Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].C[Si]([C:16]#[N:17])(C)C.Cl.C(OCC)C>ClCCl.[I-].[Zn+2].[I-]>[OH:8][CH:7]([C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:16]#[N:17]
Reactant: C[Si](C)(C)C#N
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CCOCC
Product: N#CC(O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.8 %

Procedure:
To a stirred solution of 3-nitrobenzaldehyde (5.0 g, 33.1 mmol) in dichloromethane (30 ml) at 0° C. was added trimethylsilyl cyanide (4.63 ml, 34.7 mmol). After stirring for 6 h at room temperature, zinc iodide (210 mg, 0.66 mmol) was added which caused the reaction mixture to warm and gently reflux. After 30 min, the reaction mixture was treated with hydrochloric acid (2M, 100 ml) and diethyl ether (150 ml) and stirred vigorously for 16 h. The phases were separated and the aqueous phase was further extracted with diethyl ether (3×100 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give a residue which was purified by column chromatography on silica gel eluting with hexane:ethyl acetate (3:1 and then 1:1). This gave the title compound as a clear oil (5.0 g, 85%).
Reaction SMILES: CO.C([O:6][C@@H:7]([CH3:23])[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)=[O:9])(=O)C.O.[OH-].[Li+].C(O)(=O)C>O>[CH2:16]([N:13]1[CH2:12][CH2:11][N:10]([C:8](=[O:9])[C@@H:7]([OH:6])[CH3:23])[CH2:15][CH2:14]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)O[C@@H](C)C(=O)N1CCN(Cc2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: C[C@H](O)C(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 5 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
Methanol (300 kg) was added to the residue from Example 7 containing (S)-1-(4-benzylpiperazin-1-yl)-1-oxopropan-2-yl acetate 4 and the mixture was cooled to 0-10° C. A solution of lithium hydroxide monohydrate (13.6 kg, 324 mol) in water (100 kg) was added at a rate to maintain the reaction temperature at 0-15° C. After aging for 2 h, the pH was adjusted to 7 at 5-15° C. with acetic acid (4.5 kg, 75 mol). The mixture was concentrated under reduced pressure. To the residue was added dichloromethane (150 kg) and the layers were separated. The aqueous layer was extracted with dichloromethane (2×150 kg). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Ethyl acetate (31 kg) was added to the residue, followed by slow addition of cyclohexane (183 kg). The mixture was heated to 40-50° C. and stirred for 1 h. The mixture was cooled to 0-10° C. and aged for 8 h. The solid was collected by filtration, washed with cold cyclohexane and dried under reduced pressure at 50° C. for 12 h to afford (S)-1-(4-benzylpiperazin-1-yl)-2-hydroxypropan-1-one 5 (46 kg, 71% yield, 98% purity by HPLC). 1H NMR (300 MHz, CDCl3) δ 7.42-7.20 (m, 5H), 4.43 (q, J=6.4 Hz, 1H), 3.84 (broad s, 1H), 3.76-3.55 (m, 2H), 3.53 (s, 2H), 3.48-3.32 (m, 2H), 2.46 (s, 4H), 1.32 (dd, J=6.6, 3.9 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([N:6]1[C:5]2[CH:12]=[CH:13][C:2]([F:1])=[CH:3][C:4]=2[C:9](=[O:10])[O:8][C:7]1=[O:11])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1oc(=O)n(Cc2ccccc2)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
A solution of Compound 35 (3 g, 16.57 mmol) in DMF was added slowly to a suspension of NaH (60% in mineral oil, 729 mg, 18.23 mmol) in DMF and further stirred at room temperature for 1 h. Then, neat benzyl bromide (2,17 mL, 18.23 mmol) was added and the solution was further stirred at room temperature for 3 h. The solution was poured into ice water and the solids formed were filtered, washed several times by water, and dried. The solids were suspended in hexane, sonicated briefly, filtered, and washed by hexane to yield 1.88 g (42%) of white solids. M.P. 95° C. 1H NMR (DMSO-d6): δ 5.29 (s, 2H), 7.26 (m, 2H), 7.35 (m, 5H), 7.40 (m, 2H), 7.64 (dt, J=2.9, 8.4 Hz, 1H), 7.82 (dd, J=3.2, 8.0 Hz, 1H). Anal. (C16H13NO3) C, H, N.
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[CH3:6][O:7][C:8]([C:10]1[N:11]=[C:12]([NH:15][C:16](=[O:42])[C@@H:17]([NH:25][C:26](=[O:41])[C@H:27]([NH2:40])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C@H:36]([OH:39])[CH2:37][OH:38])=[CH:30][CH:29]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:13][CH:14]=1)=[O:9].C(N(CC)CC)C>O1CCCC1.O>[CH3:6][O:7][C:8]([C:10]1[N:11]=[C:12]([NH:15][C:16](=[O:42])[C@@H:17]([NH:25][C:26](=[O:41])[C@H:27]([NH2:40])[C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][C@H:36]([O:39][Si:2]([CH3:5])([CH3:4])[CH3:3])[CH2:37][O:38][Si:2]([CH3:5])([CH3:4])[CH3:3])=[CH:32][CH:33]=2)[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[S:13][CH:14]=1)=[O:9]
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](N)c2ccc(OC[C@H](O)CO)cc2)n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](N)c2ccc(OC[C@@H](CO[Si](C)(C)C)O[Si](C)(C)C)cc2)n1
Reaction time: 3 h
Yield: 64.6 %

Procedure:
Chloro-trimethyl-silane (0.086 ml, 0.68 mmol) was added to 2-((S)-2-{(R)-2-amino-2-[4-((R)-2,3-dihydroxy-propoxy)-phenyl]-acetylamino}-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester (120 mg, 0.23 mmol) in tetrahydrofuran (5 mL) containing triethylamine (0.10 ml, 0.73 mmol) at room temperature and stirred for 3 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with water, brine and dried over magnesium sulfate. Removal of solvents gave 2-((S)-2-{(R)-2-amino-2-[4-((S)-2,3-bis-trimethylsilanyloxy-propoxy)-phenyl]-acetylamino}-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester as an oil (100 mg, 66%).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7](=[O:34])[C@H:8]([CH2:31][CH2:32][CH3:33])[NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18](C3C=CC(S(C)(=O)=O)=CC=3)=[CH:17][CH:16]=2)[C:11]([F:14])([F:13])[F:12])CC1)#[N:2].NCC#N.[Br:39]C1C=CC([C@H](N[C@@H](CCC)C(O)=O)C(F)(F)F)=CC=1>>[Br:39][C:18]1[CH:19]=[CH:20][C:15]([CH:10]([NH:9][C@H:8]([C:7]([NH:6][CH2:3][C:1]#[N:2])=[O:34])[CH2:31][CH2:32][CH3:33])[C:11]([F:14])([F:13])[F:12])=[CH:16][CH:17]=1
Reactant: CCC[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Reactant: CCC[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)O
Agent: N#CCN
Product: CCC[C@H](NC(c1ccc(Br)cc1)C(F)(F)F)C(=O)NCC#N

Procedure:
N2-[1-(4-Bromophenyl)-2,2,2-trifluoroethyl]-N1-(cyanomethyl)-L-norvalinamide was prepared in similar manner to N1-(1-cyanocyclopropyl)-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-norvalinamide using aminoacetonitrile in the coupling step with (2S)-2-[(S)-1-(4-bromophenyl)-2,2,2-trifluoroethylamino]-pentanoic acid.
Reaction SMILES: [H-].[Na+].[NH2:3][CH:4]=[CH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8].CO[CH:14]=[CH:15][C:16]#[N:17].Cl>CN(C)C=O.O>[F:8][C:7]([F:10])([F:9])[C:6](=[O:11])[CH:5]=[CH:4][NH:3][CH:14]=[CH:15][C:16]#[N:17]
Reactant: COC=CC#N
Reactant: NC=CC(=O)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC=CNC=CC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.1 %

Procedure:
Sodium hydride (60% dispersion in mineral oil suspension, 4.00 g, 100 mmol) was added and washed with hexane twice. Into this flask, N,N-dimethylformamide (100 ml) was added and then a solution prepared by dissolving 4-amino-1,1,1-trifluoro-3-buten-2-one (13.9 g, 100 mmol) and 3-methoxyacrylonitrile (8.30 g, 100 mmol) in N,N-dimethylformamide (50 ml) was added dropwise under ice-cooling. After stirring the mixture at room temperature for 3 hours, the reaction mixture was poured into water (500 ml). This mixture was acidified with concentrated hydrochloric acid under ice-cooling, the precipitate was collected by filtration and then washed with cold water. The obtained precipitate was dried under reduced pressure to obtain 8.20 g (yield 43.1%) of a mixture of compounds (IIa) and (IIb).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:21])[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:6][C:5]=1[F:22])(=[O:3])[CH3:2].[Br:23]([O-])(=O)=O.[K+].Br>C(O)(=O)C>[Br:23][CH2:2][C:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:21])[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:6][C:5]=1[F:22])=[O:3]
Reactant: CCOC(=O)c1cn(CC)c2cc(C(C)=O)c(F)cc2c1=O
Reactant: [O-][Br+2]([O-])[O-]
Agent: Br
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(CC)c2cc(C(=O)CBr)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 271.2 %

Procedure:
A solution of 2.45 g (8.0 mmol) ethyl 7-acetyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 50 ml acetic acid was treated with 0.46 g potassium bromate, and then 3.8 ml 48% hydrobromic acid was added dropwise over one half hour. The mixture was stirred 24 hours at room temperature and poured into 200 ml ice water. The precipitate was filtered, washed with water and dried to afford 2.87 g ethyl 7-bromoacetyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][CH:8]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)[CH3:9])[CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>CO.O>[O:1]1[CH2:2][CH2:3][CH:4]([O:7][CH:8]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH3:9])[CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(C(C)OC2CCOCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(OC1CCOCC1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.5 %

Procedure:
To the solution of methyl 4-(1-(tetrahydro-2H-pyran-4-yloxy)ethyl)benzoate (379 mg, 1.44 mmol) in methanol (15 mL) and water (5 mL) was added lithium hydroxide hydrate (100 mg, 2.4 mmol) were added. The mixture was stirred at room temperature for 12 hours. Then the reaction mixture was acidified by hydrochloric acid aqueous solution (1 N) to adjust pH=6 and extracted with dichloromethane (10 mL*3). The organic layers were combined and concentrated to give 4-(1-(tetrahydro-2H-pyran-4-yloxy)ethyl)benzoic acid (326 mg, 91%)
Reaction SMILES: O=[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:6]=1)[CH:3]=O.I.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26]([NH:28][NH2:29])=[NH:27]>>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26]1[N:28]=[N:29][CH:3]=[C:2]([C:5]2[CH:6]=[C:7]([N:11]3[CH2:15][CH2:14][CH2:13][C:12]3=[O:16])[CH:8]=[CH:9][CH:10]=2)[N:27]=1
Reactant: O=CC(=O)c1cccc(N2CCCC2=O)c1
Reactant: N=C(NN)c1ccc(F)cc1F
Agent: I
Product: O=C1CCCN1c1cccc(-c2cnnc(-c3ccc(F)cc3F)n2)c1

Procedure:
Oxo[3-(2-oxopyrrolidin-1-yl)phenyl]acetaldehyde was reacted with 2,4-difluorobenzenecarboximidic hydrazide hydriodide salt (0.74 g, 2.46 mmol) using the method described in Example 1 to give 1-{3-[3-(2,4-difluorophenyl)-[1,2,4]triazin-5-yl]phenyl}pyrrolidin-2-one as a yellow solid (0.5 g): δH H (400 MHz, d6-DMSO) 2.08-2.16 (2H, m), 2.55 (2H, t, J 8.2 Hz), 3.96 (2H, t, J 7.0 Hz), 7.34-7.39 (1H, m), 7.49-7.56 (1H, m), 7.65 (1H, t, J 8.0 Hz), 8.00-8.03 (1H, m), 8.16 (1H, d, J 7.8 Hz), 8.27-8.33 (1H, m), 8.59 (1H, t, J 1.8 Hz), 10.08 (1H, s); m/z (ES+) 353.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)O)[CH:10]=2)[N:5]=[C:4]([O:28]C(C)(C)C)[CH:3]=1.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[C:4]([OH:28])[CH:3]=[C:2]3[Br:1])=[CH:22][CH:23]=1
Reactant: CC(C)(C)Oc1cc(Br)c2cc(C(O)(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Oc1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of [4-bromo-2-(tert-butoxy)quinolin-6-yl]bis(4-chlorophenyl)methanol (1.5 g, 2.82 mmol, 1.00 equip) in dichloromethane (55 mL), Et3SiH (1.3 g, 4.00 equip), and trifluoroacetic acid (8 g, 70.77 mmol, 25.00 equip). The resulting solution was stirred overnight at room temperature. The pH value of the solution was adjusted to 7-8 with sodium bicarbonate. The resulting solution was extracted with DCM (3×50 ml) and the organic layers combined. The resulting mixture was washed with water (2×50 mL). The resulting mixture was washed with brine (1×50 mL). The resulting mixture was dried over anhydrous sodium sulfate and concentrated to yield 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol as a white solid. (ES, m/z): [M+H]+ 433
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([CH3:25])([CH3:24])[C:19]([O:21]CC)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([CH3:25])([CH3:24])[C:19]([OH:21])=[O:20])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)CCCCCCNS(=O)(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CCCCCCNS(=O)(=O)c1ccc(Cl)cc1)C(=O)O
Yield: 75.4 %

Procedure:
A solution of ethyl 8-(4-chlorobenzenesulphonamido)-2,2-dimethyloctanoate (1.0 g), sodium hydroxide (1.5 g) in ethanol (40 ml) and water (5 ml) was stirred at room temperature for 90 hours then refluxed for 3 hours. The solvent was removed and the residue was dissolved in dilute hydrochloric acid, the resulting solution then being extracted with chloroform (3×50 ml). The combined chloroform extracts were dried over magnesium sulphate, the solvent was removed and the residue was recrystallised from isopropanol-water to give the title compound as a white solid (0.7 g) m.p. 95°-96° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)=[CH:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2]>C(OCC)(=O)C.C1COCC1>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:18][CH:19]=1)#[N:24]
Reactant: COC(=O)C=C(C=Cc1ccc(C#N)cc1)c1cccc(C#N)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CC(CCc1ccc(C#N)cc1)c1cccc(C#N)c1
Reaction time: 1 h
Yield: 57.4 %

Procedure:
Part C. The methyl 3-(3-cyanophenyl)-5-(4-cyanophenyl)-2,4-pentadienoate (5) (0.328 gm, 1.04 mmol) was dissolved in ethyl acetate/THF (1:1) and was degassed with N2. A catalytic amount of 10% Pd on carbon was added and the flask was placed on a Parr shaker for 1 hour at 45 p.s.i. The contents of the flask are filtered through Celite and the filtrate was concentrated under vacuum. The residue was chromatographed on silica gel eluting ethyl acetate:hexanes (25:75, v:v) to give methyl 4-(cyano)-beta-[3-(cyano)phenyl]benzene pentanoate as an oil 0.190 gm (57%). MS: (M+NH4)+ 336; 1H NMR (CDCl3): 1.95 (m, 1H), 2.05 (m, 1H), 2.55 (m, 2H), 2.65 (ddd, 2H), 3.15 (m, 1H), 3.60 (s, 3H), 7.20 (d, 2H), 7.45 (d, 2H), 7.50 (s, 1H), 7.55 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12.[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:32])[CH2:28][C:29](O)=[O:30])=[CH:22][CH:21]=1.C(O)(=O)CC(O)=O.FC1C=CC(N)=CC=1.CCN=C=NCCCN(C)C>CCOC(C)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:29](=[O:30])[CH2:28][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[O:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12
Reactant: O=C(O)CC(=O)Nc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Nc1ccc(F)cc1
Agent: O=C(O)CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(CC(=O)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 11 %

Procedure:
To a stirred mixture of 3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 1-B; 26 mg, 0.10 mmol), 3-(4-fluorophenylamino)-3-oxopropanoic acid (22 mg, 0.11 mmol; prepared from malonic acid and 4-fluoroaniline according to the methods described in WO 2005/030140 and by Shih and Rankin, Synth. Comm. 1996, 26(4), 833-836), and CH2Cl2 (1 mL) was added EDCI (38 mg, 0.20 mmol). The reaction was stirred at room temperature for 2 days. The mixture was diluted with EtOAc (10 mL) and washed with water (3×5 mL), brine (5 mL), dried (Na2SO4), filtered, and concentrated. The crude was purified on a pre-packed Isoelute silica gel column (10 g silica), eluting with a gradient of 20% EtOAc/hexanes, 1:1 EtOAc/hexanes, 2:1 EtOAc/hexanes, and then neat EtOAc. The product was obtained as a waxy solid (5 mg, 11%). 1H NMR (400 MHz, CDCl3) δ 9.57 (s, 1H), 9.10 (s, 1H), 8.52 (m, 1H), 7.80 (m, 2H), 7.57 (m, 3H), 7.27 (m, 2H), 7.04 (m, 2H), 6.53 (d, J=4 Hz, 1H), 3.52 (s, 2H). LRMS (ESI pos) m/e 440 (M+1). HPLC: 97% purity (220 nm).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:6][CH2:5]2.[CH3:18][O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[N:24][CH:25]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH:7]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:6][CH2:5]3)[CH:23]=[N:24][CH:25]=1
Reactant: COc1cncc(B(O)O)c1
Reactant: CC(C)S(=O)(=O)NC1CCc2cc(O)ccc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cncc(Oc2ccc3c(c2)CCC3NS(=O)(=O)C(C)C)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of N-(5-hydroxy-2,3-dihydro-1H-inden-1-yl)propane-2-sulfonamide (50.0 mg, 0.196 mmol), 5-methoxypyridin-3-ylboronic acid (90 mg, 0.587 mmol), Copper(II)acetate (35.6 mg, 0.196 mmol), triethylamine (0.136 mL, 0.979 mmol), and crushed 4 Å molecular sieves (150 mg) in Dichloromethane (2 mL) was stirred at rt for 3 days. After this time the reaction mixture was filtered and solvent evaporated in vacuo. Purification by flash chromatography (heptane:EtOAc 3:1) afforded the title compound as a white solid. (6.7 mg, 9.4%). MS (ESI): m/z [M−H]− 361.0
Reaction SMILES: Cl.O1CCOCC1.OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[N:31]1[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH:32]1[CH2:44][O:45][C:46]1[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=1>CO>[N:48]1[CH:49]=[CH:50][CH:51]=[C:46]([O:45][CH2:44][CH:32]2[CH2:33][NH:34][CH2:35][CH2:36][N:31]2[C:23]2[O:22][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[N:24]=2)[CH:47]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3ccccc3o2)C(COc2cccnc2)C1
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: c1cncc(OCC2CNCCN2c2nc3ccccc3o2)c1
Reaction time: 1 h

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(benzo[d]oxazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate di-TFA salt (74 mg, 0.14 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure. The material was dissolved in EtOAc (40 mL), washed with 1 N NaOH (2×20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. This gave 34.7 mg (79%) of the desired product as a thick yellow oil. LC-MS: RT=4.00 min, [M+H]+=311.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH3:35][NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:35][N:36]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:27]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:33]
Reactant: CNc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)N(C)c4ccccc4)cc3)c2cc1OC
Yield: 46 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (72 mg) was suspended in toluene (7 ml), triphosgene (52 mg) was added, and the admixture was refluxed with heat for 3 hours. N-Methylaniline (0.05 ml) was added to the reaction mixture, and the admixture was refluxed for 1 hour with heat. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 48 mg of the title compound (yield: 46%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32]>>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: CC(C)OC(=O)Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)C)C3)cc1

Procedure:
Compound eq was prepared according to the procedure described in Example 5 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with isopropyl chloroformate. LC-MS: m/z=+483 (M+H)+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N([CH2:17][CH3:18])CC)C.[NH2:19][CH2:20][CH:21]([NH2:23])[CH3:22]>C(Cl)Cl>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([NH:19][CH2:20][CH:21]([NH:23][S:7]([C:4]2[CH:5]=[CH:6][C:17]([CH3:18])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH3:22])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(N)CN
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NCC(C)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 93.3 %

Procedure:
To a stirred solution of p-toluenesulfonyl chloride (270 g, 1.42 mole) and triethylamine (143 g, 1.42 mole) in CH2Cl2 (1.0 l) at 0° C. under a dry argon atmosphere was added a solution of 1,2-diaminopropane (50.0 g, 0.675 mole) in CH2Cl2 (250 ml) dropwise, maintaining the temperature <10° C. The addition required 1 h. The mixture was allowed to warm to room temperature and was stirred an additional 19 h. The mixture was poured onto ice (1000 g) and the CH2Cl2 layer was separated. The CH2Cl2 layer was washed with 1N HCl, H2O and saturated NaCl solution and was dried (MgSO4). The solvent was removed in vacuo and the resulting yellow oil was washed with hexane. The crude product was purified by recrystallization from CH2Cl2 -hexane to give 241 g (93% yield) of the product as colorless needles: mp 105°-7° C.; 1H NMR(CDCl3) δ 0.97 (d, J=6.7 Hz, 3H), 2.40 (s, 3H), 2.41 (s, 3H), 2.91 (m, 2H), 3.32 (m, 1H), 5.25 (d, J=7.6 Hz, 1H), 5.38 (t, J=6.3 Hz, 1H), 7.28 (m, 4H) 7.73, (m, 4H).