.88; H, 7.83, N, 9.08. Found: C, 77.72; H, 7.75; N, 9.04.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](Cl)=[O:8].N1C=CC=CC=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:23][C:20]1[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=1)=[O:8]
Reactant: O=C(Cl)c1cnccn1
Reactant: Cc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(OC(=O)c2cnccn2)cc1
Yield: 28.2 %

Procedure:
To 3.5 g (25 mmol) of pyrazinoyl chloride dissolved in methylene chloride (20 mL) and pyridine (2 mL) cooled to 0° C. in a 50 mL round bottom flask was added 4-methyl-phenol (3.2 g, 30 mmol). Upon completion of the reaction and isolation as described above, recrystallization from hexanes yielded 1.51 g (24% yield) of the crystalline title compound; m.p.: 120°-123° C. Elemental Analysis: C12H10N2O2Calcd: C:67.28, H:4.71. Found: C:67.4, H:4.66.
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH2:12]([C:20]1[CH:21]=[CH:22][C:23]([CH:10]([OH:11])[C:8](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:24][CH:25]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=CC(=O)c1ccccc1
Reactant: CCCCCCCCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: CCCCCCCCc1ccc(C(O)C(=O)c2ccccc2)cc1

Procedure:
Phenylglyoxal monohydrate (608 mg, 4 mM) and n-octylbenzene (1.77 ml, 8 mM) were dissolved in dichloroethane (8 ml), titanium tetrachloride (0.66 ml, 6 mM) was added, and reacted at room temperature for 30 minutes. Using the same procedure as in Example 1, 4'-n-octylbenzoin was obtained as crystal (810.0 mg, 62.6% yield).
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]2[CH:14]=[N:15][N:16]([CH2:18][C:19](O)=[O:20])[CH:17]=2)[N:7]=1.CCN(C(C)C)C(C)C.Cl.[NH2:38][CH:39]([CH3:42])[C:40]#[N:41].CCCP(=O)=O>CN(C=O)C>[C:40]([CH:39]([NH:38][C:19](=[O:20])[CH2:18][N:16]1[CH:17]=[C:13]([NH:12][C:8]2[N:7]=[C:6]([NH:5][CH2:4][C:3]3[C:2]([F:1])=[CH:25][C:24]([F:26])=[CH:23][C:22]=3[F:27])[CH:11]=[CH:10][N:9]=2)[CH:14]=[N:15]1)[CH3:42])#[N:41]
Reactant: CC(N)C#N
Reactant: O=C(O)Cn1cc(Nc2nccc(NCc3c(F)cc(F)cc3F)n2)cn1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C#N)NC(=O)Cn1cc(Nc2nccc(NCc3c(F)cc(F)cc3F)n2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(4-((4-((2,4,6-trifluorobenzyl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)acetic acid I-2 (0.1 g, 0.26 mmol, prepared by Procedure B), DIPEA (0.15 mL, 0.8 mmol), 2-aminopropanenitrile hydrochloride (34 mg, 0.3 mmol), propylphosphonic anhydride solution (50% in DMF) (0.17 g, 0.5 mmol) in DMF was stirred overnight at room temperature then extracted into water and washed with DCM. The aqueous layer was neutralised with aqueous sodium bicarbonate and extracted with three times with DCM. The combined organic layer was concentrated in vacuo and purified by prep. HPLC to afford N-(1-cyanoethyl)-2-(4-((4-((2,4,6-trifluorobenzyl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)acetamide I-5 (80 mg, 0.18 mmol). LC-MS (Method B), RT=5.15 min. (ES+) 431.