Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:27])[N:7]([CH2:25][CH3:26])[CH2:8][CH2:9][NH:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[CH:17][CH:16]=2)=[O:12])([CH3:4])[CH3:3].[CH2:28](NCCNC(C1NC2C(C=1)=CC([N+]([O-])=O)=CC=2)=O)CC>>[CH3:4][C:2]([O:5][C:6](=[O:27])[N:7]([CH2:8][CH2:9][NH:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[CH:17][CH:16]=2)=[O:12])[CH2:25][CH2:26][CH3:28])([CH3:1])[CH3:3]
Reactant: CCN(CCNC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1)C(=O)OC(C)(C)C
Reactant: CCCNCCNC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Product: CCCN(CCNC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1)C(=O)OC(C)(C)C
Yield: 88 %

Procedure:
Similar procedure as described for preparation of 78 from compound 81 (0.12 g, 0.413 mmol) gave brown powder (0.142 g, 88%). ESI MS: 391.17 (M+H+), 413.15 (M+Na+).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=[O:20])[CH2:3]1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>ClCCl>[CH3:28][S:29]([O:1][CH:2]1[CH2:5][N:4]([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=[O:20])[CH2:3]1)(=[O:31])=[O:30]
Reactant: O=C1CCCCN1c1ccccc1CCN1CC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(CCc2ccccc2N2CCCCC2=O)C1
Reaction time: 2 h

Procedure:
To 1-{2-[2-(3-hydroxyazetidin-1-yl)ethyl]phenyl}piperidin-2-one a11-1 (212 mg, 0.77 mmol, 1 eq) in dichloromethane (15 ml) under nitrogen is added triethylamine (216.04 μl, 1.55 mmol, 2 eq). Methanesulfonyl chloride (106.53 mg, 0.93 mmol, 1.2 eq) is added at 0° C. and the reaction mixture is allowed to reach room temperature while stirring for 2 hours under a nitrogen atmosphere. Additional triethylamine (216 μl, 1.55 mmol, 2 eq) and methanesulfonyl chloride (106.53 mg, 0.93 mmol, 1.2 eq) are added, and the reaction mixture stirred at room temperature under nitrogen for an additional hour. Water (50 ml) is then added, the two phases vigorously shaken and separated. The organic phase is dried over MgSO4, filtered and evaporated to dryness to give 1-{2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl}azetidin-3-yl methanesulfonate a11-2 which is used in next step without any further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[Cl-].[CH3:22][Zn+].O>O1CCCC1.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>[CH3:22][C:2]1[N:7]=[C:6]2[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3ccc(Cl)nc32)cc1
Reactant: C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3ccc(C)nc32)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 81 %

Procedure:
The synthesis was performed with reference to the known literature (US 2006/0148801). A solution of 6-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (0.38 g, 1.2 mmol) in tetrahydrofuran (20 mL) was added with tetrakis(triphenylphosphine)palladium(0) (0.069 g, 0.060 mmol) under an argon atmosphere. Then, the mixture was added dropwise with a 2 M solution of methyl zinc chloride in THF (3.6 mL, 7.2 mmol), and then the mixture was stirred at 60° C. for 48 hours. The reaction mixture was added with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with hexane/ethyl acetate (90:10→50:50)) to obtain 6-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine (0.28 g, 81%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20][CH3:21])=[O:19])[CH:8]=[CH:7]2)(=[O:3])[CH3:2].[C:22](OCC)(=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24].[O-][CH2:33]C.[Na+].[Na].Cl>C(O)C.C(OCC)(=O)C>[O:3]=[C:1]1[C:4]2[CH:5]=[C:6]3[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=2[O:14][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:2]1)[N:10]=[C:9]([C:18]([O:20][CH2:21][CH3:33])=[O:19])[CH:8]=[CH:7]3
Reactant: CC[O-]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCCc1c(O)c(C(C)=O)cc2ccc(C(=O)OC)nc12
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCc1c2nc(C(=O)OCC)ccc2cc2c(=O)cc(C(=O)OCC)oc12

Procedure:
The product of step (a) (1.75 g), and diethyl oxalate (4.38 g) dissolved in dry ethanol (50 mls) was added to sodium ethoxide solution (prepared by the addition of sodium (0.35 g), to dry ethanol (50 mls) with stirring. The reaction mixture was stirred under reflux for 1 hr, cooled, poured into ethyl acetate and dilute hydrochloric acid and the organic layer separated, washed well with water and dried. The solvent was evaporated and the residue treated with ethanol saturated with hydrogen chloride gas (100 mls) and refluxed for 10 mins. The reaction mixture was cooled, poured into water, and the precipitated product collected by filtration, washed well with water and dried to give 2.5 g of product. A recrystallisation from ethanol gave 1.25 g, mp 168°-171°.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].CC(NS(C1C=CC2CCCCC=2C=1)(=O)=[O:25])(C)C.C([Li])CCC>O1CCCC1>[CH3:4][C:2]([NH:5][S:6]([C:9]1[C:18]2[CH:17]([OH:25])[CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc2c1CCCC2
Reactant: CC(C)(C)NS(=O)(=O)c1ccc2c(c1)CCCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1cccc2c1C(O)CCC2
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 25.2 g (93.5 mmol) of a 1:1 mixture of N-(1,1-dimethylethyl)-5,6,7,8-tetrahydro-1-naphthalenesulfonamide and N-(1,1-dimethylethyl)-5,6,7,8-tetrahydro-2-naphthalenesulfonamide in 450 mL of tetrahydrofuran at -10° C., was added dropwise 75 mL (187 mmol) of a 2.5M solution of n-butyllithium in hexanes. After 90 minutes at this temperature the reaction mixture had turned red. The reaction mixture was cooled to -78° C. and oxygen was bubbled through for 15 minutes until the red color disappeared. After an additional 15 minutes, 200 mL of 5% NaHSO3 was added. The reaction mixture was extracted with ethyl acetate, dried (Na2SO4) and the solvent was removed with a rotary evaporator. The residue was purified by flash chromatography to give 6.0 g of the title compound as a sticky solid; m.p. 100°-111° C.
Reaction SMILES: [CH3:1][Mg]Cl.[CH3:4][N:5]1[C:13]2[C:8](=[CH:9][C:10](C(OC)=O)=[CH:11][CH:12]=2)[C:7]([C:18]2[N:30]([S:31]([C:34]3[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[C:21]3=[N:22][CH:23]=[C:24]4[CH:28]=[N:27][N:26]([CH3:29])[C:25]4=[C:20]3[CH:19]=2)=[CH:6]1.[CH3:41][C:42]([OH:44])=O>C1COCC1.O>[CH3:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:42]([OH:44])([CH3:41])[CH3:1])=[CH:11][CH:12]=2)[C:7]([C:18]2[N:30]([S:31]([C:34]3[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=3)(=[O:32])=[O:33])[C:21]3=[N:22][CH:23]=[C:24]4[CH:28]=[N:27][N:26]([CH3:29])[C:25]4=[C:20]3[CH:19]=2)=[CH:6]1
Reactant: CC(=O)O
Reactant: COC(=O)c1ccc2c(c1)c(-c1cc3c4c(cnc3n1S(=O)(=O)c1ccc(C)cc1)cnn4C)cn2C
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(C(C)(C)O)cc34)cc3c4c(cnc32)cnn4C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A solution of MeMgCl (3 M in THF, 0.65 mL, 1.95 mmol) in THF (4 mL) was cooled to about −40° C. then methyl 1-methyl-3-(1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-indole-5-carboxylate (0.125 g, 0.243 mmol, prepared using D from Preparation #1 and Preparation #18 in THF (3 mL) was added. The mixture was warmed to rt and stirred for about 1 h. The mixture was treated with AcOH (˜0.75 mL) then the mixture was diluted with water (30 mL). The mixture was extracted with EtOAc (2×25 mL). The combined organics were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 2-(1-methyl-3-(1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-indol-5-yl)propan-2-ol (0.115 g, 92%): LC/MS (Table 2, Method a) Rt=2.26 min; MS m/z 514 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[BH4-].[Li+].CO.C(Cl)(Cl)Cl>COCCOC>[C:12]([O:11][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@H:4]1[CH2:3][OH:2])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Yield: 92 %

Procedure:
This compound was prepared in 92% yield from the ester 4g (9.2 g, 40 mmol) by reduction with lithium borohydride in dry DME following the procedure that has been described earlier1,2. TLC Rf 0.81 (eluent MeOH/CHCl3, 7/93). 1H NMR (CDCl3) δ 1.47 (s, 9H, t-Bu), 1.58-2.18 (m, 4H, CH2CH2CH), 3.15-3.66 (m, 4H, CH2N, CH2OH), 3.73-4.07 (m, 1H, CHN), 4.40-4.80 (br s, 1H, OH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[NH:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.[OH-].[Na+].Cl>C1COCC1.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[NH:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(-c2ccc(N)c(NC(=O)c3ccc(OC)cc3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)Nc2cc(-c3ccc(C(=O)O)cc3)ccc2N)cc1
Yield: 80.3 %

Procedure:
A solution of 104 (44 mg, 0.117) and NaOH 1M (0.24 ml, 0.24 mmol) in THF (1 ml) and water (1 ml) was stirred 48 h at 40° C. HCl 1M was added and the precipitate was filtered out. The solid was further purified by flash chromatography (eluent 3-5% MeOH in DCM), to give the compound 105 (34 mg, 80% yield). 1H NMR: (DMSO) δ (ppm): 9.61 (s, 1H), 7.98 (d, J=8.6 Hz, 2H), 7.93 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.2 Hz, 2H), 7.58 (d, J=2.0 Hz, 1H), 7.40 (dd, J=8.2, 2.0 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.4 Hz, 1H), 5.23 (s, 2H), 3.84 (s, 3H). MS: (calc.) 362.1; (obt.) 363.1 (MH)+.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]([C@@:17]12[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH2:20][C@@H:19]([N:25](C(=O)C(F)(F)F)[C@@H:26]1[C@H:31]([O:32][CH3:33])[CH2:30][O:29][CH2:28][CH2:27]1)[CH2:18]2)=[O:16])=[O:7])(C)(C)C.[BH4-].[Na+].O.C([O-])([O-])=O.[Na+].[Na+]>ClCCl.C(O)C>[C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]([C@@:17]12[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH2:20][C@@H:19]([NH:25][C@@H:26]1[C@H:31]([O:32][CH3:33])[CH2:30][O:29][CH2:28][CH2:27]1)[CH2:18]2)=[O:16])([OH:7])=[O:5]
Reactant: CO[C@@H]1COCC[C@@H]1N(C(=O)C(F)(F)F)[C@@H]1C[C@H]2CCC[C@@]2(C(=O)N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2CCC[C@@]2(C(=O)N2C[C@@H]3C[C@H]2CN3C(=O)O)C1
Yield: 107.7 %

Procedure:
A solution of Example 11A (5.5 g, 9.8 mmol) and NaBH4 (1.1 g, 29.4 mmol) in dichloromethane/ethanol (20 mL/20 mL) was stirred at room temperature for 2 hours. Water was added and the resulting solution was adjusted to pH=10 with saturated Na2CO3 solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to result in the title compound (4.3 g, 95%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[N+:9]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Br)([O-:11])=[O:10].C(=O)([O-])O.[Na+]>C(O)C>[N+:9]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][NH:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])([O-:11])=[O:10]
Reactant: CCOC(=O)CN
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNCc1ccccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 8 h

Procedure:
6.35 g (45.4 mmol) of glycine ethyl ester hydrochloride, 2.45 g (11.3 mmol) of 2-nitrobenzyl bromide and 4.75 g (56.5 mmol) of sodium hydrogencarbonate were dissolved in ethanol, and the obtained solution was stirred at 70° C. overnight. The reaction solution was filtered, and the obtained filtrate was treated with ethyl acetate as the extracting solvent by an ordinary method to obtain the crude product. After the purification by the silica gel column chromatography, the title compound was obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[Br:23][C:24]1[C:29](F)=[CH:28][C:27]([NH2:31])=[C:26]([N+:32]([O-:34])=[O:33])[CH:25]=1>O>[Br:23][C:24]1[C:29]([O:11][C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:28][C:27]([NH2:31])=[C:26]([N+:32]([O-:34])=[O:33])[CH:25]=1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: Nc1cc(F)c(Br)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2cc(N)c([N+](=O)[O-])cc2Br)cc1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
5.2 g of 4-methanesulfonyl-phenol and 5.7 g of potassium carbonate were added in order to an N,N-dimethylformamide (50 ml) solution of 6.4 g of 4-bromo-5-fluoro-2-nitrophenylamine, and the reaction liquid was stirred at 120° C. for 3 hours. 200 ml of water was added to the reaction liquid, and the precipitated solid was taken out through filtration and dried to obtain the entitled compound as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]1[CH:10]=[C:11]([CH:20]2[CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]2)[C:12]2[CH2:17][O:16][C:15](=[O:18])[NH:14][C:13]=2[N:19]=1.[ClH:33]>O1CCOCC1>[ClH:33].[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]1[CH:10]=[C:11]([CH:20]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)[C:12]2[CH2:17][O:16][C:15](=[O:18])[NH:14][C:13]=2[N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3c(O)cccc3O)nc3c2COC(=O)N3)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1Nc2nc(-c3c(O)cccc3O)cc(C3CCCNC3)c2CO1
Reaction time: 3 h
Yield: 46 %

Procedure:
A mixture of 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one hydrochloride (0.070 g, 0.160 mmol), which was obtained in Example 18-1, and 2.5N HCl in 1,4-dioxane (4 mL) was stirred at 80° C. overnight. After cooled to room temperature, the mixture was concentrated under reduced pressure. The resulting residue was diluted with dichloromethane (3 mL), and triethylamine (0.064 g, 0.497 mmol) was added. To the cooled (0° C.) mixture was added di-tert-butyl dicarbonate (0.047 g, 0.218 mmol) under an argon atmosphere. The stirring was continued at room temperature overnight. After quenched by water, the mixture was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (hexane/ethyl acetate=1/1) to give tert-butyl 3-[7-(2,6-dihydroxyphenyl)-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl]-1-piperidinecarboxylate (0.019 g, 19%). To a solution of tert-butyl 3-[7-(2,6-dihydroxyphenyl)-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl]-1-piperidinecarboxylate in dioxane (1 mL) was added 4N HCl in dioxane (1 mL) at room temperature. The stirring was continued for 3 hrs. After the solvent was removed by evaporation, the resulting residue was washed with acetonitril, and dried under reduced pressure to give 7-(2,6-dihydroxyphenyl)-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]-oxazin-2-one hydrochloride as a brown solid (0.007 g, 46%).
Reaction SMILES: CN(C)CCCOC1C=CC(C2S[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=NC=2)=CC=1.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[S:35][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=3)=[N:33][CH:32]=2)=[CH:27]1.Cl.ClCCC1CCCN1C>>[CH3:16][N:18]1[CH2:22][CH2:23][CH2:24][CH:19]1[CH2:20][CH2:21][O:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][C:34]2[S:35][C:31]([C:28]3[CH:29]=[CH:30][S:26][CH:27]=3)=[CH:32][N:33]=2)=[CH:38][CH:39]=1
Reactant: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Agent: CN1CCCC1CCCl
Agent: Cl
Product: CN1CCCC1CCOc1ccc(Nc2ncc(-c3ccsc3)s2)cc1

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}-phenyl-amine but starting from 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol (Example 12) and using 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride. MPLC (CH3CN/H2O/TFA) purification affords the title compound: ES-MS: 386.0 [M+H]+; single peak at tR=3.09 min (System 2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15](O)=[O:16])=[CH:13][N:12]3[CH:18]=[CH:19][N:20]=[C:11]3[C:10]=2[Cl:21])=[C:4]([F:22])[CH:3]=1.COC(C1C(NC2C=CC(Br)=CC=2F)=C(Cl)C2N(C=CN=2)C=1)=O.[NH2:46][NH2:47]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([NH:46][NH2:47])=[O:16])=[CH:13][N:12]3[CH:18]=[CH:19][N:20]=[C:11]3[C:10]=2[Cl:21])=[C:4]([F:22])[CH:3]=1
Reactant: O=C(O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1F
Reactant: NN
Agent: COC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1F
Solvent: CCO
Product: NNC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1F

Procedure:
7-(4-Bromo-2-fluoro-phenylamino)-8-chloro-imidazo[1,2-a]pyridine-6-carboxylic acid was converted to the hydrazide according to the coupling conditions described in Step A of Example 3. Alternatively, the hydrazide can be prepared directly from 7-(4-Bromo-2-fluorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester by refluxing with hydrazine in ethanol. MS ESI (+) m/z 398, 400 (M+, Cl, Br pattern) detected.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:6]2[S:11][C:10]([CH2:12][N:13]([CH3:20])[CH2:14][CH:15]3[CH2:19][CH2:18][CH2:17][NH:16]3)=[CH:9][C:7]=2[N:8]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Cl:2][C:3]1[N:4]=[C:5]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[C:6]2[S:11][C:10]([CH2:12][N:13]([CH2:14][CH:15]3[CH2:19][CH2:18][CH2:17][N:16]3[S:35]([CH3:34])(=[O:37])=[O:36])[CH3:20])=[CH:9][C:7]=2[N:8]=1
Reactant: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)CC1CCCN1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)CC1CCCN1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-pyrrolidin-2-ylmethyl-amine hydrochloride salt (380 mg) in dichloromethane (10 mL) was added triethylamine (0.30 mL) and methane sulfonyl chloride (71 μL). The mixture was stirred at room temperature for 2 h and then partitioned between dichloromethane (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The organics were washed with brine (20 mL), dried, reduced in vacuo and purified by column chromatography to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(1-methanesulfonyl-pyrrolidin-2-ylmethyl)-methyl-amine as an off-white solid (124 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[C:16]#[N:17].Cl.[C:19]([NH:23][NH2:24])([CH3:22])([CH3:21])[CH3:20]>C(O)C.C(N(CC)CC)C>[NH2:17][C:16]1[N:23]([C:19]([CH3:22])([CH3:21])[CH3:20])[N:24]=[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=12
Reactant: CC(C)(C)NN
Reactant: CCCn1c(=O)c(C#N)c(Cl)c2ccccc21
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCn1c(=O)c2c(N)n(C(C)(C)C)nc2c2ccccc21
Yield: 87.3 %

Procedure:
In a mixture of 60 ml of ethanol and 5 ml of triethylamine, 2.00 g (8.1 mmol) of Compound b and 2.00 g (16 mmol) of t-butylhydrazine hydrochloride were refluxed for 4 hours. The reaction mixture was dried under reduced pressure, and the residue was partitioned between chloroform and water. The chloroform layer was dried under reduced pressure, and the residue was passed through a silica gel column and eluted with a 3:1 (by volume) mixed solvent of hexane and ethyl acetate. The main fraction collected was dried under reduced pressure to obtain 2.11 g (87%) of Compound 7 as a colorless crystal. The product was treated with ethyl acetate saturated with hydrogen chloride to obtain a hydrochloride of Compound 7.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][C:10]#[CH:11])=[O:6].C(=O)([O-])[O-].[Na+].[Na+]>O>[NH3:4].[C:12]1([CH:8]([NH:7][C:5]2[O:6][CH2:2][CH2:3][N:4]=2)[CH2:9][C:10]#[CH:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C#CCC(NC(=O)NCCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C#CCC(NC1=NCCO1)c1ccccc1
Product: N
Temperature: 25 °C
Yield: 4 %
Yield: 63.2 %

Procedure:
A solution of 200 mg of 1-(2-chloroethyl)-3-(1-phenylbut-3-ynyl)urea (Formula 18) in 5 mL of water was heated at 100° C. for 2.5 hours. The reaction mixture was cooled to room temperature. Then, a saturated solution of sodium carbonate was added until the pH of the solution was greater than 8. The mixture was extracted with ethyl acetate. Combined ethyl acetate was washed with brine, dried over sodium sulfate and concentrated. Column chromatography (4% 7N NH3 in CH3OH/CH2Cl2) gave 54 mg of N-(1-phenylbut-3-ynyl)-4,5-dihydrooxazol-2-amine (Formula 19) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.98-2.00 (m, 1H), 2.66-2.84 (m, 2H), 3.68-3.76 (m, 2H), 4.20-4.26 (m, 2H), 4.83-4.87 (m, 1H), 7.25-7.39 (m, 5H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[N:11]=1.C[O:22][C:23]1[C:26](=O)[C:25](=O)[C:24]=1[O:29]C.[CH3:31][NH2:32]>CO>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:26]2[C:23](=[O:22])[C:24](=[O:29])[C:25]=2[NH:32][CH3:31])[N:11]=1
Reactant: NCCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reactant: COc1c(OC)c(=O)c1=O
Reactant: CN
Solvent: CO
Product: CNc1c(NCCCCCc2csc(NC(N)=NCC(F)(F)F)n2)c(=O)c1=O
Reaction time: 4 h

Procedure:
A mixture of 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(5-aminopentyl)thiazole (0.3 g.) and 1,2-dimethoxycyclobutene-3,4-dione (0.15 g.) in methanol (3 ml.) was allowed to stand at room temperature for 4 hours. Ethanolic methylamine (33% w/v, 20 ml.) was then added and the solution allowed to stand overnight. The mixture was evaporated to dryness and the residue purified by preparative thin layer chromatography using ethyl acetate/methanol/water 6:1:1 v/v/v as developing solvent to give 1-[5-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)pentylamino]-2-methylaminocyclobutene-3,4-dione as colourless gum (0.17 g.). The n.m.r. spectrum of the hydrogen maleate salt in d6 dimethylsulphoxide using tetramethylsilane as internal standard (δ=0) included the following resonances (67 ): 1.5 (multiplet, 6H); 2.6 (multiplet, 2H); 3.1 (doublet, 3H); 3.5 (multiplet, 2H); 4.1 (multiplet, 2H); 6.55 (singlet, 1H).