Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:30])[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:23]=3)[C:17]([O:19]C)=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.CO.[OH-].[Li+].O>C1COCC1>[N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:30])[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:23]=3)[C:17]([OH:19])=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC[C@H](C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)O)c1
Yield: 89.1 %

Procedure:
A mixture of methyl 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]benzoate (240 mg, 0.1 mmol), 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (278 mg, 1.2 mmol) and potassium carbonate (276 mg, 2.0 mmol) in DMA (5 mL) was stirred at 120° C. for 16 hours. The solution was poured into water (30 mL) and acidified with 1N hydrochloric acid before being extracted with ethyl acetate (3×20 mL). The combined organics were washed with brine (20 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give methyl 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoate (as evidenced by LCMS data only m/z 435 (M+H)+) as a brownish oil (550 mg). The crude methyl 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoate (434 mg, 1 mmol) was dissolved in THF (15 mL) and methanol (5 mL) then 1N aqueous Lithium hydroxide solution (2 mL) added followed by the dropwise addition of water until a clear solution obtained. The mixture was stirred was stirred for 4 hours at RT and the organics removed by evaporation. The aqueous solution was filtered, extracted with ethyl acetate (10 mL) and the aqueous layer acidified with 2N hydrochloric acid. The acidified layer was extracted with ethyl acetate (3×30 mL) and the combined organic extracts washed with water (10 mL), brine (10 mL) and concentrated in vacuo to give the desired compound as a pale oil (375 mg). 1H NMR δ (CDCl3): 1.27 (d, 3H), 2.32 (quin, 2H), 3.34 (s, 3H), 3.42-3.55 (m, 2H), 4.13-4.34 (m, 4H), 4.54 (q, 1H), 6.93 (s, 1H), 7.40 (s, 1H), 7.48 (s, 1H), 8.08 (s, 1H), 8.19 (s, 1H), m/z 421 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19]Cl)=[N:17][CH:18]=1.C(N(CC)CC)C>C(OCC)(=O)C.O.CN(C)C=O>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:17][CH:18]=1
Reactant: ClCc1ccc(Br)cn1
Reactant: Oc1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Fc1ccc(OCc2ccc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.6 %

Procedure:
To an N,N-dimethylformamide (40.0 mL) solution of 4-fluorophenol (3.00 g, 26.8 mmol) was added sodium hydride (1.00 g, 25.0 mmol, 60% in oil) on an ice bath (0° C.) under nitrogen atmosphere, which was stirred for 20 minutes at room temperature. To the reaction solution was then added a mixture of 5-bromo-2-chloromethyl-pyridine hydrochloride (4.6 g, 22.3 mmol) described in Manufacturing Example 54-1-2 and triethylamine (30.6 mL, 20.4 mmol), which was stirred for 10 minutes at room temperature. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. This organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated from the filtrate under a reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:4) to obtain the title compound (4.0 g, 63.6%).
Reaction SMILES: O.C(=O)([O-])[O-].[K+].[K+].[NH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[C:29](=[O:30])[C:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[CH:27][N:26]([CH2:38][CH2:39][F:40])[CH:25]=3)=[O:23])=[CH:17][CH:16]=2)=[CH:13][C:12](Br)=[CH:11][N:10]=1.[CH3:42][C:43]1[CH:48]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:46]=[CH:45][N:44]=1>O1CCOCC1.C(Cl)(Cl)Cl.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>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:47]2[CH:46]=[CH:45][N:44]=[C:43]([CH3:42])[CH:48]=2)=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[C:29](=[O:30])[C:28]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:27][N:26]([CH2:38][CH2:39][F:40])[CH:25]=2)=[O:23])=[CH:17][CH:16]=1
Reactant: Nc1ncc(Br)cc1-c1ccc(NC(=O)c2cn(CCF)cc(-c3ccc(F)cc3)c2=O)cc1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
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: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2cnc(N)c(-c3ccc(NC(=O)c4cn(CCF)cc(-c5ccc(F)cc5)c4=O)cc3)c2)ccn1
Temperature: 100 °C
Reaction time: 6 h
Yield: 38.5 %

Procedure:
Water (0.1 ml), potassium carbonate (48 mg) and tetrakis(triphenylphosphine)palladium (13 mg) were added to a solution of the compound obtained in Step 1 of Example 43 (61 mg) and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (28 mg) in 1,4-dioxane (1.2 ml), and the mixture was stirred at 100° C. for six hours. After leaving to cool, the reaction solution was diluted with chloroform. The organic layer was washed with water and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=300:1->10:1 (v/v)] to give 24 mg of the title compound as a solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[N:8][C:9]([CH:12]([N:14]2[CH2:19][CH2:18][N:17]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:16][CH2:15]2)[CH3:13])=[N:10][CH:11]=1)=O)C.[BH4-].[Na+].CC#N>C(O)C>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([S:20]([N:17]2[CH2:16][CH2:15][N:14]([CH:12]([C:9]3[N:8]=[C:7]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[C:6]([CH2:4][OH:3])=[CH:11][N:10]=3)[CH3:13])[CH2:19][CH2:18]2)(=[O:21])=[O:22])=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cnc(C(C)N2CCN(S(=O)(=O)c3ccc(OC)cc3)CC2)nc1N1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N2CCN(C(C)c3ncc(CO)c(N4CCCCC4)n3)CC2)cc1

Procedure:
To a solution of 2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-pyrimidine-5-carboxylic acid ethyl ester (104 mg, 0.2 mmol) in ethanol (1 mL) was added sodium borohydride (38 mg, 1.0 mmol) and the reaction mixture was heated to reflux for 1 day. The reaction was then partition between dichloromethane and saturated sodium bicarbonate solution. The organic layer was concentrated in vacuo and then the residue was dissolved in DMSO (1 mL) and purified by LC-MS to yield the product. 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 4.62 (s, 2H), 4.53 (q, J=6.6 Hz, 1H), 3.93 (m, 7H), 3.25 (m, 8H), 1.77 (m, 6H), 1.67 (d, J=6.8 Hz, 3H); HPLC ret. time 2.49 min, 10-99% CH3CN, 5 min run; ESI-MS m/z 476.1 (M+1)+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][NH:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][N:31]([C:39](=[O:38])[CH2:40][OH:41])[CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1cc(-c2ccnc3c(C(=O)N[C@@H]4CN(C(=O)CO)C[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f24) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]([NH2:15])[CH2:6]1.Cl[C:22]1[N:27]=[C:26]([NH2:28])[N:25]=[C:24]2[NH:29][N:30]=[CH:31][C:23]=12.C(N(C(C)C)CC)(C)C.O>CC(N(C)C)=O>[F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]([NH:15][C:22]2[N:27]=[C:26]([NH2:28])[N:25]=[C:24]3[NH:29][N:30]=[CH:31][C:23]=23)[CH2:6]1
Reactant: NC1Cc2ccccc2N(Cc2ccc(F)cc2F)C1
Reactant: Nc1nc(Cl)c2cn[nH]c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1nc(NC2Cc3ccccc3N(Cc3ccc(F)cc3F)C2)c2cn[nH]c2n1
Temperature: 25 °C

Procedure:
1-(2,4-difluorobenzyl)-1,2,3,4-tetrahydroquinolin-3-amine, 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine (200 mg, 1.2 mmol) and diisopropylethylamine (1 mL) in dimethylacetamide (6 mL) was stirred at 126° C. for 20 hours. After cooling to room temperature, water (15 mL) was added and the mixture extracted with ethyl acetate (3×15 mL). The combined organics were dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (100% ethyl acetate) to provide N4-(1-(2,4-difluorobenzyl)-1,2,3,4-tetrahydroquinolin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine as a light yellow solid (160 mg). M.p.=110-114° C. 1H NMR (DMSO-d6, 400 MHz) δ 12.43 (s, 1H), 7.83 (s, 1H), 7.62 (d, J=6.0 Hz, 1H), 7.34-7.21 (m, 2H), 7.03-6.95 (m, 3H), 6.58-6.54 (m, 2H), 6.00 (s, 2H), 4.66 (br, 1H), 4.54 (m, 2H), 3.55-3.51 (m, 1H), 3.39-3.29 (m, 1H), 3.09-3.04 (m, 1H), 2.89-2.81 (m, 1H). LCMS m/e 408 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:9]1[N:10]=[CH:11][C:12]([CH:36]2[CH2:38][CH:37]2[C:39]([O:41]CC)=[O:40])=[N:13][C:14]=1[C:15]1[O:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH3:28])=[CH:22][CH:21]=2)=[N:18][N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO.CCOC(C)=O>[C:47]([O:46][C:44]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]1[N:10]=[CH:11][C:12]([CH:36]2[CH2:38][CH:37]2[C:39]([OH:41])=[O:40])=[N:13][C:14]=1[C:15]1[O:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([CH2:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH3:28])=[CH:24][CH:25]=2)=[N:18][N:19]=1)=[O:45])([CH3:48])([CH3:49])[CH3:50]
Reactant: CCOC(=O)C1CC1c1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c2nnc(-c3ccc(CN(C)C(=O)OC(C)(C)C)cc3)o2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(Cc1ccc(-c2nnc(-c3nc(C4CC4C(=O)O)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Temperature: 50 °C

Procedure:
To a solution of ethyl 2-[5-[bis(tert-butoxycarbonyl)amino]-6-[5-[4-[[tert-butoxycarbonyl(methyl)amino]methyl]phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]cyclopropanecarboxylate (825 mg, 1.2 mmol) in THF:MeOH solvent mixture (3.2 mL:1.6 mL) at room temperature was added aqueous NaOH (594 μL, of 4 M, 2.37 mmol) and reaction mixture was heated at 50° C. for 20 minutes. The reaction mixture was cooled to room temperature and diluted with EtOAc and washed with 1M HCl solution. The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to obtain 2-[5-[bis(tert-butoxycarbonyl)amino]-6-[5-[4-[[tert-butoxycarbonyl(methyl)amino]methyl]phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]cyclopropanecarboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.73 (s, 1H), 8.07 (d, J=8.2 Hz, 2H), 7.47 (t, J=6.7 Hz, 2H), 4.49 (s, 2H), 2.83 (s, 5H), 1.91 (s, 2H), 1.49-1.33 (m, 27H). LC/MS m/z 567.6 [M+H]+. (less 1 Boc)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](=[S:8])[NH2:7].Br[CH2:17][C:18](=O)[CH2:19][C:20]([O:22][CH3:23])=[O:21]>>[CH3:15][O:14][C:10]1[CH:9]=[C:5]([C:6]2[S:8][CH:17]=[C:18]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[N:7]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:11]=1[O:12][CH3:13]
Reactant: COC(=O)CC(=O)CBr
Reactant: COc1cc(C(N)=S)cc(OC)c1OC
Product: COC(=O)Cc1csc(-c2cc(OC)c(OC)c(OC)c2)n1

Procedure:
3,4,5-Trimethoxybenzothioamide (1.0 g) and methyl 4-bromoacetoacetate (858 mg)) were reacted in the same manner in Preparation Example 2 to obtain the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[BrH:15]>C(O)(=O)C>[BrH:15].[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1
Reactant: COc1ccccc1C1CCNCC1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccccc1C1CCNCC1

Procedure:
2-Methoxybenzaldehyde (200 g) and ethyl acetoacetate (400 g) were mixed and cooled to 5° C. Piperidine (25 ml) was added and the mixture was stirred overnight at room temperature. The next day potassium tert-butoxide (25 g) was added. After 1.5 hours the mixture totally solidified and was left for 2 days. Ethanol (2000 ml) was added and the pricipitate was filtered off, washed with ethanol and finally dried in vacuo. Yield: 326 g. All of the thus obtained solid product (325 g) was added in small portions during one hour to a solution of potassium hydroxide (260 g) in water (320 ml) kept at 80-90° C. After stirring for further two hours at 80°, water (2000 ml) and diethyl ether (1000 ml) were added. After stirring, the organic phase was separated and discarded. To the remaining aqueous solution was added ice and concentrated hydrochloric acid until pH<1. After stirring for 45 minutes, the precipitated product was filtered off and dried. Yield of 3-(2-methoxyphenyl)-1,5-pentanedicarboxylic acid: 137 g, mp: 183-185° C. A mixture of the pentane-dicarboxylic acid (97 g) and urea (28 g) was heated at 160-165° C. for 2 hours. After cooling to 70° C., ethanol (150 ml) was added. The precipitated 4-(2-methoxyphenyl)-2,6-piperidinedione was filtered off and subsequently dried. Yield 66 g. Mp: 127-129° C. To a suspension of LiAlH4 (30 g) in dry THF (1000 ml) were added small portions (in total 65 g) of the piperidinedione while the temperature gradually raised to reflux. After reflux for 2.5 hours, the mixture was cooled below 10° C. and diluted aqueous NaOH solution (4M) (60 ml) was cautiously added. Precipitated inorganic salts were filtered off. The solvent was evaporated and the remaining oil was dissolved in dichloromethane, dried (anh. Na2SO4), filtered and dichloromethane evaporated leaving 56 g of 4-(2-methoxyphenyl)piperidine as an oil. All of the piperidine was dissolved in a mixture of 48% aqueous hydrobromic acid (400 ml) and a 33% solution of hydrogenbromide in acetic acid (400 ml). The solution was refluxed for 19 hours. Excess hydrobromic and acetic acids was evaporated in vacuo leaving 47 g of 4-(2-hydroxyphenyl)piperidine hydrobromide as a visceous oil. The hydrobromide (45 g) was dissolved in a mixture of water (300 ml) and THF (150 ml). Potassium carbonate (80 g) was added in small lots. A solution of di-tert-butyldicarbonate (40 g) in THF (150 ml) was added dropwise. The mixture was stirred overnight. The aqueous phase was separated and washed with dietyl ether (2×100 ml). The combined organic phases were dried (anh. MgSO4) and the solvents evaporated. The remaining product was stirred with diisopropyl ether and the precipitated product was filtered off. Yield of the title phenol derivative 5a: 24 g, mp: 187-189° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=CC=1.C1(CCN2CCN(C3SC(C(O)=O)=C(C)N=3)C2=O)CC1.[F:43][C:44]1[CH:51]=[CH:50][C:47]([CH2:48][NH2:49])=[CH:46][CH:45]=1>>[CH:7]1([CH2:2][CH2:1][N:8]2[CH2:12][CH2:11][N:10]([C:13]3[S:14][C:15]([C:19]([NH:49][CH2:48][C:47]4[CH:50]=[CH:51][C:44]([F:43])=[CH:45][CH:46]=4)=[O:21])=[C:16]([CH3:18])[N:17]=3)[C:9]2=[O:22])[CH2:6][CH2:5]1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1ccc(F)cc1
Agent: Cc1nc(N2CCN(CCC3CC3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CCC3CC3)C2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 34 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(2-cyclopropylethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 4-fluorobenzylamine in place of benzylamine, the title compound was obtained as a white powder in 34% yield: mp 122-123° C.; 1H NMR (300 MHz, CDCl3) δ 7.27-7.23 (m, 2H), 7.00-6.94 (m, 2H), 5.98 (s, 1H), 4.48 (d, J=5.7 Hz, 2H), 4.05 (t, J=7.8 Hz, 2H), 3.56 (t, J=8.7 Hz, 2H), 3.35 (t, J=7.8 Hz, 2H), 2.57 (s, 3H), 1.47-1.40 (m, 2H), 0.67-0.56 (m, 1H), 0.46-0.37 (m, 2H), 0.06-0.01 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 163.8, 162.5, 157.4, 155.3, 153.2, 133.9, 129.5, 116.8, 115.6, 44.0, 43.2, 42.7, 42.0, 32.4, 17.2, 8.4, 4.3; MS (ES+) m/z 403.2 (M+1).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C)C=O.[N+:26]([O-:34])([O:28][CH2:29][CH2:30][CH2:31][CH2:32]Br)=[O:27]>ClCCl>[C:4]([O:3][C:1]([NH:8][CH:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:18]([O:20][CH2:32][CH2:31][CH2:30][CH2:29][O:28][N+:26]([O-:34])=[O:27])=[O:19])=[O:2])([CH3:5])([CH3:7])[CH3:6]
Reactant: O=[N+]([O-])OCCCCBr
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(Cc1ccc(O)cc1)C(=O)OCCCCO[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55.2 %

Procedure:
To a solution of Boc-(L)-tyrosine (5.0 g, 17.77 mmol) in N,N-dimethylformamide (40 ml) cesium carbonate (5.79 g, 17.77 mmol) was added. The reaction was cooled at 0° C. and a solution of 4-bromobutyl nitrate (17.77 mmol) in dichloromethane (20% w/w, 17.06 g) was added drop wise. The reaction was stirred at 0° C. for 20 minutes and then at room temperature for 22 hours. The mixture was poured into a 5% aqueous NaH2PO4 solution and extracted with diethyl ether (40×4 ml), the organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, (Biotage System, column FLASH 65+M™ KP-Sil, eluent: gradient n-hexane/ethyl acetate 9/1 (500 ml), to n-hexane/ethyl acetate 1/1 during 4000 ml, n-hexane/ethyl acetate 1/1 (1000 ml)). The product (3.91 g) was obtained.
Reaction SMILES: C1(S([N:10]2[C:19]3[CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][NH:15][C:14](=[O:22])[C:13]=3[S:12][CH:11]2[C:23]2[CH:28]=[CH:27][N:26]=[C:25]3[NH:29][CH:30]=[CH:31][C:24]=23)(=O)=O)C=CC=CC=1.[OH-].[Na+]>CCO>[CH3:20][C:17]1([CH3:21])[CH2:16][NH:15][C:14](=[O:22])[C:13]2[S:12][C:11]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]4[NH:29][CH:30]=[CH:31][C:24]=34)=[N:10][C:19]=2[CH2:18]1
Reactant: CC1(C)CNC(=O)C2=C(C1)N(S(=O)(=O)c1ccccc1)C(c1ccnc3[nH]ccc13)S2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CNC(=O)c2sc(-c3ccnc4[nH]ccc34)nc2C1
Temperature: 25 °C

Procedure:
N-Benzene sulfonyl-5,6,7,8-tetrahydro-7,7-dimethyl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)thiazolo[5,4-c]azepin-4-one (Made using methods D and E) (79 mg, 1.0 Eq.) was suspended/dissolved in EtOH (4.5 mL) and NaOH (15 wt %, 0.5 mL, 11 Eq.) was added. The reaction mixture was refluxed for 4 hours. The reaction mixture was then allowed to cool to RT, and the solvent removed in vacuo. The mixture was partitioned between EtOAc/sat. aq. NH4Cl, and extracted into EtOAc (3×20 mL). The combined organic layers were washed with 15 wt % NaOH (1×10 mL), brine (1×10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification was achieved using column chromatography (5% MeOH/95% DCM), followed by tritration in Et2O. The precipitate was then washed with pentane. The title compound was obtained as a tangerine solid (27.8 mg, 52% yield); 1H NMR (DMSO D6) 1.1 (6H, s), 3.0 (4H, m), 7.0 (1H, m), 7.6 (1H, m), 7.7 (1H, m), 8.3 (2H, m), 12.1 (1H, br s); LC/MS M+1 (obs.) 313.20; LC/MS M−1 (obs.) 311.40.
Reaction SMILES: [CH3:1][C:2]1OC(=O)[S:4][N:3]=1.[CH3:8][O:9][C:10]([C:12]#[C:13][C:14]([O:16][CH3:17])=[O:15])=[O:11]>ClC1C=CC=CC=1>[CH3:8][O:9][C:10]([C:12]1[C:2]([CH3:1])=[N:3][S:4][C:13]=1[C:14]([O:16][CH3:17])=[O:15])=[O:11]
Reactant: Cc1nsc(=O)o1
Reactant: COC(=O)C#CC(=O)OC
Solvent: Clc1ccccc1
Product: COC(=O)c1snc(C)c1C(=O)OC
Reaction time: 6 h
Yield: 53.6 %

Procedure:
A solution of 5-Methyl-[1,3,4]oxathiazol-2-one (37.94 mmol) and dimethylacetylenedicarboxylate (75.89 mmol) in chlorobenzene (22.3 mL) was refluxed with stirring for 6 h before the mixture was concentrated in vacuo. Distillation of the residue gave the desired product (4.38 g) at by 100-105° C. (1.0 Torr) as an oil: MS (m/z) 216.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:31]([N:38]=[C:39]=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CO.CC#N>[CH2:31]([NH:38][C:39]([NH:30][C:29]1[C:9]([C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:10][C:11]2[CH:16]=[N:15][C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[N:13][C:12]=2[N:28]=1)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Reactant: O=C=NCc1ccccc1
Solvent: CO
Solvent: CC#N
Product: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(NC(=O)NCc4ccccc4)nc3n2)CC1
Yield: 63.4 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.08 g) from Example 36 was reacted with 0.298 g of benzyl isocyanate according to the general procedure of Example 37 to give 0.822 g of 1-benzyl-3-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-urea, ESMS (20/80 MeOH/CH3CN+0.1% AcOH): M+ +H=579; mp 144°-148.5° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15]1([O:21][CH2:22][CH2:23]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[ClH:25].C(=O)(O)[O-].[Na+]>CCOCC.CN(C=O)C.C(N(CC)CC)C>[ClH:25].[ClH:25].[O:21]([CH2:22][CH2:23][N:12]1[CH2:13][CH2:14][CH:9]([CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:10][CH2:11]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C1CCN(CCC2CCNCC2)CC1
Reactant: BrCCOc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: c1ccc(OCCN2CCC(CCN3CCCCC3)CC2)cc1

Procedure:
A mixture of 4-(2-piperidinoethyl)piperidine (3.27 g), 2-bromoethyl phenyl ether (3.35 g), triethylamine (2.3 ml) and DMF (50 ml) was heated on a steam bath for 16 hours. The mixture was worked up as described in Example 16. The crude solid hydrochloride was treated with sodium bicarbonate solution and the mixture extracted with dichloromethane to give the free base which was purified by flash chromatography on silica using methanol/triethylamine, 99:1 as the mobile phase. The oil obtained was dissolved in ether and acidified with ethereal hydrogen chloride to give 1-(2-phenoxyethyl)-4-(2-piperidinoethyl)piperidine dihydrochloride, m.p. 285° C.