Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([OH:14])=[O:13].C([Li])(C)(C)C.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C>C1COCC1>[C:12]([CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([B:20]([OH:25])[OH:21])[CH:3]=2)[NH:7][CH:6]=1)([OH:14])=[O:13]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: O=C(O)Cc1c[nH]c2ccc(Br)cc12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: O=C(O)Cc1c[nH]c2ccc(B(O)O)cc12
Temperature: -30 °C
Reaction time: 1 h
Yield: 21.4 %

Procedure:
To a solution of (5-bromo-1H-indol-3-yl)-acetic acid (1 g, 3.94 mmol) in THF (66 mL) at −78° C. is added tert-butyl lithium (1.7 M in pentane, 11.6 mL, 19.7 mmol) dropwise and stirred at −78° C. for 30 minutes at −30° C. for 1 hour. Cooled down to −78° C. again and treated dropwise with triisopropyl borate (4.53 mL, 19.7 mmol). The reaction mixture is allowed to warm to room temperature during 1 hour quenched with 2N hydrochloric acid. This mixture is extracted with ether. The extract is dried over sodium sulfate and concentrate to obtain an oil which is subjected to silica gel chromatography affording 3-carboxymethyl-1H-indol-5-yl boronic acid (185 mg, 20%) as a solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][NH2:10].[C:11](N1C(=O)C2C(=CC=CC=2)C1=O)(=[S:13])[CH3:12]>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][NH:10][C:11](=[S:13])[CH3:12]
Reactant: NCCOc1ccccn1
Reactant: CC(=S)N1C(=O)c2ccccc2C1=O
Solvent: ClC(Cl)Cl
Product: CC(=S)NCCOc1ccccn1
Reaction time: 0.25 h
Yield: 49.3 %

Procedure:
Add 2-(pyridin-2-yloxy)ethylamine (500 mg, 3.62 mmol) to a solution of 2-thioacetyl-isoindole-1,3-dione (743 mg, 3.62 mmol) in CHCl3 (18 mL) at 0° C. After stirring for 15 minutes, concentrate the solution, redissolve in ethyl acetate (25 mL), filter, and concentrate again. Flash chromatography (SiO2, 1:1 EtOAc/Hex) gives N-(2-(pyridin-2-yloxy)ethyl)thioacetamide (350 mg, 49%) as a beige/pink solid. 1H NMR (CDCl3) δ 8.79 (br s, 1H), 8.10-8.08 (m, 1H), 7.58-7.65 (m, 1H), 6.92-7.00 (m, 1H), 6.76-6.82 (m, 1H), 4.57-4.65 (m, 2H), 3.98-4.05 (m, 2H), 2.56 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH:4]=[CH:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:16]3[C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=4)=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=34)=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1.[H][H]>CO.ClCCl.[Pd]>[CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:16]3[C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=4)=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=34)=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: COC(=O)C=Cc1ccc2c(-c3c(-c4cccc(C)n4)nn4ccccc34)ccnc2c1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCc1ccc2c(-c3c(-c4cccc(C)n4)nn4ccccc34)ccnc2c1
Reaction time: 0.25 h
Yield: 58.1 %

Procedure:
Add Pd/C (10%, 0.46 g) to a solution of 3-{4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinolin-7-yl}-acrylic acid methyl ester (0.462 g, 1.1 mmol) in MeOH (10 mL) and dichloromethane (10 mL). Bubble nitrogen for 15 minutes. Connect the hydrogen balloon to the reaction flask and stir overnight. Filter through celite and wash the celite pad with dichloromethane (50 mL). Remove the solvent. Chromatograph the residue (elute with 2% MeOH in dichloromethane) to give the desired product as a pale yellow solid 0.27 g (59%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[CH:10](OCC)=[O:11]>>[CH:10]([NH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)=[O:11]
Reactant: CCOC=O
Reactant: NCCN1CCOCC1
Product: O=CNCCN1CCOCC1
Yield: 100 %

Procedure:
The procedure of B. V. Cheney et al. [J. Med. Chem., 28, 1853-1864 (1985)] was used. A solution of 4-(2-aminoethyl)morpholine (1.00 g, 76.8 mmol) and ethyl formate (213 mL, 2640 mmol) was refluxed overnight under an atmosphere of nitrogen. Vacuum distillation gave 11.46 g (100% yield) of a clear, colorless liquid (bp0.3 118°-120° C.). The 1H NMR spectral data were consistent with the structure of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][O:36][C:37]4[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=4)=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)=[O:20])[CH:5]=[C:6]([CH3:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][N:10]=1.[CH3:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49]Br)=[CH:47][CH:46]=1.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][O:36][C:37]4[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=4)=[CH:30][CH:29]=3)[CH2:25][CH2:26]2)=[O:20])[CH:5]=[C:6]([CH3:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:44][C:45]2[CH:52]=[CH:51][C:48]([CH3:49])=[CH:47][CH:46]=2)=[CH:11][N:10]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: Cc1ccc(OCCc2ccc(CN3CCN(C(=O)/C=C/c4cc(C)c(Oc5ccc(O)cn5)c(Cl)c4)CC3)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(COc2ccc(Oc3c(C)cc(/C=C/C(=O)N4CCN(Cc5ccc(CCOc6ccc(C)cc6)cc5)CC4)cc3Cl)nc2)cc1
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a DMF (5 mL) solution of (E)-3-{3-chloro-4-[(5-hydroxypyridin-2-yl)oxy]-5-methylphenyl}-1-(4-{4-[2-(4-methylphenoxy)ethyl]benzyl}piperazin-1-yl)prop-2-en-1-one (479 mg) and 4-methylbenzyl bromide (155 mg) was added sodium hydride (60% w/w in oil, 42 mg) at 0° C., and stirred for 1 hour. The reaction mixture was quenched by addition of saturated aqueous NH4Cl (10 mL), and extracted with AcOEt. The organic layer was washed with water, saturated aqueous NaCl, dried over anhydrous Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (AcOEt/MeOH=1/0 to 9/1) to afford (E)-3-[3-chloro-5-methyl-4-({5-[(4-methylbenzyl)oxy]pyridin-2-yl}oxy)phenyl]-1-(4-{4-[2-(4-methylphenoxy)ethyl]benzyl}piperazin-1-yl)prop-2-en-1-one (480 mg).
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[Cl:25])=[CH:14][C:13]1=[O:26])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[Cl:25])=[CH:14][C:13]2=[O:26])[C:3]([OH:27])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cc(Cl)ccc2Cl)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2cc(Cl)ccc2Cl)=CC1=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(2,5-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (370 mg, 0.001 mol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (106 mg, 0.004 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-[4-(2,5-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (300 mg, 84%) as a light brown solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][S:9][C:10]2[NH:11][C:12]3[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:13]=3[N:14]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C[OH:24]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:8][S:9]([C:10]2[NH:11][C:12]3[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[CH:15][C:13]=3[N:14]=2)=[O:24])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1CSc1nc2ccc(C(F)(F)F)cc2[nH]1
Reactant: CO
Solvent: ClCCl
Product: Cc1cccnc1CS(=O)c1nc2ccc(C(F)(F)F)cc2[nH]1
Reaction time: 1 h

Procedure:
6.7 g of 2-[[(3-methyl-2 -pyridyl)methyl]thio]-5-(trifluoromethyl)benzimidazole are dissolved in 250 ml of methylene chloride and 20 ml of methanol and then cooled to -20°. 4.7 g of m-chloroperbenzoic acid, recrystallized from methylene chloride/petroleum ether, are then introduced within 10 minutes. The solution is stirred further at -20° for 60 minutes and then poured into a mixture of 100 ml of 2N sodium carbonate solution and ice. The organic phase is washed neutral with water, dried over sodium sulphate and evaporated in vacuo. Crystallization from methylene chloride/methanol/petroleum ether gives 2-[[(3-methyl-2-pyridyl)methyl]sulphinyl]-5 -(trifluoromethyl)benzimidazole of melting point 156°-158°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1.[CH3:29][N:30]([CH3:38])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH2:37])[CH:32]=1>>[CH3:29][N:30]([CH3:38])[C:31]1[CH:32]=[C:33]([NH:37][C:2]2[CH:3]=[C:4]([N:8]([CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: CN(C)c1cccc(N)c1
Reactant: CC(C)(C)[Si](C)(C)OCCN(CCO[Si](C)(C)C(C)(C)C)c1cccc(Br)c1
Product: CN(C)c1cccc(Nc2cccc(N(CCO[Si](C)(C)C(C)(C)C)CCO[Si](C)(C)C(C)(C)C)c2)c1

Procedure:
By proceeding as described in the coupling general procedure, but starting from 1.85 g (3.8 mmol) of (3-bromo-phenyl)-bis-[2-(tert-butyldimethylsilanyloxy)ethyl]amine and 1.15 g (4.42 mmol) of N,N-dimethylbenzene-1,3-diamine, [3-(3-dimethylaminophenylamino)phenyl]-bis-[2-(tert-butyldimethylsilanyloxy)ethyl]amine is obtained as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[N:38]1([CH2:43][CH2:44][NH2:45])[CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:45][CH2:44][CH2:43][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: NCCN1CCCC1
Product: O=C(Nc1ccc(Oc2ccnc(NCCN3CCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 2-pyrrolidin-1-yl-ethylamine according to conditions described in general procedure C. Mp: 92-94° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.58 (m, 10 H), 2.20-2.47 (m, 6 H), 2.91 (bs, 2 H), 3.27 (s, 4 H), 6.20-6.32 (m, 1 H), 6.94-6.98 (m, 2 H), 7.15 (d, J=8.4 Hz, 1 H), 7.37 (d, J=8.0 Hz, 1 H), 7.43 (s, 1 H), 7.51-7.61 (m, 3 H), 7.78-7.80 (m, 1 H), 7.96 (d, J=7.3 Hz, 1 H), 8.21 (s 1 H), 10.40 (s, 1 H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([F:17])[CH:13]=2)[N:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:7]=1)=[O:5])C.[Na]>C(O)C>[F:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[F:18])[N:8]([C:19]([CH3:21])([CH3:22])[CH3:20])[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15]2=[O:16]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2cc(F)c(F)cc2c1=O
Agent: [Na]
Solvent: CCO
Product: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reaction time: 8 h

Procedure:
A mixture of 6.08 g (19.7 mmoles) of 6,7-difluoro-1-(1,1-dimethylethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester and 19.7 mmoles of 2N aqueous sodium hydroxyde in 80 mL of ethanol was stirred overnight. The resulting mixture was concentrated in vacuo, taken up with 200 mL of water and extracted with dichloromethane. About 8 mL of 2N HCl was added to the aqueous layer to adjust the pH to 3. The precipitate was collected by filtration, washed with H2O and dried to give 4.47 g, of titled compound. MP>260° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CC(C)(C)C(O)=O.Br[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1>CN(C)C(=O)C.FC1C=CC(P(C2C=CC(F)=CC=2)C2C=CC(F)=CC=2)=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]2[C:29]3[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=3)[O:23][CH2:22][C:16]=2[CH:17]=1
Reactant: COc1cccc(OCc2cc(Cl)ccc2Br)c1
Agent: CC(C)(C)C(=O)O
Agent: Fc1ccc(P(c2ccc(F)cc2)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(c1)OCc1cc(Cl)ccc1-2
Temperature: 60 °C
Yield: 99.9 %

Procedure:
To a degassed mixture of potassium carbonate (1.27 g, 9 mmol), palladium(II)trimethyl acetate (47 mg, 0.15 mmol), tris(p-fluorophenyl)phosphine (48 mg, 0.15 mmol) and trimethylacetic acid (93 mg, 0.9 mmol) was added 1-bromo-4-chloro-2-((3-methoxyphenoxy)methyl)benzene (1 g, 3 mmol) in N,N-dimethylacetamide (14 mL). The reaction was heated to 60° C. under argon for 18 hours. Upon completion, the reaction mixture was cooled to room temperature. The products were loaded directly onto a silica gel packed column and eluted using Hexanes/ethyl acetate to yield 8-chloro-3-methoxy-6H-benzo[c]chromene (739 mg, 98%)
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([O:34][C:35]2[C:40]([Cl:41])=[CH:39][CH:38]=[C:37]([CH2:42][NH:43][CH3:44])[C:36]=2[F:45])[CH:33]=1)[C:29]#[N:30].[NH:46]1[CH:50]=[CH:49][N:48]=[C:47]1[C:51]([OH:53])=O.C([O-])(O)=O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[Cl:41][C:40]1[CH:39]=[CH:38][C:37]([CH2:42][N:43]([CH3:44])[C:51]([C:47]2[NH:46][CH:50]=[CH:49][N:48]=2)=[O:53])=[C:36]([F:45])[C:35]=1[O:34][C:32]1[CH:31]=[C:28]([C:29]#[N:30])[CH:27]=[C:26]([Cl:25])[CH:33]=1
Reactant: O=C(O)c1ncc[nH]1
Reactant: CNCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(Cc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F)C(=O)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
HATU (0.16 g, 0.43 mmol) was added to a solution of 3-chloro-5-({6-chloro-2-fluoro-3-[(methylamino)methyl]phenyl}oxy)benzonitrile (0.10 g, 0.30 mmol) and 1H-imidazole-2-carboxylic acid (0.05 g, 0.43 mmol) in DMF (3 mL) and the solution was stirred at RT overnight. After 16 h, ethyl acetate (100 ml) and saturated NaHCO3 solution (100 ml) were added. The organic layer was separated, washed with saturated NaHCO3 solution (2×100 ml), brine (150 mL), dried over MgSO4, filtered and concentrated. The crude material was purified by Reverse Phase HPLC to give the title compound (0.025 g, 20%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.82 (s, 1H), 7.46-7.57 (m, 3H), 7.27-7.37 (m, 2H), 7.18 (s, 1H), 5.57 (s, 1H), 4.77 (s, 1H), 3.53 (s, 1.5H), 2.98 (s, 1.5H). 19F NMR (376 MHz, DMSO-d6) δ ppm −75.19 (s, 1F). LCMS m/z 418 (M−1).
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[O:31][C:30]([CH:32]=O)=[CH:29][CH:28]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:34][S:35]([NH:38][CH2:39][CH2:40][NH2:41])(=[O:37])=[O:36].Cl>O>[ClH:1].[ClH:1].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[O:31][C:30]([CH2:32][NH:41][CH2:40][CH2:39][NH:38][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:29][CH:28]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Reactant: CS(=O)(=O)NCCN
Agent: Cl
Solvent: O
Product: CS(=O)(=O)NCCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Yield: 156 %

Procedure:
In an analogous manner to Example 10, 5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde hydrochloride (0.200 g, 0.436 mmol) was reacted with 2-(methanesulphonamido)ethylamine (0.350 g, 2.53 mmol). On completion of the reaction the mixture was acidified with dilute HCl and diluted with water, but no solid was formed. The mixture was concentrated in vacuo, and the residue was washed with acetone, 2N HCl and acetone again, and dried at 60° C. in vacuo to give the title compound as a yellow solid (0.210 g, 0.340 mmol, 78%); δH [2H6]DMSO 12.01 (1H,s), 9.82 (1H, br s), 9.77 (1H,s), 8.88 (1H,s), 8.40 (1H,d), 8.02 (1H,d), 7.76 (2H,d), 7.31-7.53 (6H,m), 7.14 (2H,d), 6.84 (1H,d), 5.18 (2H,s), 4.40 (2H,s), 3.34-3.48 (2H, m), 3.08-3.18 (2H,m), 2.96 (3H,s); m/z (M+1+) 544.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.[CH3:38][NH:39][O:40][CH3:41]>C(#N)C.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH3:14])[CH2:10][C:11]([N:39]([O:40][CH3:41])[CH3:38])=[O:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: C[C@H](CC(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CON(C)C(=O)C[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of (3R)-3-[(tert-butoxycarbonyl)amino]butanoic acid (1 g, 5 mmol) in acetonitrile (40 mL) was treated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC; 1.05 g, 5.5 mmol), 1-hydroxybenzotriazole (HOBt; 810 mg, 6 mmol), N,O-dimethylhydroxylamine hydrochloride (1.0 g, 10 mmol) and triethylamine (1.4 mL) and stirred at room temperature for 2 d. The solution was evaporated and the residue purified by flash chromatography on a Biotage® system (silica gel, 40-90% ethyl acetate/hexane gradient) to yield the desired product as a colorless viscous oil. MS 269.1 (M+Na).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH:17]3[CH2:22][CH2:21][SiH:20](Cl)[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:24]1[CH2:28]OC[CH2:25]1>>[F:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C@H:17]3[CH2:22][CH2:21][Si@H:20]([CH2:25][CH2:24][CH3:28])[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(OC[C@H]2CC[C@H](C3CC[SiH](Cl)CC3)CC2)cc1F
Reactant: C1CCOC1
Product: CCC[Si@H]1CC[C@H]([C@H]2CC[C@H](COc3ccc(F)c(F)c3)CC2)CC1

Procedure:
2.5 g (20 mmols) of n-propyl bromide was dropped in a mixture of 0.5 g of magnesium (21 mmols) and 50 ml of THF to obtain a Grignard reagent. Subsequently, the solution was dropped in 50 ml of a THF solution of 7.2 g (20 mmols) of 4-(trans-4-(3,4-difluorophenyloxymethyl)cyclohexyl)-1-chloro-1-silacyclohexane to obtain a crude product. This product was found to be a mixture of trans and cis isomers with respect to the silacyclohexane ring. The product was after-treated by a usual manner and isolated through column chromatography to obtain 6.7 g (yield: 91%) of the intended trans-trans isomer product. The results of measurement of phase transition temperatures and the IR analysis are shown below.
Reaction SMILES: [NH2:1][C:2]1([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C@@H:16]([N:18]3[CH2:23][CH2:22][C@:21]([CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:20][C:19]3=[O:35])[CH3:17])=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:45](OC(=O)C)(=[O:47])[CH3:46]>C(Cl)Cl>[OH:34][C:31]([CH3:32])([CH3:33])[CH2:30][C@@:21]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:20][C:19](=[O:35])[N:18]([C@H:16]([C:13]2[CH:14]=[CH:15][C:10]([C:9]#[C:8][C:2]3([NH:1][C:45](=[O:47])[CH3:46])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[CH:11][CH:12]=2)[CH3:17])[CH2:23][CH2:22]1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H](c1ccc(C#CC2(N)CCCCC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NC1(C#Cc2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)CCCCC1
Yield: 47.2 %

Procedure:
A vial equipped with a flea stir bar was charged with (S)-3-((S)-1-(4-((1-aminocyclohexyl)ethynyl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (12 mg, 0.025 mmol), i-Pr2NEt (0.015 mL, 0.08 mmol) and CH2Cl2 (2 mL). Acetic anhydride (0.005 mL, 0.043 mmol) was added. The mixture was stirred overnight at rt and evaporated to dryness. The residue was purified by prep HPLC to afford the title compound (6.1 mg, 47%). LC-MS Method 1 tR=1.65 min, m/z=517, 459; 1H NMR (CDCl3) 1.12 (s, 3H), 1.18 (s, 3H), 1.30 (m, 1H), 1.51 (d, 3H), 1.65 (m, 6H), 1.87 (m, 2H), 1.99 (s, 3H), 2.14 (m, 3H), 2.21 (s, 2H), 2.35 (m, 1H), 2.78 (m, 1H), 5.65 (q, 1H), 6.88 (d, 2H), 7.18 (d, 2H), 7.30-7.40 (5H)
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12]CC)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)C>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([OH:12])=[O:11])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CCN(C(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)N1CCC(C(=O)O)CC1
Temperature: 34 °C
Yield: 99.3 %

Procedure:
Crude ethyl 1-isopropylpiperidine-4-carboxylate (63.39 g, 318.0 mmol) was dissolved in ethanol (500 mL), and NaOH (25.3 g, 632 mmol) was added. The solution was heated to reflux for 15.75 h at which point it was allowed to cool to 34° C. A solution of ethanolic HCl (220 mL, 2.9 M solution) was added rapidly which caused a mild exotherm and immediate precipitation. The resulting NaCl was filtered using a fritted funnel, and the cloudy filtrate was refiltered through diatomaceous earth. The filtrate was concentrated and dissolved in 50% EtOAc/EtOH (600 mL) and heated on a steam bath. The insoluble material was removed by a filtration through diatomaceous earth, and the resulting filtrate was concentrated to a solid which was dried in a 50° C. vacuum oven to yield 54.09 g of yellow solid (corrected for 0.2 wt % EtOH by 1H-NMR analysis) which is a 99% yield over two steps. No further purification was attempted:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[S:14][C:15]([NH2:18])=[CH:16][N:17]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C[Al](C)C.[NH:23](/[C:27](/[CH3:33])=[CH:28]\[C:29](OC)=[O:30])[C:24]([CH3:26])=O>C(Cl)Cl>[CH3:26][C:24]1[N:18]([C:15]2[S:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[CH:12][CH:11]=3)=[N:17][CH:16]=2)[C:29](=[O:30])[CH:28]=[C:27]([CH3:33])[N:23]=1
Reactant: Nc1cnc(-c2ccc(N3CCOCC3)cc2)s1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2cnc(-c3ccc(N4CCOCC4)cc3)s2)c(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
To a solution of 2-(4-morpholinophenyl)thiazol-5-amine (0.20 g, 0.77 mmol) in CH2Cl2 (20 mL) was added trimethylaluminum (2.3 mL, 4.6 mmol, 2 M in toluene) dropwise at rt. The reaction mixture was stirred at rt for 1 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (132 mg, 0.84 mmol) in anhydrous CH2Cl2 (5 mL). The reaction mixture was stirred at rt overnight, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC to give the title compound as a pale yellow solid (20 mg, 7%). The compound was characterized by the following spectroscopic data: