Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=1.C1(C)C=CC(S([O-])=O)=CC=1.[Na+].[H-].[Na+]>C1COCC1>[C:7]([CH:6]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=1)[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1)#[N:8]
Reactant: Cc1ccnc(Br)c1
Reactant: N#CCc1ccc(F)cc1
Agent: Cc1ccc(S(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccnc(C(C#N)c2ccc(F)cc2)c1
Yield: 45.3 %

Procedure:
p-Fluorobenzyl cyanide (4.1 g), 2-bromo-4-methylpyridine (5.2 g) and sodium p-toluene sulfinate (5.4 g) were suspended in THF (50 ml), and to the solution was added a suspension of 40% sodium hydride (1.2 g) in THF (5 ml) under ice-cooling. The mixture was refluxed for 3 hours, the solvent was distilled off, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give 2-(α-cyano-4-fluorobenzyl)-4-methylpyridine (3.1 g) as brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[NH:19][N:20]=[C:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>N1C=CC=CC=1>[CH3:28][S:29]([O:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([S:15]([CH3:18])(=[O:16])=[O:17])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[NH:19][N:20]=[C:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:31])=[O:30]
Reactant: CCOC(=O)C(C)=NNc1ccc(Oc2ccc(S(C)(=O)=O)nc2)cc1O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C(C)=NNc1ccc(Oc2ccc(S(C)(=O)=O)nc2)cc1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of ethyl 2-[(2-hydroxy-4-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)hydrazono]propanoate (21.1 g) in pyridine (220 mL) was added methanesulfonyl chloride (5.0 mL) at 0° C. The mixture was stirred at 0° C. for 2 h, and then at room temperature for 16 h. The mixture was cooled to 0° C., and methanesulfonyl chloride (5.0 mL) was added to the mixture again. After stirring at room temperature for 2 h, water was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed successively with 1M hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual oil was solidified with ethyl acetate-diethyl ether, and the resulting solid was washed with diethyl ether to give the title compound (20.0 g, 79%) as a pale yellow solid. MS 472 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[NH:10][C:9]2=[N:11][C:12]([CH2:14][CH3:15])=[CH:13][C:8]2=[C:7]([Cl:16])[N:6]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>O1CCCC1.C(Cl)Cl>[CH3:3][S:4][C:5]1[N:6]=[C:7]([Cl:16])[C:8]2[CH:13]=[C:12]([CH2:14][CH3:15])[N:11]([CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([C:18]([F:17])([F:27])[F:28])[CH:20]=3)[C:9]=2[N:10]=1
Reactant: CCc1cc2c(Cl)nc(SC)[nH]c-2n1
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1cc2c(Cl)nc(SC)nc2n1Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.9 %

Procedure:
To a suspension of 48 mg (2.00 mmol) of sodium hydride in 4.0 mL of tetrahydrofuran was added 227 mg (1.00 mmol) of 2-(methylthio)-4-chloro-6-ethyl-1H-pyrrolo[2,3-d]pyrimidine and 478 mg (2.00 mmol) of 3-(trifluoromethyl)benzyl bromide. The reaction was stirred at ambient temperature for 18 hours then diluted with 30 mL of methylene chloride and washed with 20 mL of saturated sodium bicarbonate solution. The organic phase was dried with sodium sulfate and concentrated. The crude product was purified by flash chromatography (25 g silica, methylene chloride-heptane gradient 1:1 to 100:0) to provide 320 mg (83%) of 2-(methylthio)-4-chloro-6-ethyl-7-[[3-(trifluoromethyl)-phenyl]methyl]-7H-pyrrolo[2,3-d]pyrimidine as a white solid. nmr (500 MHz, CDCl3) δ1.31 (t, J=7.3 Hz, 3H), 2.58 (s, 3H), 2.59 (q, J=7.3 Hz, 2H), 5.44 (s, 2H), 6.31 (s, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.41 (t, J=7.8 Hz, 1H), 7.45 (s, 1H), 7.54 (d, J=7.8 Hz, 1H)
Reaction SMILES: C(O)(=O)C.CC1(C)[O:13][CH2:12][CH2:11][CH:10]2[N:7]1[C:8](=[O:17])[CH:9]2[N:14]=[N+:15]=[N-:16]>O>[N:14]([CH:9]1[CH:10]([CH2:11][CH2:12][OH:13])[NH:7][C:8]1=[O:17])=[N+:15]=[N-:16]
Reactant: CC1(C)OCCC2C(N=[N+]=[N-])C(=O)N21
Solvent: O
Solvent: CC(=O)O
Product: [N-]=[N+]=NC1C(=O)NC1CCO
Temperature: 60 °C
Reaction time: 4 h
Yield: 22.5 %

Procedure:
To a mixture of 8 ml of acetic acid and 2 ml of water is added 1.0 g of 2,2-dimethyl-7-azido-1-aza-3-oxa-bicyclo[4,2,0]octane-8-one (1:4 cis-trans mixture) and the mixture is stirred at 60° C. for 4 hours and concentrated to dryness. Tetrahydrofuran (15 ml) is added and the insoluble matter is filtered off. The filtrate is concentrated to dryness and the residue is dissolved in a small amount of chloroform and subjected to column chromatography using silica gel (20 g), elution being carried out with chloroform-ethyl acetate (1:1) and ethyl acetate in that order to give 179 mg of 3-azido-4-hydroxyethyl-2-azetidinone as a colorless oil.
Reaction SMILES: C1(S[CH2:8][N:9]2[C:13](=[O:14])[CH:12]([CH2:15][CH2:16][CH3:17])[N:11]([CH2:18][CH3:19])[S:10]2(=[O:21])=[O:20])C=CC=CC=1.S(Cl)([Cl:25])(=O)=O>C(Cl)Cl>[Cl:25][CH2:8][N:9]1[C:13](=[O:14])[CH:12]([CH2:15][CH2:16][CH3:17])[N:11]([CH2:18][CH3:19])[S:10]1(=[O:21])=[O:20]
Reactant: CCCC1C(=O)N(CSc2ccccc2)S(=O)(=O)N1CC
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCCC1C(=O)N(CCl)S(=O)(=O)N1CC
Yield: 77 %

Procedure:
A solution of 2-phenylthiomethyl-4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1, 1-dioxide (3.97 g) and sulfuryl chloride (1.47 ml) in 80 ml of methylene chloride was stirred for 3 hours at room temperature. The mixture was concentrated in vacuo and the residue triturated in hexane. The solvent was concentrated in vacuo and the residue was purified by flash chromatography (silica gel) to afford 2.4 g (77%) of 2-chloromethyl-4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula II: R1 =H; R2 =propyl; R3 =ethyl; X'=Cl) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[CH:6](Cl)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[CH:6]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3
Reactant: C1CNCCN1
Reactant: Clc1ccc2c(c1)SCc1cccnc1C2Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)SCc1cccnc1C2N1CCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
Add a solution of 8,11-dichloro-5,11-dihydro[1]benzothiepino[4,3-b]pyridine (8.15 g, 0.029 mol) in tetrahydrofuran (100 mL) to a stirred suspension of piperazine (28.9 g, 0.34 mol) in tetrahydrofuran (290 mL) at 18°-19° C. over 20 minutes. Stir the mixture for 4 hours at room temperature and then pour it into 2.5M aqueous NaOH (250 mL) containing ice. Separate the layers, and extract the aqueous portion with EtOAc (3×100 mL). Combine the organic portions, and wash with H2O (3×75 mL) and brine (150 mL). Dry the mixture over MgSO4, filter, and concentrate the organic layer in vacuo to obtain the crude product (8.9 g). Purify the crude product via flash chromatography (9:1:0.125 CH2Cl2 /MeOH/NH4OH) to obtain the title compound (7.6 g, 78% yield).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH2:23](I)[CH3:24]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:23]([N:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[S:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:24]
Reactant: CCI
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Product: CCN1c2ccccc2Sc2ccccc21
Yield: 83.8 %

Procedure:
Into a 1-liter reaction flask were introduced 25 g (0.126 mol) of phenothiazine, 50.0 g (0.757 mol) of 85% KOH, 4.3 g (0.013 mol) of tetra-n-butylammonium hydrogensulfate, 28.0 g (0.203 mol) of potassium carbonate, and 500 ml of toluene. Thereto was gradually added 39.0 g (0.250 mol) of ethyl iodide. The mixture was reacted at 60 to 70° C. for 5 hours and then filtered. The filtrate was washed twice with water, dried with magnesium sulfate, and then concentrated. As a result, 28.7 g of a crude reaction product was obtained. This crude product was recrystallized from 100 ml of isopropanol to obtain 23.99 g of 10-ethylphenothiazine (4a).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)([CH2:12][OH:13])[CH2:10]O)=[CH:5][CH:4]=1.C([Li])CCC.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2([C:14]3[S:15][CH:16]=[CH:17][N:18]=3)[CH2:12][O:13][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COC(CO)(CO)c2nccs2)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(COC2(c3nccs3)COC2)cc1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 2-(4-methoxybenzyloxy)-2-(thiazol-2-yl)propane-1,3-diol (Example 11C) (4.02 g, 13.61 mmol) in tetrahydrofuran (120 mL) was added n-butyllithium (5.4 mL, 13.6 mmol, 2.5 M solution in hexane) dropwise. After 0.5 hours, a solution of para-toluenesulfonyl chloride (2.59 g, 13.61 mmol) in tetrahydrofuran (16 mL) was added to the suspension. The reaction was stirred for an additional 0.5 hours. Thereafter, n-butyllithium (5.4 mL, 13.6 mmol, 2.5 M solution in hexane) was added to the reacton dropwise, and the reaction was heated to 65° C. for 1 hour. The reaction was cooled to room temperature and quenched by the addition of water and ethyl acetate. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate (2×). The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 30% ethyl acetate in hexane, to give the title product. MS ESI(+) m/z 278.3 [M+H]+;
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]2[C:13]([NH:15][C:16]2([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[CH2:18][CH2:17]2)=[O:14])=[CH:4][C:3]=1[CH3:31].O[Li].O>>[F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]2[C:13]([NH:15][C:16]2([C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)[CH2:18][CH2:17]2)=[O:14])=[CH:4][C:3]=1[CH3:31]
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3Cc3ccc(F)c(C)c3)CC2)cc1
Agent: [Li]O
Solvent: O
Product: Cc1cc(CN2CCCC[C@@H]2C(=O)NC2(c3ccc(C(=O)O)cc3)CC2)ccc1F
Yield: 31.7 %

Procedure:
The title compound (E12) (10.1 mg) was prepared according to the general procedure for esters hydrolysis starting from (R)-methyl 4-(1-(1-(4-fluoro-3-methylbenzyl)piperidine-2-carboxamido)cyclopropyl)benzoate (D29) (33 mg). (LiOH H2O: 3 eq; reaction time: 3 hrs)
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH:10]1([C:13]2[N:18]=[C:17]([Cl:19])[C:16]([CH3:20])=[C:15](Cl)[N:14]=2)[CH2:12][CH2:11]1.[NH:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[N:31][CH:32]=[CH:33][CH:34]=3)[N:29]=2)[CH2:24][CH2:23]1.N1C2C(=CC=CN=2)C=CC=1.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C.CC(N(C)C)=O>[CH:10]1([C:13]2[N:14]=[C:15]([N:22]3[CH2:23][CH2:24][CH:25]([C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[N:31][CH:32]=[CH:33][CH:34]=5)[N:29]=4)[CH2:26][CH2:27]3)[C:16]([CH3:20])=[C:17]([Cl:19])[N:18]=2)[CH2:11][CH2:12]1
Reactant: Cc1c(Cl)nc(C2CC2)nc1Cl
Reactant: c1cnc2nc(C3CCNCC3)ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1cnc2ncccc2c1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1c(Cl)nc(C2CC2)nc1N1CCC(c2ccc3cccnc3n2)CC1
Temperature: 100 °C
Yield: 51.7 %

Procedure:
20 ml of dimethylacetamide and 3.36 ml (19.2 mmoles) of diisopropylethylamine are added into a single-necked flask containing 1.5 g (7.39 mmoles) of 2-cyclopropyl-4,6-dichloro-5-methyl-pyrimidine and 1.58 g (7.39 mmoles) of 2-piperidin-4-yl-[1,8]naphthyridine. This mixture is heated at 100° C. overnight. The next day 0.2 equivalent of naphthyridine is added and the reaction mixture is heated for another 6 hours, followed by returning to ambient temperature before concentration to dryness. The residue obtained is taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is separated and the aqueous phase reextracted with ethyl acetate. The collected organic phases are dried over magnesium sulphate then the solvent is evaporated off under reduced pressure (2 kPa). The residue is chromatographed on silica gel eluting with a gradient of heptane-ethyl acetate (50-50) to 100% ethyl acetate. 1.45 g of expected product is obtained.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]([C:14]3[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[N:15]=3)[C:10]([F:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1.[H][H]>CCO.CCOC(C)=O.[OH-].[Pd+2].[OH-]>[F:13][C:10]1[C:9]([C:14]2[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[N:15]=2)=[CH:8][C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:12][N:11]=1
Reactant: [H][H]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C4=CCOCC4)cnc3F)n2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C4CCOCC4)cnc3F)n2)cc1
Reaction time: 18 h
Yield: 76.3 %

Procedure:
A solution of 4-(5-(3,6-dihydro-2H-pyran-4-yl)-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (300 mg, 0.569 mmol) in 5 mL of EtOH and 5 mL of EtOAc was placed with palladium hydroxide (20% wt.) (80 mg, 0.114 mmol) and hydrogenated with a balloon full of hydrogen. After 18 h, the mixture was filtered through a pad of Celite® (diatomaceous earth) and rinsed with 2×10 mL of EtOAc. The filtrate was concentrated and the residue was purified on a silica gel column and eluted with 20-65% EtOAc in hexanes to provide 4-(2-fluoro-5-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (230 mg, 76% yield) as an off white amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.36 (dd, J=9.4, 1.6 Hz, 1H), 8.30 (d, J=1.9 Hz, 1H), 7.24 (m, 4H), 6.90 (m, 4H), 4.79 (s, 2H), 4.75 (s, 2H), 3.94 (m, 2H), 3.74 (s, 3H), 3.72 (s, 3H), 3.45 (m, 2H), 2.95 (m, 1H), 2.47 (s, 3H), 1.70 (m, 4H). m/z (ESI, positiive ion) 530.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:6]=1F)[CH3:2].[O:16]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17]1.CC([O-])(C)C.[K+].CO>CN(C=O)C.[Pd].C1COCC1>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:6]=1[O:21][CH:18]1[CH2:19][CH2:20][O:16][CH2:17]1)[CH3:2]
Reactant: OC1CCOC1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(N)ccc1OC1CCOC1

Procedure:
Prepared analogously to example 53a with 2-fluoro-5-nitro-benzic acid ethylester (1 g; 4.69 mmol); tetrahydrofuran-3-ol (379 μL; 4.69 mmol); KOtBu (578 mg; 5.16 mmol) in DMF and for step ii) 10 mL MeOH; 5 mL THF and Pd/C (40 mg), H2 (3 bar).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:4][C:3]=1[N+:22]([O-:24])=[O:23].[ClH:25]>O1CCOCC1>[ClH:25].[N+:22]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1)([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2ccc([N+](=O)[O-])c(N)n2)C1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nc(NC2CCCNC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
610 mg (1.62 mmol) of tert-butyl 3-[(6-amino-5-nitropyridin-2-yl)-amino]piperidine-1-carboxylate (Example 14A) were dissolved in 40 ml of a hydrochloric acid solution in dioxane (4 M) and stirred at RT for 30 min. On completion of reaction, the solvent was removed completely. 662 mg of the crude product were obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:24]=[C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:31])[CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)C.Cl.O1CCOCC1>[ClH:31].[ClH:31].[Cl:31][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[N:24]=[C:23]2[N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(N3CCOCC3)c3cc(Cl)ccc3n2)CC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Clc1ccc2nc(NC3CCNCC3)nc(N3CCOCC3)c2c1

Procedure:
A solution of 4-(6-chloro-4-morpholin-4-yl-quinazolin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.6 g, 1.34 mmol) in ethanol (5 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 348.4 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:28].[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1B(O)O.CC(C)([O-])C.[K+]>COCCOC.O.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>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[S:29][CH:33]=[CH:32][CH:31]=4)=[C:3]([F:28])[CH:4]=3)(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: OB(O)c1cccs1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2cccs2)c(F)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-3-fluorobenzenesulfonamide (E105) (100 mg, 0.21 mmol) and 2-thienylboronic acid (54 mg, 0.42 mmol) in DME (3 ml) was added potassium tert-butoxide (212 mg, 1.89 mmol) and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. Additional 2-thienylboronic acid (27 mg, 0.21 mmol) and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol) were then added and the mixture stirred in a microwave (set at high absorbance) at 100° C. for a further 45 minutes. The solvent was evaporated with addition of a few drops of toluene and the residue passed through an SCX column eluting with methanol followed by 2M ammonia in methanol. The abasic fractions were combined and the solvent evaporated. The crude product was purified by mass directed autoprep HPLC, the relevant fractions collected and solvent evaporated to afford the title compound (E114). MS (ES+) m/e 476 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[ClH:8].[CH3:9]O>>[ClH:8].[CH3:9][O:6][C:5](=[O:7])[C@H:2]([CH2:3][OH:4])[NH2:1]
Reactant: CO
Reactant: N[C@H](CO)C(=O)O
Agent: Cl
Product: COC(=O)[C@@H](N)CO
Yield: 99 %

Procedure:
A solution of 47.7 mmol of D-serine in 476 ml of methanol was saturated with hydrochloric acid gas and allowed to react at room temperature for 2 hrs. Following the evaporation of the solvent, recrystallization with methanol and ether produced the object compound L-serine methyl ester hydrochloric acid salt (Yield: 99%, m.p.: 163-164° C., [α]25 D=−4.3(c 1.8, EtOH)). The structure of the synthesized compound was identified using FTIR, 1H-NMR and 13C-NMR.
Reaction SMILES: [O:1]([C:8]1[C:9]([NH:24][C:25]2[S:26][CH:27]=[C:28]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[N:29]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[CH:21]=[CH:22][S:23][C:16]=23)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:43]([Cl:46])(=[O:45])[CH3:44].C([O-])(O)=O.[Na+].[ClH:52]>C1COCC1>[ClH:46].[ClH:52].[O:1]([C:8]1[C:9]([NH:24][C:25]2[S:26][CH:27]=[C:28]([CH:30]3[CH2:35][CH2:34][N:33]([C:43](=[O:45])[CH3:44])[CH2:32][CH2:31]3)[N:29]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[CH:21]=[CH:22][S:23][C:16]=23)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Oc2cc(Sc3ccnc4ccsc34)cnc2Nc2nc(C3CCNCC3)cs2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2csc(Nc3ncc(Sc4ccnc5ccsc45)cc3Oc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35.9 %

Procedure:
A 20 mL vial was charged with 3-phenoxy-N-(4-(piperidin-4-yl)thiazol-2-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine (80 mg, 0.15 mmol), triethylamine (0.043 mL, 0.31 mmol), and THF (2 mL). Acetyl chloride (0.011 mL, 0.15 mmol) was added and stirred at ambient temperature for 10 minutes. The reaction was poured into saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried with sodium sulfate, filtered and concentrated. The residue was purified on silica gel (5 to 10% methanol in EtOAc) to afford the title compound (35.1 mg, 35.9% yield) as a yellow solid after HCl salt formation. 1H NMR (d6-DMSO) δ 8.65 (d, 1H), 8.48 (d, 1H), 8.46 (d, 1H), 7.77 (d, 1H), 7.54 (d, 1H), 7.41 (m, 2H), 7.18 (m; 4H), 6.82 (s, 1H), 4.43 (m, 1H), 3.88 (m, 1H), 3.14 (m, 1H), 2.89 (m, 1H), 2.64 (m, 1H), 2.01 (s, 3H), 1.96 (m, 2H), 1.58 (m, 1H), 1.45 (m, 1H). Mass spectrum (apci) m/z=560.4 (M+H-2HCl).
Reaction SMILES: [Li+].[BH4-].C[O:4][C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([Br:15])[CH:8]=1.O>C1COCC1>[Br:15][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][OH:4])[CH:12]=[CH:11][C:10]=1[C:13]#[N:14]
Reactant: COC(=O)Cc1ccc(C#N)c(Br)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(CCO)cc1Br
Reaction time: 12 h

Procedure:
LiBH4 (1.48 mL, 2.95 mmol, 2 M in THF) was added to a stirred solution of methyl(3-bromo-4-cyanophenyl)acetate (0.50 g, 2.0 mmol) in THF (25 ml) at 0° C. The resulting solution was stirred for 12 h. Water (15 ml) was added, and the resulting solution was extracted with dichloromethane (2×50 ml). The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure to yield the crude product as a cloudy oil. 1H NMR (500 MHz, CDCl3) δ 7.63 (s, 1H), 7.61 (d, J=5.7, 1H), 7.33 (d, J=7.8 Hz, 1H), 3.93 (t, J=1.6, J=4.8 Hz, 2H), 2.92 (t, J=6.6, J=5.1 Hz, 2H). LC-MS (IE, m/z): 210.1 [(M+1)]+−OH].