Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[C:16]([CH3:20])=[CH:17][CH:18]=[N:19][C:5]2=3)[CH2:3][CH2:2]1.[H-].[Na+].C([N-]C(C)C)(C)C.[Li+].[CH:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[C:16]([CH2:20][C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:38])=[CH:17][CH:18]=[N:19][C:5]2=3)[CH2:3][CH2:2]1
Reactant: O=Cc1ccccc1
Reactant: Cc1ccnc2c1NC(=O)c1cccnc1N2C1CC1
Agent: CC(C)[N-]C(C)C
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1ccnc2c1NC(=O)c1cccnc1N2C1CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.2 %

Procedure:
To a solution of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (1.0 g) in tetrahydrofuran (25 m L) was added NaH (80% in oil, 0.12 g). The mixture was stirred at room temperature for 30 min. and then cooled to -78° C. Lithium diisopropylamide (1.5 M in cyclohexane, 6.6 mL) was added and the mixture was stirred for an additional 45 min. Benzaldehyde (0.53 g) was added, the mixture was stirred at -65° C. for 1 hour and then allowed to warm to room temperature. The reaction was quenched with water and the volatile materials were removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried, filtered, and evaporated. The residue was chromatographed over silica gel with 40% ethyl acetate/hexane, and then purified by preparative layer chromatography to give 0.1 g of the title compound, m.p. 195°-197° C.
Reaction SMILES: C(O[CH2:9][CH2:10][C:11]1[N:12]([CH2:28][CH2:29][OH:30])[C:13]([S:19][C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)=[C:14]([CH:16]([CH3:18])[CH3:17])[N:15]=1)C1C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:37]([O:39][CH2:40][CH3:41])C>O>[CH2:40]([O:39][CH2:37][CH2:9][CH2:10][C:11]1[N:12]([CH2:28][CH2:29][OH:30])[C:13]([S:19][C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)=[C:14]([CH:16]([CH3:18])[CH3:17])[N:15]=1)[C:41]1[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1
Reactant: CCOCC
Reactant: CC(C)c1nc(CCOCc2ccccc2)n(CCO)c1Sc1cc(Cl)cc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: CC(C)c1nc(CCCOCc2ccccc2)n(CCO)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
In 30 ml of dry diethyl ether was dissolved 3.0 g (5.8 mmol) of the ester (130d), to the mixture was added 220 mg (5.8 mmol) of lithium aluminium hydride under ice-cooling. The mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and further recrystallized from n-hexane to provide 2.4 g (yield 87%) of 2-(2-(3-benzyloxypropyl)-5-(3,5-dichlorophenylthio)-4-isopropyl-1H-imidazol-1-yl)-ethanol (136e) as crystals. mp 104-106° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:23]1[CH2:27][CH2:26][NH:25][C:24]1=[O:28].Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:18][C:17]1([CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=2)[NH:9][CH:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:23]2[CH2:27][CH2:26][NH:25][C:24]2=[O:28])[CH:3]=1
Reactant: O=C1NCCN1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(Br)c1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CCNC2=O)c1
Temperature: 120 °C
Reaction time: 12 h
Yield: 6 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (360 mg, 1 mmol), imidazolidin-2-one (430 mg, 5 mmol), copper(I) iodide (115 mg, 0.6 mmol), N,N-dimethylglycine hydrochloride (112 g, 0.8 mmol) and potassium carbonate (415 mg, 3 mmol) in dimethyl sulfoxide (5 mL) was stirred at 120° C. for 12 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (22 mg, 6%) as a white solid: LC/MS m/e calcd for C21H23N3O3 (M+H)+: 366.44, observed: 366.1.
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:6]([N:7]3[N:13]([CH3:14])[C:12](=[O:15])[NH:11][CH:8]3[N:9]=2)=[C:5]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[N:4]=[CH:3]1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:37][CH:38]1[CH2:42][CH2:41][N:40]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[CH2:39]1)(=O)=O>O>[NH2:1][N:2]1[C:10]2[C:6]([N:7]3[N:13]([CH3:14])[C:12](=[O:15])[N:11]([CH2:37][CH:38]4[CH2:42][CH2:41][N:40]([C:43]5[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=5)[CH2:39]4)[CH:8]3[N:9]=2)=[C:5]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[N:4]=[CH:3]1
Reactant: CN1C(=O)NC2N=C3C(=C(c4ccco4)N=CN3N)N21
Reactant: COc1ccc(N2CCC(COS(C)(=O)=O)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N2CCC(CN3C(=O)N(C)N4C5=C(c6ccco6)N=CN(N)C5=NC34)C2)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 7.1 %

Procedure:
A mixture of 5-amino-8-(2-furyl)-1-methyl-3H-[1,2,4]triazolo[5,1-f]purin-2-one (0.1 g, 0.368 mmol), DMF (3 ml), potassium carbonate (0.76 g, 0.553 mmol) and [1-(4-methoxyphenyl)pyrrolidin-3-yl]methyl methanesulfonate (0.115 g, 0.405 mmol) stirred at 60° C. for 48 hours. Reaction mixture was cooled to 0° C. Water was added and solid obtained was filtered off. The crude product was purified by HPLC/MS to obtain 5-amino-8-(2-furyl)-3-[[1-(4-methoxyphenyl)pyrrolidin-3-yl]methyl]-1-methyl-[1,2,4]triazolo[5,1-f]purin-2-one (0.012 g, 7%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:5]([CH2:7][CH:8]=[CH:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]2)=[O:6]>[C].[Pd].C(O)C>[OH:1][CH2:2][CH2:3][N:4]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]2)=[O:6]
Reactant: O=C1CCc2cc(OCC=CCC(=O)N(CCO)CC3CCCCC3)ccc2N1
Agent: [Pd]
Solvent: CCO
Product: O=C1CCc2cc(OCCCCC(=O)N(CCO)CC3CCCCC3)ccc2N1
Reaction time: 5 h
Yield: 83.6 %

Procedure:
Into 100 ml of ethanol were added 5 g of 6-{4-[N-(2-hydroxyethyl)-N-cyclohexylmethylaminocarbonyl]-2-butenyloxy}-3,4-dihydrocarbostyril and 1 g of 1% palladium-carbon. The mixture was catalytically hydrogenized under an atmospheric pressure at a room temperature for 5 hours. After the reaction was completed, the catalyst was removed by filtration and the filtrate was concentrated. The residue thus obtained was recrystallized from ethyl acetate-petraleum ether to obtain 4.2 g of 6-{4-[N-(2-hydroxyethyl)-N-cyclohexylmethylaminocarbonyl]butoxy}-3,4-dihydrocarbostyril as in the form of colorless plate-like crystals. Melting point: 123°-125° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[CH2:18](Cl)[Cl:19]>O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([O:12][CH2:18][Cl:19])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: ClCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)OCCl

Procedure:
The title compound was prepared according to the procedure as described in Example 17 Step 1 using 2-((tert-butoxycarbonyl)amino)acetic acid (1 g, 5.7 mmol) in DCM (25 mL) and H2O (25 mL), NaHCO3 (1.92 g, 22.8 mmol), TBAHSO4 (194 mg, 0.57 mmol) and a solution of chloromethyl sulfochloridate (693 mL, 6.8 mmol) in DCM (5 mL). The title compound was obtained as colorless oil (911 mg, 71.3%).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][N:4]=[C:5]=[S:6].[F:9][C:10]([F:28])([F:27])[CH2:11][N:12]=[C:13]([NH2:26])[NH:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])[N:16]=1>C(#N)C>[F:28][C:10]([F:9])([F:27])[CH2:11][N:12]=[C:13]([NH2:26])[NH:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:5]([NH:4][CH2:3][C:2]([F:8])([F:7])[F:1])=[S:6])[N:16]=1
Reactant: NCCCCc1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: FC(F)(F)CN=C=S
Solvent: CC#N
Product: NC(=NCC(F)(F)F)Nc1ccnc(CCCCNC(=S)NCC(F)(F)F)n1
Reaction time: 18 h
Yield: 25.5 %

Procedure:
2,2,2-Trifluoroethylisothiocyanate (0.31 g.) was added to a solution of 4-[2-(2,2,2-trifluoroethyl)-guanidino]-2-(4-aminobutyl)pyrimidine (0.58 g.) in acetonitrile (5 ml.), and the solution kept at room temperature for 18 hours and then evaporated to dryness. The residual gum was purified by preparative thin layer chromatography using ethyl acetate/methanol/ammonia 6:1:0.5 v/v/v as developing solvent to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[4-(3-(2,2,2-trifluoroethyl)thioureido)butyl]pyrimidine (0.22 g.) characterised as the hydrogen maleate, m.p. 142°-145° (after recrystallisation from acetonitrile).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.O1CCCCC1[N:25]1[CH:33]=[C:32]2[C:27]([CH:28]=[C:29]([C:35]3[CH:40]=[CH:39][C:38]([O:41]C4CCCCO4)=[CH:37][CH:36]=3)[CH:30]=[C:31]2[NH2:34])=[N:26]1.[OH-].[Na+]>C(Cl)Cl>[OH:41][C:38]1[CH:37]=[CH:36][C:35]([C:29]2[CH:28]=[C:27]3[C:32]([CH:33]=[N:25][NH:26]3)=[C:31]([NH:34][C:16]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)=[O:17])[CH:30]=2)=[CH:40][CH:39]=1
Reactant: Nc1cc(-c2ccc(OC3CCCCO3)cc2)cc2nn(C3CCCCO3)cc12
Reactant: O=C(Cl)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cc(-c2ccc(O)cc2)cc2[nH]ncc12)C1CCCCC1
Reaction time: 1 h

Procedure:
DIPEA (82 mg, 0.635 mmol) and cyclohexanecarbonyl chloride (37 mg, 0.254 mmol) were added to 2-(tetrahydro-2H-pyran-2-yl)-6-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2H-indazol-4-amine (50 mg, 0.127 mmol) in DCM (1 ml) and the reaction was stirred for 1 h. 2 M Sodium hydroxide (aq) (2 ml) was added and the reaction stirred for 1 h. The organic layer was passed through a hydrophobic frit and the aqueous layer was extracted with DCM. The organic layers were combined and the solvent removed under a stream of nitrogen. The residue was dissolved in MeOH (2 ml), 4 M HCl in 1,4-dioxane (2 ml) was added and the reaction was stirred at RT for 1 h. The solvent was removed under a stream of nitrogen. The residue was purified by MDAP using the following method:
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:13]2[C:8](=[C:9]([F:14])[CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][N:5]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][CH:17]=1>CN(C=O)C>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[N:7]=[CH:6][N:5]=[C:4]2[O:24][CH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=1
Reactant: Fc1cccc2c(Cl)ncnc12
Reactant: Cc1ccc(CCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CCOc2ncnc3c(F)cccc23)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.6 g of sodium hydride (50%, suspension in oil) and 2 g of 4-chloro-8-fluoroquinazoline in 20 ml of DMF was added 1.64 g of 2-(4-methylphenyl)ethanol, and the mixture was stirred for one hour. Then the mixture was poured into ice water. The solid was collected by filtration. Yield: 0.7 g (20.5%). M.P. 72°-74° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.[Cl:14]N1C(=O)CCC1=O.Cl.CCOCC>C(Cl)(Cl)Cl>[Cl:14][C:2]1[NH:1][C:9]2[C:4]([C:3]=1[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(Cl)[nH]c2ccccc12
Reaction time: 1 h
Yield: 47.7 %

Procedure:
A stirred suspension of methyl indole-3-carboxylate (6.0 g, 0.034 mole) in chloroform (200 ml) was treated with N-chlorosuccinimide (5.04 g, 0.038 mole) to afford a clear solution within 15 minutes. After 2 h at room temperature this was treated with 1M HCl/ether (34 ml, 0.034 mole) and allowed to stir for a further 1 h, then treated with excess 10% Na2 CO3 solution and the chloroform layer separated, dried (Na2 SO4) and concentrated in vacuo. The residual yellow solid was recrystallised from chloroform/60-80 petrol to afford the title compound (D 11a) as a beige solid (3.4 g, 48%).
Reaction SMILES: O=O.[Br:3]/[C:4](=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])/[C:5]([OH:7])=[O:6].C(N(CC)CC)C.Cl>O>[Br:3][C@@H:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:5]([OH:7])=[O:6]
Reactant: CCCCC/C=C(\Br)C(=O)O
Agent: Cl
Agent: O=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCC[C@H](Br)C(=O)O
Reaction time: 0.25 h
Yield: 89.2 %

Procedure:
A catalyst solution was prepared by dissolving 59.6 mg (0.045 mmol) of Ru(CF3COO)2 [(S)-MeOBIPHEP-TS-Na] in 20 ml of water in a glove box (O2 content <1 ppm) and was stirred at 20° for 15 min. Then, 1.0 g (4.52 mmol) of (Z)-2-bromo-2-octenoic acid, 30 ml of water and 0.46 g (4.52 mmol) of triethylamine were placed in a 185 ml autoclave and the above-prepared 20 ml of catalyst solution were added. The autoclave was sealed and the hydrogenation was carried out at 20° while stirring and under a constant pressure of 50 bar. After 4 hours the conversion was 100%. The hydrogenation solution was acidified to pH 1 with 1N HCl solution and extracted with diethyl ether. After drying and evaporating the ether extract (40°/20 mbar) the residue was distilled at 115°/0.2 mbar in a bulb tube oven. There was obtained 0.9 g (90%) of (S)-2-bromo-octanoic acid as a colourless oil; chem. purity 98.9 GC area %; 93.0% ee.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([C:11]#[N:12])[CH:3]=1.[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:15]3[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=3[CH3:13])[CH2:22][CH2:23]2)=[O:8])=[C:4]([CH:3]=1)[C:11]#[N:12]
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: N#Cc1cc(Br)ccc1C(=O)O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Yield: 84 %

Procedure:
Using 4-bromo-2-cyanobenzoic acid (1.81 g) described in Preparation Example 76 and 1-(2,4-dimethylphenyl)piperazine (1.67 g) and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (2.68 g) was obtained.
Reaction SMILES: [Na].CC1(C)[O:7][C@H:6]([C:8]([O-:10])=O)[CH2:5][O:4]1.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.Cl.[CH3:37][O:38][C:39](=[O:44])[C@H:40]([CH2:42][SH:43])[NH2:41].CN1CCOCC1>CN(C)C=O>[CH3:37][O:38][C:39](=[O:44])[C@H:40]([CH2:42][SH:43])[NH:41][C:8](=[O:10])[C@@H:6]([OH:7])[CH2:5][OH:4]
Reactant: CC1(C)OC[C@@H](C(=O)[O-])O1
Reactant: COC(=O)[C@@H](N)CS
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CS)NC(=O)[C@@H](O)CO
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
To a solution of 60.0 g of sodium-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]carboxylate in 500 ml of dimethylformamide were added 136.0 g of O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium-hexafluorophosphate. The mixture was stirred at 20° C. for 0.5 hours, then 62 g L-cysteine methyl ester hydrochloride and subsequently 36.7 g of N-methylmorpholine were added. The mixture was stirred at 20° C. for 3.5 hours. The solvent was evaporated in vacuo and the oily residue was partitioned between water and ethyl acetate. The organic layer was washed successively with saturated sodium carbonate solution, saturated potassium hydrogensulfate solution, and brine, and then dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residual oil was heated at reflux in a mixture of 50 ml of trifluoroacetic acid and 500 ml of methanol for 2.5 hours. The solvent was evaporated in vacuo, and the residue was crystallized from tert-butyl-methyl-ether to give 33.4 g of N-[(S)-2,3-dihydroxypropionyl]-L-cysteine methyl ester as white crystals of m.p. 90°-92° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[C:8]([N:33]2[CH2:36][CH:35]([N:37]([CH3:39])[CH3:38])[CH2:34]2)=[CH:9][C:10]([O:31][CH3:32])=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:21]=[N:22][N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=34)[C:17]([C:29]#[N:30])=[CH:16][N:15]=2)[CH:12]=1>C(Cl)Cl.CO>[C:29]([C:17]1[C:18]([C:20]2[CH:21]=[N:22][N:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=23)=[N:19][C:14]([NH:13][C:11]2[C:10]([O:31][CH3:32])=[CH:9][C:8]([N:33]3[CH2:36][CH:35]([N:37]([CH3:38])[CH3:39])[CH2:34]3)=[C:7]([NH:6][C:1](=[O:4])[CH:2]=[CH2:3])[CH:12]=2)=[N:15][CH:16]=1)#[N:30]
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1ncc(C#N)c(-c2cnn3ccccc23)n1
Solvent: ClCCl
Solvent: CO
Product: C=CC(=O)Nc1cc(Nc2ncc(C#N)c(-c3cnn4ccccc34)n2)c(OC)cc1N1CC(N(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A solution of acryloyl chloride (0.025 mL, 0.31 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred solution of 2-{[5-amino-4-(3-dimethylaminoazetidin-1-yl)-2-methoxyphenyl]amino}-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-5-carbonitrile (Intermediate 122, 136 mg, 0.30 mmol) in CH2Cl2 (15 mL), which was cooled in an ice bath to approximately 0° C. The mixture was stirred for 1 h, and was then diluted with iii CH2Cl2 (50 mL) and methanol (to fully dissolve suspension). This solution was then washed with sat. NaHCO3 (100 mL) which had been diluted with water (10 mL). The aqueous wash solution was then extracted with CH2Cl2 (2×50 mL) and the combined organic solutions were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (136 mg, 89%) as a yellow solid; 1H NMR: 2.10 (6H, s), 3.05-3.13 (1H, m), 3.62 (2H, t), 3.74 (3H, s), 4.00 (2H, s), 5.67 (1H, d), 6.17 (1H, d), 6.27 (1H, s), 6.45 (1H, dd), 7.16 (1H, br s), 7.25 (1H, s), 7.42 (1H, br s), 7.95 (1H, br s), 8.68 (1H, s), 8.87 (1H, br s), 8.91 (1H, s), 9.28 (1H, s), 9.32 (1H, br s); m/z: ES+ MH+ 510.18.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[C:22]2[N:21]=[CH:20][CH:19]=[N:18][C:17]=2[C:16]([C:23](O)=[O:24])=[CH:15][CH:14]=1.[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=2)[CH2:30][CH2:29]1)[CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[CH2:26]([N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:23]([C:16]3[C:17]4[N:18]=[CH:19][CH:20]=[N:21][C:22]=4[C:13]([C:3]4[C:4]([F:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[F:1])=[CH:14][CH:15]=3)=[O:24])=[N:39][CH:40]=2)[CH2:32][CH2:33]1)[CH3:27]
Reactant: COc1cc(OC)c(F)c(-c2ccc(C(=O)O)c3nccnc23)c1F
Reactant: CCN1CCN(Cc2ccc(N)nc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: CCN1CCN(Cc2ccc(NC(=O)c3ccc(-c4c(F)c(OC)cc(OC)c4F)c4nccnc34)nc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (Step 88.1), 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Step 26.1), and stirring the reaction mixture for 48 h at rt and for 5 h at 50° C. after addition of further 1.2 equiv of TBTU. The crude product was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1). Title compound: ESI-MS: 549.1 [M+H]+; tR=3.39 min (System 1); TLC: Rf=0.24 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:27]([NH:30][CH2:31][CH2:32][CH3:33])[CH2:28][CH3:29].Cl>C(#N)C>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][CH:13]([CH2:12][N:30]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:28][CH3:29])[O:18][C:17]=2[CH:19]=1)(=[O:24])=[O:25]
Reactant: CCCNCCC
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Agent: Cl
Solvent: CC#N
Product: CCCN(CCC)CC1COc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 14 using [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.175 g, 0.44 mmol), N-propylpropan-1-amine (1 ml) and ACN (3 ml). Yield: 0.11 g, 77%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 182° C. MS m/z (rel. intensity, 70 eV) 327 (M+, 1) 114 (100), 298 (17), 115 (8), 86 (6).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>C1COCC1.[Cl-].[Cl-].[Zn+2].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>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:8][CH:9]=1
Reactant: Brc1ccc(Br)cc1
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Brc1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
nBuLi (1.6M in hexanes, 34.4 mls, 55 mmol) was added dropwise to a stirred solution of 1,4-dibromobenzene (11.8 g, 50 mmol) in 100 ml of dry THF at −60° C. The mixture was stirred for 15 min at this temperature before a solution of ZnCl2 (0.5M in THF, 100 ml, 50 mmol) in THF was added dropwise. The mixture was allowed to warm to room temperature over 90 min, and then Pd(PPh3)4 (200 mg) was added, followed immediately by 2-bromopyridine (4.8 ml, 50 mmol). The whole was stirred at room temperature overnight, then evaporated to low (10 ml) volume and diluted with EtOAc (400 ml). The solution was washed with a solution of 32 g of EDTA in 200 ml water and brine (200 ml), dried (MgSO4) and evaporated to a yellow/green solid. This solid was purified by column chromatography using 1:1 hexane:DCM as eluant to provide the title product (8.3 g; 71%); m/z MH+ 234 (TS+); Found C, 56.61%, H, 3.37%, N, 5.90%; Calcd. C, 56.44%, H, 3.44%, N, 5.98%.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]#[C:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:18]=[C:17]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH:16]=2)=[CH:9][C:8]=1[CH3:39])C.[OH-].[Na+].Cl>C(O)C>[F:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][O:30][C:17]2[CH:16]=[C:15]([CH:20]=[C:19]([C:21]#[C:22][CH2:23][N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH:18]=2)[CH2:14][S:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:40])=[O:3])=[C:8]([CH3:39])[CH:9]=2)=[CH:37][CH:36]=1
Reactant: CCOC(=O)COc1ccc(SCc2cc(C#CCN3CCOCC3)cc(OCc3ccc(F)cc3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(SCc2cc(C#CCN3CCOCC3)cc(OCc3ccc(F)cc3)c2)ccc1OCC(=O)O
Reaction time: 1 h

Procedure:
{4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-1 ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethanol (20 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 190 mg. HPLC-MS: m/z: 536.1 (M+); Rt: 1.76 min.