Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@@H:14]([N:15]2[CH:19]=[CH:18][N:17]=[N:16]2)[C@@H:13]([CH3:20])[CH2:12][N:11]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[NH:27][C:28]([C:30]2[C:39]([NH:40]C(=O)OCC3C=CC=CC=3)=[CH:38][C:37]3[C:32](=[CH:33][C:34]([N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)=[CH:35][CH:36]=3)[N:31]=2)=[O:29])[CH2:10]1)=O)(C)(C)C.C1COCC1.Cl.O1CCOCC1>CO>[NH2:40][C:39]1[C:30]([C:28]([NH:27][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:21]=2[N:11]2[CH2:12][C@H:13]([CH3:20])[C@H:14]([N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[C@H:9]([NH2:8])[CH2:10]2)=[O:29])=[N:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[C:34]([N:51]1[CH2:52][CH2:53][O:54][CH2:55][CH2:56]1)[CH:33]=2
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4)ccc3cc2N)C[C@@H](N)[C@H]1n1ccnn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a solution of benzyl {2-[({4-[(3R,4S,5S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-morpholin-4-ylquinolin-3-yl}carbamate (5.4 mg, 0.007 mmol) in MeOH (0.27 mL) and THF (0.14 mL) 10% Pd on carbon (2.8 mg) was added. The reaction mixture was deoxygenated under reduced pressure and hydrogen was introduced via a balloon. The reaction mixture was stirred at room temperature under hydrogen for 1 h. The mixture was filtered and concentrated under reduced pressure to give an intermediate. The intermediate was treated with 4.0 M HCl in dioxane (0.0701 mL, 0.28 mmol), stirred at room temperature for 30 min. then concentrated under reduced pressure. The residue was diluted with MeOH and NH4OH, filtered and purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the title compound as a yellow powder (2.4 mg, 64%). LCMS calc. for C27H33N10O2 (M+H)+: m/z=529.3. Found: 529.3.
Reaction SMILES: [Na].[CH3:2][CH:3]([CH3:10])[CH2:4][C:5](=[O:9])[C:6]([OH:8])=[O:7].Cl>>[OH:9][C@H:5]([CH2:4][CH:3]([CH3:10])[CH3:2])[C:6]([OH:8])=[O:7]
Reactant: CC(C)CC(=O)C(=O)O
Agent: Cl
Agent: [Na]
Product: CC(C)C[C@@H](O)C(=O)O
Yield: 87 %

Procedure:
The sodium salt of 4-methyl-2-oxo-pentanoic acid 7 (152 mg, 1 mmol), RLB2HADH (13.8 mg, 276 U), HCl (1 ml, 1 mmol, 1 eq.). A reaction time of 24 hours gave 8 (114 mg, 0.87 mmol, 87% yield, >99.5% e.e.); δH1 (270 MHz) ppm: 6.63 (1H, br s, 2-OH), 4.29 (1H, br t, J=6.5 Hz, 2-H), 1.95-1.85 (1H, m, 4-H), 1.64-1.60 (2H, m, 3-H2), 0.98-0.95 (6H, 2×s, 5-H3 and 5'-H3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([Cl:15])[N:12]=[C:11](Cl)[C:7]=3[NH:8][C:9]=2[CH:10]=1.[CH3:17][CH2:18][O-:19].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([Cl:15])[N:12]=[C:11]([O:19][CH2:18][CH3:17])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: CC[O-]
Reactant: Clc1nc(Cl)c2[nH]c3cc(Br)ccc3c2n1
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(Cl)nc2c1[nH]c1cc(Br)ccc12
Temperature: 25 °C
Yield: 98.8 %

Procedure:
5 g (15.8 mmol) 7-bromo-2,4-dichloro-5H-pyrimido[5,4-b]indole was suspended in 20 ml ethanol and mixed with 15.8 ml (31.5 mmol) 2M sodium ethylate solution (EtOH). The mixture was refluxed for 9.5 h. Having cooled down to room temperature, the solvent was concentrated and water was added. The resulting precipitate was sucked off and washed with water. 5.1 g (99%) 7-bromo-2-chloro-4-ethoxy-5H-pyrimido[5,4-b]indole was obtained. ESI-MS [m/z]: 324, 326 [M−H]−
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[CH2:19])[C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1>CN(C)C=O>[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:16](=[O:18])[CH3:17])[CH2:4][CH2:19]2)=[CH:11][CH:10]=1
Reactant: C=C(C(C)=O)c1ccc(C)cc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)C1(c2ccc(C)cc2)CC1
Temperature: 0 °C
Yield: 48.6 %

Procedure:
507 mg of sodium hydride (55% in paraffin oil) is introduced into 20 ml of dimethylformamide under nitrogen at 0° C., and 1.36 g of trimethylsulfonium iodide is added. After 30 minutes at this temperature, 845 mg of ketone 40 is added in drops to 4 ml of dimethylformamide. It is stirred for 1 more hour at 0° C., then quenched with sodium chloride solution, extracted with ethyl acetate, dried on sodium sulfate and concentrated by evaporation. After chromatography on silica gel with ethyl acetate/hexane, 447 mg of title compound 41 is obtained as a colorless oil.
Reaction SMILES: [O-]CC.[Na+].[F:5][C:6]1[CH:7]=[C:8]([CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=[CH:10][C:11]=1[F:12].[C:24](#[N:27])[CH:25]=[CH2:26].[Cl-].[NH4+]>C(O)(C)(C)C>[C:24]([CH2:25][CH2:26][C:13]([C:8]1[CH:9]=[CH:10][C:11]([F:12])=[C:6]([F:5])[CH:7]=1)([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:27]
Reactant: C=CC#N
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(F)c(F)c1
Agent: CC[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)(C)O
Product: CCOC(=O)C(CCC#N)(C(=O)OCC)c1ccc(F)c(F)c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, sodium ethoxide (20% ethanol solution, 1.7 g) was added to a mixture of diethyl (3,4-difluorophenyl)propanedioate (13.8 g) in tert-butylalcohol (50 mL) at room temperature, and the mixture was stirred at 40° C. for 30 min. Acrylonitrile (3.34 mL) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (15.2 g).
Reaction SMILES: [O-]CC.[Na+].[Na].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[CH:10][C:9]=1[CH2:22][C:23]#[N:24].[C:25](=O)([O:29]CC)[O:26][CH2:27][CH3:28]>C1(C)C=CC=CC=1.C(O)C>[C:23]([CH:22]([C:9]1[CH:10]=[C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH:12]=[CH:13][C:8]=1[O:7][CH3:6])[C:25]([O:26][CH2:27][CH3:28])=[O:29])#[N:24]
Reactant: COc1ccc(Oc2ccccc2Cl)cc1CC#N
Reactant: CCOC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C#N)c1cc(Oc2ccccc2Cl)ccc1OC
Yield: 96 %

Procedure:
A mixture of sodium ethoxide prepared from sodium metal (415 mg) and ethanol (20 ml), 2-[2-methoxy-5-(2-chlorophenoxy)phenyl]acetonitrile (4.7 g) and diethyl carbonate (7.8 g) in toluene (50 ml) was treated in a similar manner to that of Example 10-(4) to give oily ethyl 2-cyano-2-[2-methoxy-5-(2-chlorophenoxy)phenyl]acetate (5.7 g).
Reaction SMILES: [Li]CCCC.[N+:6]([CH2:9][CH2:10][CH3:11])([O-:8])=[O:7].[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>C1COCC1.C(Cl)Cl>[C:13]1([CH:12]([OH:19])[CH:9]([N+:6]([O-:8])=[O:7])[CH2:10][CH3:11])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCC[N+](=O)[O-]
Reactant: O=Cc1ccccc1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCC(C(O)c1ccccc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 58.4 %

Procedure:
n-BuLi (1.6 M in hexane, 6.24 mL) was added dropwise with stirring to a solution of nitropropane (0.9 mL, 10 mmol) in THF (12 mL) at -78° C. After 15 minutes a solution of TiCl3 (OPriso) (5 mmol) in THF (2 mL) and CH2Cl2 (3 mL) solution was added. After a further 15 minutes benzaldehyde (0.5 mL, 5 mmol) was added and the mixture allowed to warm up to room temperature (~ 30 min.). Stirring was continued for a further 3.5 hours at room temperature and the mixture was quenched with an aqueous slurry of disodium EDTA (1.86 g, 5 mmol) and extracted with Et2O (3×75 mL). The combined Et2O fractions were washed with dilute hydrochloric acid (2 M, 75 mL), aqueous sodium bicarbonate (75 mL) and water (75 mL), dried and evaporated in vacuo. Flash column chromatography (SiO2 , hexane:Et2O, 6:1 v.v] gave 1-phenyl-2-nitro-butan-1-ol (0.57 g, 61%) erythro:threo ratio 6:1.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([CH2:16][CH3:17])[C:3]=1[C:18]([NH2:20])=[O:19].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30](Cl)=O)[CH:26]=[CH:27][CH:28]=1.[O-]CC.[Na+]>C(O)C>[Cl:13][C:12]1[CH:11]=[C:10]([Cl:14])[CH:9]=[C:8]([Cl:15])[C:7]=1[N:6]1[C:2]2=[N:1][C:30]([CH2:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=3)=[N:20][C:18](=[O:19])[C:3]2=[C:4]([CH2:16][CH3:17])[NH:5]1
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: CCc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C(N)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3cccc(OC)c3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.3 %

Procedure:
Part B: To a stirred solution of 167 mg (0.5 mmol) of 5-amino-3-ethyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 6 mL of absolute ethanol was added 550 mg (3.0 mmol) of 3-methoxyphenylacetyl chloride followed by 2.3 mL (6.0 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 18 h at reflux, and the heating mantle was then removed. The reaction was treated with 5 mL of 10% aq. HOAC, cooled to ambient temperature, and filtered. The filtrate was washed with 6 mL of 1:1 water-methanol then 6 mL of 1:1 ether-hexanes. The off-white solid was briefly air-dried to give 170 mg (76%) of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one, mp 235-238° C. Mass Spec. 463(M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[S:22][C:21]([C:23]([OH:25])=O)=[CH:20][CH:19]=1)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:38][CH:39]([NH2:43])[CH2:40][CH2:41][CH3:42]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[S:22][C:21]([C:23](=[O:25])[NH:43][CH:39]([CH3:38])[CH2:40][CH2:41][CH3:42])=[CH:20][CH:19]=1)=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(=O)O)s1
Reactant: CCCC(C)N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCC(C)NC(=O)c1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)s1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a solution of 4.4 g (12.1 mmol) 5-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-thiophene-2-carboxylic acid in 80 ml THF were added 2.2 g (13.6 mmol) carbonyldiimidazol. The reaction mixture was stirred at 45° C. for 1 h and then cooled to rt. After addition of 1.05 g (12 mmol) 2-pentylamine the reaction mixture was kept at rt for 12 h. The solvent was evaporated and the residue was dissolved in 150 ml CH2 Cl2. The solution was washed twice with 150 ml water each and dried over magnesium sulfate. The solvent was evaporated and the residue was washed with diethyl ether to yield (2-{[5-(1-methyl-butylcarbamoyl)-thiophene-2-carbonyl]-amino}-phenyl)-carbamic acid tert-butyl ester as a white solid, mp. 183° C.
Reaction SMILES: O(C([N:10]1[CH2:15][CH2:14][C:13]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)=O)C1C=CC=CC=1.[OH-].[K+]>C(O)C>[C:27]1([C:13]2([O:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=3)[CH2:12][CH2:11][NH:10][CH2:15][CH2:14]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Oc1ccccc1)N1CCC(Oc2ccc(C(F)(F)F)cc2)(c2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: FC(F)(F)c1ccc(OC2(c3ccccc3)CCNCC2)cc1

Procedure:
A sample of 7.4 g of 1-phenoxycarbonyl-4-phenyl-4-(p-trifluoromethylphenoxy)piperidine is dissolved in 70 ml. of ethanol and 48 ml. of 45% aqueous KOH added, and the solution is stirred and refluxed under nitrogen for 4 hours. After cooling most of the ethanol is removed under reduced pressure and the resultant oily dispersion is extracted with ether. The ether was dried and then evaporated under reduced pressure to give a waxy, white solid of 4-phenyl-4(p-trifluoromethylphenoxy)piperidine.
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH3:6][C:7](OC(C)=O)=[O:8].[CH2:13]([O:15][C:16](=[O:32])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:14]>C(Cl)Cl>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][O:25][C:20]1[CH:21]=[CH:22][C:23]([C:7](=[O:8])[CH3:6])=[CH:24][C:19]=1[O:18][CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)COc1ccccc1OCC(=O)OCC
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(C(C)=O)cc1OCC(=O)OCC

Procedure:
Perchloric acid (70% aq.; 1.0 ml) was added slowly to freshly distilled Ac2O (25 ml) at 0° C. The compound of example 20a (31.8 g; 125 mmol) in CH2Cl2 (13 ml) was added drop wise at 10-15° C. The reaction mixture was heated on steam bath for 1 h, concentrated, poured over crushed ice and NaHCO3 (˜25 g) and extracted with ether. The ether layer was washed with brine, dried (Na2SO4), concentrated and purified using flash chromatography (silica gel, 5% CH3CN in CHCl3) to obtain the title compound. Yield, 24.6 g (61.5%), semisolid; analysis: C16H20O7: requires C, 59.25; H, 6.22; found: C, 59.57; H, 6.28%.
Reaction SMILES: [OH-].[Na+].Cl.[Cl:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1.Br[CH2:18][CH2:19][CH2:20][Cl:21]>CC(C)=O>[ClH:4].[Cl:21][CH2:20][CH2:19][CH2:18][N:14]1[CH2:15][CH2:16][N:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([Cl:4])[CH:6]=2)[CH2:12][CH2:13]1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: ClCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: ClCCCN1CCN(c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 111 %

Procedure:
A 25% NaOH solution (320 ml, 2.0 mol) is added dropwise to a stirred solution of 1-(3-chlorophenyl)-piperazine hydrochloride (196.5 g, 1.0 mol) and 1-bromo-3-chloropropane (99.0 ml, 1.0 mol) in acetone (200 ml) while maintaining temperature of 0°-10° C. After the addition is completed, the mixture is allowed to warm to room temperature and is stirred for 18 hours. The upper organic phase is then separated and concentrated under reduced pressure. The residual oil is taken up in 250 ml acetone and filtered. The filtrate is concentrated under reduced pressure and the oily residue is dissolved in 1 l of 15% boiling HCl solution. A viscous oil is separated from the cooled mixture and poured into 1 l of ice-H2O with vigorous stirring, forming white precipitates. Recrystallization of the solid from boiling water gave 171.8 g (55.6% yield) of 1-(3-Chloropropyl)-4-(3-chlorophenyl)piperazine hydrochloride; m.p 199.5-200.5° C. 1H nmr (d-DMSO) δ 11.55 (bs, 1H, HCl), 7.29 (t, 1H, J=8.1 Hz, phenyl H), 7.08 (t, 1H, J=2.0 Hz, phenyl H), 6.99 (dd, 1H, J=2.1, 8.3 Hz, phenyl H), 6.89 (dd, 1H, J=1.5, 7.7 Hz, phenyl H), 3.90 (d, 2H, J=12.8 Hz, CH2), 3.80 (t, 2H. J=6.4 Hz, CH2), 3.58 (d, 2H, J=11.4 Hz, CH2), 3.09-3.41 (overlapping 8H, CH2), 2.30 (m, 2H, CH2); 13C nmr (d-DMSO) δ 150.8, 134.0, 130.7, 119.2, 115.3, 114.2, 53.3, 50.5, 44.8, 42.5, 26.2.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2.[CH2:28]([O:30][C:31](=[O:36])[CH2:32][C:33](O)=[O:34])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:36])[CH2:32][C:33]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2)=[O:34])[CH3:29]
Reactant: CCOC(=O)CC(=O)O
Reactant: N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Product: CCOC(=O)CC(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-benzyloxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and malonic acid monoethyl ester, the title compound was prepared in the same manner as described for example 1c. Colorless oil (>98%). MS: m/e=473(M+H+).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:41][CH3:42])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]5[CH2:40][CH2:39]C[CH2:37][CH2:36]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:43][S:44]([N:47]1CCNCC1)(=[O:46])=[O:45]>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:41][CH3:42])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]5[CH2:40][CH2:39][N:47]([S:44]([CH3:43])(=[O:46])=[O:45])[CH2:37][CH2:36]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCN1CCCCC1
Reactant: CS(=O)(=O)N1CCNCC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCN1CCN(S(C)(=O)=O)CC1
Yield: 21.9 %

Procedure:
The title compound was prepared as described in Example 57B by using 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea from Example 57B (200 mg, 0.37 mmol) and N-methylsulfonyl-piperazine (182 mg, 1.11 mmol) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(4-(methylsulfonyl)piperazin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea (54.17 mg, 22%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.00 (s, 1H), 9.69 (s, 1H), 7.85 (s, 1H), 7.51-7.26 (m, 5H), 6.49 (s, 1H), 4.22 (bs, 2H), 3.99 (s, 3H), 3.14 (s, 4H), 2.86 (s, 3H), 2.20-1.90 (m, 2H), 1.28 (s, 9H); LC-MS (ESI) m/z 670 (M+H)+.
Reaction SMILES: [Li][CH2:2]CCC.C(NC(C)C)(C)C.[Li+].CC([N-]C(C)C)C.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:28]=[C:29]([CH2:33][C:34]([OH:36])=[O:35])[CH:30]=[CH:31][CH:32]=1.CI>C1COCC1>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:28]=[C:29]([CH:33]([CH3:2])[C:34]([OH:36])=[O:35])[CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)Cc1cccc(-c2ccccn2)c1
Reactant: [Li]CCCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: CI
Solvent: C1CCOC1
Product: CC(C(=O)O)c1cccc(-c2ccccn2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60.9 %

Procedure:
nBuLi (ml, 2.5 M in hexanes, 52.16 mmol) was added dropwise to a solution of diisopropyl amine (5.2 ml, 37.6 mmol) in THF (20 ml) at −78 degrees C. The reaction was stirred 20 minutes warming to 0 degrees C., then the reaction was cooled to −78 degrees C. The LDA solution was then added dropwise into a cooled solution of 3-(2-pyridyl)phenyl acetic acid (2.0 g, 9.4 mmol) in THF (10 ml) at −78 degrees C. After addition, the reaction mixture was warmed to 0 degrees C., then cooled again to −78 degrees C Methyl iodide (1.2 ml, 18.6 mmol) was then added dropwise. The reaction mixture was stirred for 1 h. then warmed to RT, then quenched with water (20 ml). The THF from the reaction mixture was then removed in vacuo, then the pH of the solution was adjusted to 7 by adding con HCl and pH 7 buffer (1 M). The aqueous reaction mixture was then extracted twice with CHCl3. The combined organic extracts were dried with magnesium sulfate, concentrated in vacuo, and chromatographed (silica gel, 1% AcOH, 3% MeOH—CH2Cl2) to yield a white solid (1.3 g, 61%): MS ES(+) 228.1 (M+H+).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.C([Mg]Cl)(C)C.[B:14](OC(C)C)([O:19]C(C)C)[O:15]C(C)C.Cl>C(OCC)C.C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:14]([OH:19])[OH:15]
Reactant: Ic1ccccc1I
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: OB(O)c1ccccc1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To a solution of 1,2-diiodobenzene (0.102 g, 3.08 mmol) in 60 mL of a mixture of THF and diethylether (Et2O) (1:1) was added dropwise at −78° C. isopropylmagnesium chloride (2 M in THF, 1.54 mL, 3.08 mmol). After the mixture was stirred for 2 h at that temperature, B(OiPr)3 (1.74 g 2.12 mL, 9.24 mmol) was added. The solution was warmed to room temperature overnight; then 40 mL of HCl (10%) was added, and the resulting mixture was stirred for 30 min at room temperature. The aqueous layer was extracted with Et2O (50 mL, 3 times). Drying over Na2SO4, evaporation and purification by flash chromatography gave 0.62 g of the pure product (82%).
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[CH:14][N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.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>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[CH:14][N:9]2[C:10](=[O:13])[C:11]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: CC(N=[N+]=[N-])c1nc2sccn2c(=O)c1Br
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(N=[N+]=[N-])c1nc2sccn2c(=O)c1-c1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.34 g, 1.1 mmol) and phenylboronic acid (0.16 g, 1.4 mmol) in 1,4-dioxane (10 mL) was added a 1 N solution of sodium carbonate in water (1.5 mL, 1.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.065 g, 0.057 mmol). The mixture was stirred at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, concentrated, and purified on silica gel (0-50% ethyl acetate/hexanes) to give the desired product (0.23 g, 68%). LCMS calculated for C14H12N5OS (M+H)+: m/z=298.1. Found: 298.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>ClCCl>[Si:14]([O:9][CH2:8][C:6]1[N:7]=[C:2]([NH2:1])[CH:3]=[CH:4][CH:5]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1cccc(CO)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cccc(N)n1
Reaction time: 24 h
Yield: 76.7 %

Procedure:
To a solution of dichloromethane (15 mL) was added (6-aminopyridin-2-yl)methanol (0.72 g, 5.8 mmol), tert-butyl(chloro)dimethylsilane (1.05 g, 6.95 mmol) and triethylamine (1.05 mL, 7.53 mmol). The mixture was stirred for 24 h and washed with saturated sodium bicarbonate (2×30 mL) and aqueous hydrochloric acid (2×30 mL, 0.1 N). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification was done using silica gel chromatography eluting with hexane: ethyl acetate (1:1) and fractions were combined and concentrated to afford the titled product as a white solid (1.06 g, 70%). HPLC: Rt 2.58 min. (96.5% area). 1H NMR (400 MHz, CDCl3), δ: 7.34 (t, J=7.6 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.25 (d, J=8.1 Hz, 1H), 4.54 (s, 2H), 4.27 (bs, 2H), 0.84 (s, 9H), 0.11 (s, 6H); LRMS (ESI): m/z: 239.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=O.[CH3:12][CH2:13][CH2:14][CH:15]([NH2:19])[CH2:16][CH2:17][CH3:18]>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([NH:19][CH:15]([CH2:16][CH2:17][CH3:18])[CH2:14][CH2:13][CH3:12])=[O:7]
Reactant: CCCC(N)CCC
Reactant: Nc1cc(C(=O)O)ccc1O
Product: CCCC(CCC)NC(=O)c1ccc(O)c(N)c1
Yield: 57 %

Procedure:
3-amino-4-hydroxy-N-(1-propylbutyl)benzamide was prepared in a similar manner to example 4 using 3-Amino-4-hydroxybenzoic acid and 4-heptylamine. Yield 57%. 1H NMR (500 MHz, CDCl3): δ 0.93 (t, 6H); 1.26-1.51 (m, 8H); 4.09 (m, 1H); 6.74 (m, 1H); 7.05 (s, 1H); 7.43 (m, 2H); 7.77 (m, 2H). MS: (251, M+H).