Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[N:4][CH:3]=1.O.NN>CCO>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][NH2:10])[CH:5]=[N:4][CH:3]=1
Reactant: Cc1cncn1CCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cncn1CCCN
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
2-(3-(5-Methyl-1H-imidazol-1-yl)propyl)isoindoline-1,3-dione (i.e. 8.92 mmol, 1 eq., which may be prepared as described in D3) and hydrazine monohydrate (17.84 mmol, 2 eq.) were dissolved in dry EtOH (50 mL). The mixture was kept under reflux over night, then mixture was concentrated down to a volume of 25 mL. Hydrochloric acid (conc., 55 mL) was then added and the mixture was heated to 50° C. and kept at this temperature for 30 min. The formed precipitate was then filtered. The filtrate was cooled to 0° C. and solid NaOH was added until a final pH-value of 10-12 was reached. The aqueous solution was extracted by means of CHCl3 (3×50 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed. The product was purified by means of flash-chromatography using silica gel and a CHCl3/MeOH-gradient.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17](O)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:23]=[CH:22][CH:21]=[CH:20][C:16]=2[CH2:17][Cl:26])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccnc1NC1CCN(Cc2ccccc2)CC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1cccnc1NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(1-benzylpiperidin-4-ylamino)nicotinic acid (311 mg, 1.0 mmol, 1.0 eq) prepared in Preparation Example 16, and thionyl chloride (1.5 mmol) in 5 ml of methylene chloride was stirred for 1 hr under reflux. The reaction mixture was cooled to room temperature and immediately used in the next step without further purification.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].N1C=CN=C1.[CH3:13][C:14]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:17]([O:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7])([C:14]([CH3:16])([CH3:15])[CH3:13])([CH3:19])[CH3:18]
Reactant: O=C1NCC[C@@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCNC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of commercial (S)-3-hydroxypyrrolidin-2-one (5 g, 49.5 mmol) in DCM (198 ml) was treated with DMAP (0.199 g, 1.632 mmol), imidazole (6.73 g, 99 mmol), and TBDMS-Cl (8.94 g, 59.3 mmol). The reaction mixture was stirred at rt for 16 h, and then was washed with a satd. NaHCO3 solution. The organic layer was concentrated and the crude reaction product was purified by silica gel chromatogpraphy eluting with 50% ethyl acetate in petroleum ether. The desired product was isolated as a white solid (8.1 g, 76%). LC/MS (M+H)+=216.2. 1H NMR (400 MHz, chloroform-d) δ 6.40 (br. s., 1H), 4.26 (t, J=7.8 Hz, 1H), 3.42-3.34 (m, 1H), 3.29-3.21 (m, 1H), 2.36 (dtd, J=12.7, 7.3, 3.3 Hz, 1H), 2.07-1.96 (m, 1H), 0.91 (s, 9H), 0.15 (d, J=7.0 Hz, 6H).
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[C:20]1([C:26]2([CH2:29][NH2:30])[CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(O)C>[C:20]1([C:26]2([CH2:29][NH:30][C:5]3[C:4]4[N:8]=[CH:9][N:10]([C:3]=4[N:2]=[CH:1][N:6]=3)[C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[CH2:27][CH2:28]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NCC1(c2ccccc2)CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC4(c5ccccc5)CC4)ncnc32)[C@H](O)[C@@H]1O
Yield: 77.5 %

Procedure:
A mixture of 6-chloropurine riboside (8.61 g, 30 mmol), (1-phenylcyclopropyl)methylamine (4.41 g, 30 mmol) and triethylamine (6.06 g, 60 mmol) are refluxed in stirring ethanol (300 mL) under N2 for 20 h. On cooling to 0° the product crystallized. Vacuum filtration and drying in vacuo gives N6-((1-phenylcyclopropyl)methyl)adenosine (9.24 g, 79%) as a very pale khaki solid m.p. 118°-23° C. Found: C, 59.58; H, 5.77; N, 17.49%. C20H23N5O4 calculated requires: C, 60.45; H, 5.79; N, 17.63%.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14]([C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[N:20][CH:21]=1)#[CH:15].C(N(CC)C(C)C)(C)C>CN(C=O)C.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.[Cu]I>[C:23]([NH:22][C:19]1[N:20]=[CH:21][C:16]([C:14]#[C:15][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=2[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:17][CH:18]=1)(=[O:25])[CH3:24]
Reactant: CCOC(=O)c1ccc(C)c(I)c1
Reactant: C#Cc1ccc(NC(C)=O)nc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(C)c(C#Cc2ccc(NC(C)=O)nc2)c1
Temperature: 25 °C

Procedure:
A mixture of ethyl 3-iodo-4-methylbenzoate (845 mg, 2.9 mmol, 0.8 eq), N-(5-ethynylpyridin-2-yl)acetamide (3.5 mmol, 1.0 eq). Pd(PPh3)4 (51 mg, 0.044 mmol), CuI (20.4 mg, 0.11 mmol), and N,N-diisopropylethylamine (0.8 ml, 4.4 mmol) in 2 ml of DMF is heated at 55° C. (oil bath) for 1 hr under nitrogen. After cooling to r.t., the solvent is evaporated and DCM is added to dissolve the residue. The solution is washed with water and brine, dried and evaporated and the crude material is chromatographed with CombiFlash (DCM/MeOH).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:16][CH:17](O)[CH3:18])[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P([N:67]=[N+:68]=[N-:69])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.ClCCl>[N:67]([CH:17]([CH3:18])[CH2:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[N+:68]=[N-:69]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(O)Cc1cccc(CO[Si](C)(C)C(C)(C)C)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(Cc1cccc(CO[Si](C)(C)C(C)(C)C)c1)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirring solution of 1-[3-(tert-butyldimethylsilyloxymethyl)-phenyl]-propan-2-ol (130 mg, 0.46 mmol) in THF (1.5 mL) under nitrogen at 0° C. was added diisopropyl azodicarboxylate (140 mg, 0.7 mmol), triphenylphosphine (180 mg, 0.7 mmol), and diphenylphosphoryl azide (190 mg, 0.7 mmol) and the mixture was stirred at 0° C. for 15 min. The mixture was diluted with dichloromethane, washed with water, brine, dried over magnesium sulfate, and purified by flash column chromatography (ethyl acetate/hexanes). 1H NMR (CDCl3) 7.27 (m, 1H), 7.2 (m, 1H), 7.16 (s, 1H), 7.08 (m, 1H), 4.74 (s, 2H), 3.65 (m, 1H), 2.82 (dd, 1H), 2.73 (dd, 1H), 1.25 (d, 3H), 0.94 (s, 9H), 0.10 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](OCC)=O)[S:5][C:6]=1[Cl:7].[H-].C([Al+]CC(C)C)C(C)C.[ClH:28]>O1CCCC1>[Cl:28][CH2:13][C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:4]1[S:5][C:6]([Cl:7])=[C:2]([Cl:1])[CH:3]=1
Reactant: CCOC(=O)c1cnoc1-c1cc(Cl)c(Cl)s1
Reactant: Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: ClCc1cnoc1-c1cc(Cl)c(Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of ethyl 5-(4,5-dichloro-2-thienyl)isoxazole-4-carboxylate (3.30 g) in tetrahydrofuran (60 ml) was gently added diisobutylaluminum hydride (0.95 M hexane solution, 29.7 ml) at 0° C. and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was dissolved in toluene (60 ml), thionyl chloride (2.02 g) was added dropwise at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 4-chloromethyl-5-(4,5-dichloro-2-thienyl)isoxazole (2.41 g, yield 79%) was obtained as crystals from a fraction eluted with ethyl acetate-hexane (1:9, volume ratio) and recrystallized from hexane to give a colorless prism. melting point: 60–61° C.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:13]=NNC(N)=O.[OH-].[K+].Cl>C(O)COCCO.O>[CH3:13][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:11]([OH:12])[C:2]=1[OH:1]
Reactant: NC(=O)NN=Cc1c(O)c(O)cc2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: Cc1c(O)c(O)cc2ccccc12

Procedure:
131 g of 2,3-dihydroxy-naphthaldehyde semicarbazone were boiled at reflux overnight with 250 g of powdered potassium hydroxide in 1350 ml of diethyleneglycol under an argon stream in a 1.5 l sulfonation flask equipped with stirrer, condenser, theremometer and calcium chloride tube. The cooled solution was diluted with 4,5 l of water, made acid with 450 ml of concentrated hydrochloric acid and extracted eight times with 1 l ether. The combined ether extracts were dried over sodium sulfate and evaporated in vacuo. Recrystallization from water gave 61.5 (65.5% of theory) of 1-methyl-2,3-dihydroxy-naphthalene. Melting point 97°-100° C.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1>O>[CH3:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(F)n1
Reactant: C[C@@H]1CCCN1
Solvent: O
Product: C[C@@H]1CCCN1c1cccc(N)n1
Temperature: 205 °C
Yield: 81.9 %

Procedure:
A suspension of 6-fluoropyridin-2-amine (448 mg, 4 mmol) and (R)-2-methylpyrrolidine (511 mg, 6 mmol) in water (0.5 mL) was heated to 205° C. in a microwave oven for 30 minutes. The reaction mixture was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give (R)-6-(2-methylpyrrolidin-1-yl)pyridin-2-amine (581 mg, 82%) as a light yellow oil. LC-MS: [M+H]+, 178.2, tR=1.049 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.C([N:20](CC)CC)C.C(Cl)(=O)OCC.N>O.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([NH2:20])=[O:17])=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)CCc1conc1-c1ccc(Cl)cc1
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)CCc1conc1-c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a mixture of 3-[3-(4-chlorophenyl)-4-isoxazolyl]propionic acid (1.28 g), triethylamine (1.1 ml) and tetrahydrofuran (100 ml) was added ethyl chlorocarbonate (0.6 ml) at −30° C. and the mixture was stirred at −20° C. for 1 hr. To the obtained mixture was added aqueous ammonia (15 ml) and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated to give 3-[3-(4-chlorophenyl)-4-isoxazolyl]propionamide (0.91 g, yield 71%) as colorless crystals. The crystals were recrystallized from acetone-hexane. melting point: 158–159° C.
Reaction SMILES: [CH3:1][N:2]([C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)=[O:20])[CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)[CH2:7][CH2:6]1.[CH2:32]([NH:35][CH3:36])[CH:33]=[CH2:34]>CN(C)C(=O)C.CCOCC>[F:29][C:28]([F:31])([F:30])[C:25]1[CH:26]=[CH:27][C:22]([O:21][C:19](=[O:20])[N:2]([CH2:3][CH2:4][C@H:5]2[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][CH2:13][N:35]([CH2:32][CH:33]=[CH2:34])[CH3:36])[CH2:7][CH2:6]2)[CH3:1])=[CH:23][CH:24]=1
Reactant: C=CCNC
Reactant: CN(CC[C@H]1CC[C@H](CCCOS(C)(=O)=O)CC1)C(=O)Oc1ccc(C(F)(F)F)cc1
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: C=CCN(C)CCC[C@H]1CC[C@H](CCN(C)C(=O)Oc2ccc(C(F)(F)F)cc2)CC1

Procedure:
A solution of 200 mg (0.43 mmol) trans-methanesulfonic acid 3-(4-{2-[methyl-(4-trifluoromethyl-phenoxycarbonyl)-amino]-ethyl}-cyclohexyl)-propyl ester and 0.204 ml (2.15 mmol) of allyl methyl amine in 2 ml of N,N-dimethylacetamide was stirred over night at 60° C. The reaction mixture was then taken up in ether and the ether phases were washed with water. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure and the residue then chromatographed on silica gel with a 9:1 v/v mixture of dichloromethane and 1N ammonia in methanol as the eluent giving 124 mg (65.5%) trans-(2-{4-[3-(allyl-methyl-amino)-propyl]-cyclohexyl}-ethyl)-methyl-carbamic acid 4-trifluoromethyl-phenyl ester as colorless viscous oil, MS: 441 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][C:3]=1[NH:17][C:18](=[O:27])[CH:19]=[CH:20]C1C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3]>ClC1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)=[C:4]2[C:3]=1[NH:17][C:18](=[O:27])[CH:19]=[CH:20]2
Reactant: O=C(C=Cc1ccccc1)Nc1cc(OCCN2CCCCC2)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Clc1ccccc1
Product: O=c1ccc2c(OCCN3CCCCC3)ccc(Cl)c2[nH]1
Temperature: 125 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
N-(2-chloro-5-(2-(piperidin-1-yl)ethoxy)phenyl)cinnamamide (436 mg, 1.1 mmol, 1 eq.) was placed in chlorobenzene (2.1 mL), in the presence of aluminium trichloride (906 mg, 1.5 mmol, 6 eq.). The reaction mixture was heated at 125° C. and stirred for 2 hours. After cooling down to room temperature, it was diluted with a water and ice mixture and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford 8-chloro-5-(2-(piperidin-1-yl)ethoxy)quinolin-2(1H)-one (225 mg, 67%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:20]4[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=4)[CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2cccc(Br)c2)c1-c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: Cc1onc(-c2cccc(Br)c2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Yield: 39 %

Procedure:
As described for Example 44, 3-(3-bromo-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (91 mg, 0.3 mmol) using 1-fluoro-4-nitrobenzene instead of 4-fluoroacetophenone was converted to the title compound (50 mg, 39%) which was obtained as a light yellow solid. MS: m/e=425.1/427.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.[CH3:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[NH:29][CH2:28][CH2:27][CH2:26]2.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:6]([C:7]([N:29]2[C:30]3[C:25](=[CH:24][CH:23]=[CH:22][C:21]=3[O:20][CH3:19])[CH2:26][CH2:27][CH2:28]2)=[O:9])=[CH:10][CH:11]=[CH:12][N:13]=1
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Reactant: COc1cccc2c1NCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1N(C(=O)c1cccnc1Oc1cc(Cl)ccc1Cl)CCC2
Temperature: 50 °C
Yield: 12.3 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-nicotinic acid (56.6 mg, 0.2 mmol, 1.0 equiv; Example 31, Step 1) in anhydrous DMF (1 mL) was added 8-methoxy-1,2,3,4-tetrahydro-quinoline (39.2 mg, 0.24 mmol, 1.2 equiv; [CAS RN 53899-17-5]), N-ethyldiisopropylamine (129.0 mg, 175 μL, 1.0 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and HATU (91.2 mg, 0.24 mmol, 1.2 equiv; [CAS RN 148893-10-1]) and the reaction mixture stirred at 50° C. over night. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 10.6 mg (12%) of the title compound. MS (ISP): 429.3 [M+H]+.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[N:22]=[CH:21][C:20]([N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[C:9]([CH3:29])=[C:8]([C:30]([O:32]CC)=[CH2:31])[C:7]2=[O:35])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>C(OCC)(=O)C.ClCCl.C([O-])(O)=O.[Na+]>[C:30]([C:8]1[C:7](=[O:35])[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:11]2[N:12]=[C:13]([NH:16][C:17]3[N:22]=[CH:21][C:20]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)=[CH:19][CH:18]=3)[N:14]=[CH:15][C:10]=2[C:9]=1[CH3:29])(=[O:32])[CH3:31]
Reactant: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCCCC4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCCCC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
8-Cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (0.180 g, 0.379 mmol) was dissolved in ethyl acetate (10 mL) and 6 N HCl (10 mL) was added then the mixture was stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane and aqueous NaHCO3. The layers were separated and the organic layer was dried over MgSO4, filtered, and the solvent evaporated to give 6-acetyl-8-cyclopentyl-5-methyl-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one as a yellow solid (0.120 g, 71.0%). 1H NMR δ (400 MHz, CDCl3) 8.78 (s, 1H), 8.20 (d, J=8.5 Hz, 1H), 7.95 (s, 1H), 7.39 (m, 1H), 5.85 (m, 1H), 3.15 (m, 4H), 2.53 (s, 3H), 2.36 (s, 3H), 2.33 (m, 2H), 2.05 (m, 2H), 1.87 (m, 2H), 1.77–1.56 (m, 8H). MS (APCI); M++1: Calc'd, 447.2, Found 447.2. Anal. Calc'd for C25H30N6O2 0.35 H2O: C, 66.31; H, 6.83; N, 18.56. Found: C, 66.68; H, 6.76; N, 18.07.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:22])[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)=[C:9]([CH:19]([CH3:21])[CH3:20])[S:8][C:6]=2[N:7]=1.[C:23]1([C:29]2[N:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([CH:19]([CH3:20])[CH3:21])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[C:5]2=[C:4]([NH:22][S:35]([C:32]2[CH:33]=[N:34][C:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:30][CH:31]=2)(=[O:36])=[O:37])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)nc1
Reactant: COc1cccc(-c2c(C(C)C)sc3nc(C)cc(N)c23)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(-c2c(C(C)C)sc3nc(C)cc(NS(=O)(=O)c4ccc(-c5ccccc5)nc4)c23)c1

Procedure:
Following general method outlined in Example 52, starting from 6-methyl-2-(1-methylethyl)-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (40 mg, 0.128 mmol) (Description 21) and 6-phenyl-3-pyridinesulfonyl chloride (39 mg, 0.154 mmol), the title compound (12.2 mg) was isolated as a TFA salt. LCMS (B) m/z: 530 [M+1]+, Rt 3.02 min.
Reaction SMILES: [NH2:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH2:19])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH:29]=O>>[NH2:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][NH:19][CH2:29][C:28]3[CH:31]=[CH:32][C:33]([Cl:34])=[C:26]([Cl:25])[CH:27]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCN)CC1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCNCc2ccc(Cl)c(Cl)c2)CC1
Yield: 93.2 %

Procedure:
4-Amino-N-(1-(3-aminopropyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (2 g) as starting compound and 3,4-dichlorobenzaldehyde (0.99 g) were reacted and treated in the same manner as in Example 121 to give 2.7 g of 4-amino-5-chloro-N-((1-(3-(3,4-dichlorobenzylamino)propyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [N:1]1([C:7](=[O:24])[CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[C:10]([OH:12])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:25]([O:29][C:30]([N:32]1[CH2:36][CH:35]([OH:37])[CH:34]([NH2:38])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>>[C:25]([O:29][C:30]([N:32]1[CH2:36][C:35](=[O:37])[CH:34]([NH:38][C:10](=[O:12])[CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[CH2:8][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:24])[CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(N)C(O)C1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(=O)C(NC(=O)C(CC(=O)N2CCOCC2)CS(=O)(=O)Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid (120 mg, 0.34 mmol), 3-amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.74 mmol), prepared as in reference 13, EDC (0.3 g, 1.6 mmol), and HOBt (150 mg, 0.96 mmol) were combined. Dichloromethyl (10 mL) was added and then 4-methylmorpholine (0.5 mL). The mixture was stirred at ambient temperature for 2 hours. After dilution with ethyl acetate (200 mL) the solution was washed with 1N aqueous HCl (50 mL), saturated aqueous NaHCO3 (50 mL) and brine (50 mL), dried with MgSO4 and evaporated under vacuum. The pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in DMSO (5 mL). Triethylamine (0.5 mL) and then SO3 pyridine complex (150 mg) were added and the mixture was stiffed at ambient temperature for 3 hours. After dilution with ethyl acetate (100 mL), the solution was washed with water (50 mL) and brine, dried with MgSO4 and evaporated under vacuum. The residue was purified by flash chromatography on silica gel. Eluent: 5% methanol in ethyl acetate. Yield: 40 mg 3-(4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyrylamino)-4-oxo-1-pyrrolidine-1-carboxylic acid tert-butyl ester as white solid as mixture of diastereomers; 1H NMR: (DMSO) 8.80–8.66 (m, 1H), 7.42–7.34 (m, 5H), 4.52–4.41 (m, 2H), 4.34–4.20 (m, 1H), 3.98–3.88 (m, 1H), 3.82 (d, J=18.5 Hz, 1H), 3.70–3.05 (m, 13H), 2.70–2.52 (m, 2H), 1.41 (s, 9H); MS: (M+H)+ 538.