Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:5][S:6][CH:7]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]([NH:28][CH2:29][C:30]1[N:34]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:33]2[CH:43]=[CH:44][CH:45]=[CH:46][C:32]=2[N:31]=1)[CH3:27].CCN(C(C)C)C(C)C>CC#N>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]([N:28]([CH2:2][C:3]1[C:4]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:5][S:6][CH:7]=1)[CH2:29][C:30]1[N:34]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:41])[CH3:42])[C:33]2[CH:43]=[CH:44][CH:45]=[CH:46][C:32]=2[N:31]=1)[CH3:27]
Reactant: O=C1c2ccccc2C(=O)N1Cc1cscc1CBr
Reactant: CC(NCc1nc2ccccc2n1COCC[Si](C)(C)C)c1ccccn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1ccccn1)N(Cc1cscc1CN1C(=O)c2ccccc2C1=O)Cc1nc2ccccc2n1COCC[Si](C)(C)C

Procedure:
Using General Procedure A: Reaction of 2-(4-bromomethyl-thiophen-3-ylmethyl)-isoindole-1,3-dione, (1-pyridin-2-yl-ethyl)-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-2-ylmethyl]-amine, DIPEA and KI in CH3CN gave 2-[4-({(1-pyridin-2-yl-ethyl)-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-2-ylmethyl]-amino}-methyl)-thiophen-3-ylmethyl]-isoindole-1,3-dione.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][NH:8][C:7]=2[CH:14]=1)#[N:2].[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=[O:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:12])([CH3:13])[CH2:9][N:8]([C:15]3[C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH:20]=3)[C:7]=2[CH:14]=1)#[N:2]
Reactant: CC1(C)CNc2cc(C#N)ccc2O1
Reactant: O=C1CCCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)CN(C2=CCCCC2=O)c2cc(C#N)ccc2O1
Yield: 66.7 %

Procedure:
In 15 ml of toluene were dissolved 0.5 g of 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine, 0.33 g of cyclohexane-1,2-dione and a catalytic amount of p-toluenesulfonic acid and using a Dean-Stark trap, the solution was refluxed under heating for 4 hours. After cooling, the reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and the resulting crude crystals were washed with ethanol to give 0.5 g of 6-cyano-3,4-dihydro-2,2-dimethyl-4-(6-oxo-1-cyclohexen-1-yl)-2H-1,4-benzoxazine.
Reaction SMILES: COCC[N:5]1[C:9]([CH:10]([O:12][CH3:13])[CH3:11])=[C:8]([Cl:14])[N:7](Cl)[CH:6]1[C:16]1[C:21]([CH2:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:24][CH3:25].[Li]CCCC.CN([CH:34]=[O:35])C>C1COCC1>[CH2:24]([C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([CH2:22][CH3:23])[C:16]=1[C:6]1[N:7]([CH:34]=[O:35])[C:8]([Cl:14])=[C:9]([CH:10]([O:12][CH3:13])[CH3:11])[N:5]=1)[CH3:25]
Reactant: CCc1cccc(CC)c1C1N(Cl)C(Cl)=C(C(C)OC)N1CCOC
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1-c1nc(C(C)OC)c(Cl)n1C=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of N-methoxyethyl 2-(2,6-diethylphenyl)-1-methoxyethyl-3,4-dichloroimidazole (3.27 g, 10 mmol.) in anhydrous THF is added n-BuLi (1.6M in hexane) (9.4 ml, 15 mmol) dropwise at −78° C. After the reaction mixture is stirred at −78° C. for 2 h, anhydrous DMF (3 equiv.) is added in one portion. The mixture is stirred at −78° C. for 30 min, then allowed to warm to room temperature slowly. The reaction mixture is quenched with water and extracted with ethyl acetate, dried over MgSO4, filtered, concentrated in vacuo and purified by chromatography on silica gel to give 2-(2,6-diethylphenyl)-1-methoxyethyl-4-chloro-imidazole-3-carboxaldehyde. This material is used to make various compounds of Formula I as depicted in Scheme 10 and further illustrated in Examples 4–9 and related examples.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([C:10]3[CH:11]=C[C:13]([NH2:16])=[N:14][CH:15]=3)[O:9][C:5]=2[CH:4]=1.[NH2:19]C1N=CC(B2OC(C)(C)C(C)(C)O2)=CN=1>>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[N:14][C:13]([NH2:16])=[N:19][CH:11]=3)[O:9][C:5]=2[CH:4]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: COc1ccc2nc(-c3ccc(N)nc3)oc2c1
Product: COc1ccc2nc(-c3cnc(N)nc3)oc2c1

Procedure:
The title compound was synthesised according to the procedure described for 5-(6-methoxy-1,3-benzoxazol-2-yl)pyridin-2-amine starting from 2-aminopyrimidine-5-boronic acid pinacol ester. 1H NMR δ ppm 8.89 (s, 2H) 7.61 (d, 1H) 7.48 (s, 2H) 7.37 (d, 1 H) 6.97 (dd, 1H) 3.83 (s, 3H); MS m/z 243 (M+H).
Reaction SMILES: C[O:2][C:3]1[C:4](=[O:40])[C:5](=O)[C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[NH:15][CH2:16][CH2:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=1.[NH3:41]>C(O)C>[NH2:41][C:5]1[C:4](=[O:40])[C:3](=[O:2])[C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[NH:15][CH2:16][CH2:17][CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:9]=1
Reactant: N
Reactant: COc1ccc(C(NCCC(c2ccccc2)c2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Solvent: CCO
Product: COc1ccc(C(NCCC(c2ccccc2)c2ccccc2)c2cccc(Nc3c(N)c(=O)c3=O)c2)cc1

Procedure:
In a similar maiser to that described in Example (1d), 3-methoxy-4-{3-[(4-methoxyphenyl)-(3,3-diphenylpropylamino)methyl]phenylamino}-3-cyclobutene-1,2-dione (1.86 g) [prepared as described in step (c) above] and a solution of ammonia in ethanol (2N, 7 ml) were reacted, to give the title compound (1.36 g) as a pale yellow solid.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:8][C:7]([O:11][CH3:12])([O:9][CH3:10])[CH2:6]1)=[O:4].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[Br-].[Mg+2].[Br-]>C(#N)C>[CH3:12][O:11][C:7]1([O:9][CH3:10])[CH2:6][CH:5]([C:3]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:4])[CH2:8]1
Reactant: C1CCNC1
Reactant: COC(=O)C1CC(OC)(OC)C1
Agent: [Br-]
Agent: [Mg+2]
Solvent: CC#N
Product: COC1(OC)CC(C(=O)N2CCCC2)C1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a stirring solution of 3,3-dimethoxy-cyclobutanecarboxylic acid methyl ester, (J. Org. Chem. 1988, 53, 3841 and J. Org. Chem. 1996, 61, 2174) (1.0 g, 5.7 mmol) in acetonitrile (200 mL) was added pyrrolidine (951 uL, 11.5 mmol), followed by magnesium bromide (0.53 g, 2.9 mmol). The reaction was then heated to 60 □C (oil bath) for 18 hours. After 18 hours a second portion of pyrrolidine (1.9 mL, 23 mmol) and magnesium bromide (0.8 g, 4.3 mmol were added. The reaction was then heated to 80 □C (oil bath) for 48 hours. TLC and MS analysis indicated complete consumption of starting material. The reaction was cooled to room temperature and quenched with a saturated solution of NaHCO3, and diluted with CH2Cl2. The layers were separated and the organic layer was dried over magnesium sulfate, filtered through a fritted funnel and concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography using a 40M Biotage column, eluting with 70% EtOAc/toluene. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (1.0 g, 86% yield) as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:5][CH:4]1[CH2:6][OH:7].C(S([C:12]1[S:13][C:14]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[CH:25])=[O:18])=[CH:15][N:16]=1)=O)C>O1CCCC1>[O:5]1[CH:4]([CH2:6][O:7][C:12]2[S:13][C:14]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[CH:25])=[O:18])=[CH:15][N:16]=2)[CH2:3]1
Reactant: OCC1CO1
Reactant: C#CCCCCNC(=O)c1cnc(S(=O)CC)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCCCCNC(=O)c1cnc(OCC2CO2)s1
Temperature: -5 °C

Procedure:
In this preparation 0.0525 mole of sodium hydride in a 50% mineral oil mixture is stirred in 300 ml. of anhydrous tetrahydrofuran, under nitrogen, then cooled to -30° C and 0.055 mole glycidol is added dropwise. The mixture is allowed to warm -5° C and stirred for 10 minutes and then recooled to -30° C. A solution of 0.05 mole of 2-ethylsulfinyl-5-(hex-5-ynylaminocarbonyl)thiazole in 100 ml. of anhydrous tetradrofuran is added dropwise and the resulting solvent is added as needed to facilitate stirring. The mixture is maintained for 30 minutes at 0° C and then poured into 500 ml. of ethyl acetate, extracted with 100 ml. of water, and then with 100 ml. of aqueous saturated sodium chloride and dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated under vacuum affording an oily residue which is then further purified by chromatography on silica gel eluting with 40% ethyl acetate-60% hexane, by vol., affording 1,2-epoxy-3-[5-(hex-5-ynylaminocarbonyl)thiazol-2-yloxy]propane.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([CH3:14])([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:46][O:47][C:48]1[CH:49]=[C:50]([O:54][C:55]2[CH:60]=[CH:59][C:58]([NH2:61])=[CH:57][CH:56]=2)[CH:51]=[CH:52][CH:53]=1>CN(C)C=O>[CH3:14][C:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:10])[C:11]([NH:61][C:58]1[CH:57]=[CH:56][C:55]([O:54][C:50]2[CH:51]=[CH:52][CH:53]=[C:48]([O:47][CH3:46])[CH:49]=2)=[CH:60][CH:59]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: COc1cccc(Oc2ccc(N)cc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc(Oc2ccc(NC(=O)C(C)(C)NC(=O)OC(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.1 %

Procedure:
To a solution of N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-methylalanine (1.7 g, 8.36 mmol) in dry N,N-dimethylformamide (35 mL), DIPEA (2.434 mL, 13.94 mmol) and then TBTU (2.80 g, 8.71 mmol) were added and the reaction mixture was stirred for 15 minutes at room temperature. (4-{[3-(methyloxy)phenyl]oxy}phenyl)amine (1.5 g, 6.97 mmol) was then added and the reaction mixture was stirred overnight at the same temperature. The reaction was quenched with brine (100 mL) and extracted with ethyl acetate (twice 150 mL). The organic layer was washed with ice cold brine (3 times 100 mL), dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography (Biotage system, 100 g SNAP column) using as eluent a gradient and cyclohexane/ethyl acetate from 100/0 to 70/30 to afford the title compound as a white solid (1.90 g).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[I:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29]>>[I:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:29]
Reactant: O=C(O)c1cccc(I)c1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(I)c2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-Iodo-benzoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[CH3:2]>CO.CCOC(C)=O.[Pt]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:14][CH2:15][N:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH2:21][CH2:20]3)[CH2:17][CH2:18]2)[CH:7]=[CH:8][C:9]=1[NH2:10])[CH3:2]
Reactant: CCOc1cc(N2CCN(C3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOc1cc(N2CCN(C3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1N
Reaction time: 20 h
Yield: 95.4 %

Procedure:
A mixture of 1-[3-(ethyloxy)-4-nitrophenyl]-4-{1-[2-(methylsulfonyl)ethyl]-4-piperidinyl}-piperazine (290 mg, 0.65 mmol) and platinum (sulfided, 5 wt. % on carbon, 50 mg, 0.013 mmol) in 20% MeOH/EtOAc (20 mL) was added to a high-pressure hydrogenation reaction flask. The reaction was purged with N2 and vacuum (3×). The reaction was purged with H2 and vacuum (3×). The reaction was then treated with H2 at 50 psi and stirred for approximately 20 h. The reaction was degassed, then poured through a Teflon filter, washing the solid with MeOH and DCM. The filtrate was concentrated under vacuum to give the title compound of step B (256 mg, 0.62 mmol, 97%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 6.50 (d, 1H, J=8.43 Hz), 6.44 (d, 1H, J=2.38 Hz), 6.26 (cd, 1H, J=2.38 and 8.43 Hz), 4.17 (br s, 2H), 3.95 (q, 2H, J=6.96 Hz), 3.25 (t, 2H, J=6.69 Hz), 3.01 (s, 3H), 2.91 (M, 6H), 2.65 (t, 2H, J=6.78 Hz), 2.57 (m, 4H), 2.10-2.20 (m, 1H), 1.89-1.97 (m, 2H), 1.76 (m, 2H), 1.28-1.32 (m, 5H).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:24][O:25][C:26](=[O:40])[C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]2[S:38][C:37]([NH2:39])=[N:36][CH:35]=2)=[CH:29][CH:28]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C>[CH3:24][O:25][C:26](=[O:40])[C:27]1[CH:28]=[CH:29][C:30]([O:33][C:34]2[S:38][C:37]([NH:39][C:14](=[O:15])[CH:13]([C:10]3[CH:9]=[CH:8][C:7]([S:4]([CH:1]4[CH2:2][CH2:3]4)(=[O:5])=[O:6])=[CH:12][CH:11]=3)[O:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[N:36][CH:35]=2)=[CH:31][CH:32]=1
Reactant: COC(=O)c1ccc(Oc2cnc(N)s2)cc1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2cnc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)cc1
Yield: 33.3 %

Procedure:
The compound of example A76 was obtained by similar method described in example A75 using (4-Cyclopropanesulfonyl-phenyl)-[(tetrahydro-pyran-4-yloxy)]-acetic acid (Preparation 14) (0.5 g, 1.47 mmol), 4-(2-Amino-thiazol-5-yloxy)-benzoicacid methyl ester (0.441 g, 1.76 mmol), HOBt (0.237 g, 1.76 mmol), and EDCI (0.337 g, 1.76 mmol), N-methyl morpholine (0.178 g, 1.76 mmom) in DMF (10 mL) to provide the title compound (280 mg).
Reaction SMILES: [CH:1](N)=O.[NH2:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=2)[N:8]=[CH:7][C:6]=1[C:18]([NH2:20])=[O:19]>O>[CH3:16][C:14]1[CH:15]=[C:10]([N:9]2[C:5]3[N:4]=[CH:1][NH:20][C:18](=[O:19])[C:6]=3[CH:7]=[N:8]2)[CH:11]=[C:12]([CH3:17])[CH:13]=1
Reactant: Cc1cc(C)cc(-n2ncc(C(N)=O)c2N)c1
Reactant: NC=O
Solvent: O
Product: Cc1cc(C)cc(-n2ncc3c(=O)[nH]cnc32)c1
Temperature: 190 °C
Yield: 69.21 %

Procedure:
Charged 300.0 g of formamide into a 2.0 L 4 necked round bottom flask connected to a mechanical stirrer, thermo meter socket, and condenser under nitrogen atmosphere. 90.0 g (0.39 mol) of 5-Amino-1-(3,5-dimethyl-phenyl)-1H-pyrazole-4-carboxylic acid amide (Compound No. 77) was charged. Reaction mass temperature was raised to reflux (185-195° C.). Maintained the mass temperature at reflux for 60-90 min. Reaction mass temperature was cooled to 140-150° C. 900.0 ml of water was added slowly at maintaining the mass temperature 80-150° C. Maintained the mass temperature at 80-90° C. for 45-60 min. Reaction mass temperature was cooled to 25-30° C. Maintained the mass temperature at 25-30° C. for 90-120 min. Solid was filtered and solid was washed with 150.0 ml of water. 500.0 ml of DM Water and wet crude compound were charged into a 2.0 L 4 necked round bottom flask connected to a mechanical stirrer, thermo meter socket, and condenser. Mass temperature was raised to reflux. Maintained the mass temperature at reflux for 75-90 min and mass temperature was cooled to 25-30° C. Maintained the mass temperature at 25-30° C. for 90-120 min. Solid was filtered and solid was washed with 100.0 ml of water. Compound was dried under vacuum at 60-65° C. Dry weight of the compound: 65.0 g (yield 69.21%)
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[NH2:11][C@@H:12]([CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[O:14]>>[N:2]1([CH2:7][C:8]([NH:11][C@@H:12]([CH2:30][O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([S:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:20][CH:21]=2)=[O:14])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(O)Cn1cncn1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Sc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(Cn1cncn1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Sc2ccc(F)cc2)cc1
Yield: 18 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenylthio)phenyl)propanamide, gave Compound 178, (S)-2-(2-(1H-1,2,4-triazol-1-yl)acetamido)-3-(benzyloxy)-N-(4-(4-fluorophenylthio)phenyl)propanamide (100.1 mg, 18%). 1H-NMR (400 MHz, CDCl3): δ 8.57 (s, 1H), 8.19 (s, 1H), 8.03 (s, 1H), 7.38-7.21 (m, 13H), 7.03-6.96 (m, 2H), 4.92 (s, 2H), 4.73-4.67 (m, 1H), 4.61 (d, 1H), 4.52 (d, 1H), 3.97-3.91 (dd, 1H), 3.57 (t, 1H). MS (EI) for C26H25FN5O3S found 506 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:13]([NH2:15])[CH3:14].C([O:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]2[C:44]3[C:39](=[CH:40][C:41]([C:45](O)=[O:46])=[CH:42][CH:43]=3)[C:38]([CH3:48])=[C:37]2[CH3:49])=[CH:31][CH:30]=1)=[O:22])(C)(C)C>>[Cl:2][C:3]1[C:8]([C:9]([F:11])([F:12])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:13]([NH:15][C:45]([C:41]1[CH:40]=[C:39]2[C:44](=[CH:43][CH:42]=1)[N:36]([CH2:35][C:32]1[CH:31]=[CH:30][C:29]([C:24]3[C:23]([C:21]([OH:22])=[O:20])=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:34][CH:33]=1)[C:37]([CH3:49])=[C:38]2[CH3:48])=[O:46])[CH3:14]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1cccc(C(F)(F)F)c1Cl
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(F)(F)F)c3Cl)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(2-chloro-3-(trifluoromethyl)phenyl)ethanamine hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 605 [M+H]+.
Reaction SMILES: O[CH:2]=[C:3]1[C:8](=O)[C:7]([CH:10]([CH3:12])[CH3:11])=[C:6]([O:13][CH3:14])[CH2:5][CH2:4]1.C(=O)(O)O.[NH2:19][C:20]([NH2:22])=[NH:21]>CN(C=O)C>[CH:10]([C:7]1[C:6]([O:13][CH3:14])=[CH:5][CH:4]=[C:3]2[C:8]=1[N:21]=[C:20]([NH2:22])[N:19]=[CH:2]2)([CH3:12])[CH3:11]
Reactant: COC1=C(C(C)C)C(=O)C(=CO)CC1
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CN(C)C=O
Product: COc1ccc2cnc(N)nc2c1C(C)C
Temperature: 150 °C

Procedure:
A mixture of 6-hydroxymethylene-2-isopropyl-3-methoxy-cyclohex-2-enone (3.5 g) and guanidine carbonate (7 g) in DMF (40 mL) was heated at 150° C. for 4 hours. The solvent was removed under reduced pressure, then ice-cold water was added to the residue. The product was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, then brine, and dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure to give a crude mixture of dihydroquinazolines (4 g). The dihydroquinazolines were aromatized to the title compound by heating in nitrobenzene (70 mL) at 150° C. in the presence of 10% Pd-C (400 mg) for 3 days. The catalyst was removed by filtration, then the filtrate was concentrated, and the resulting product was purified on a column of silica gel (Hex:EtOAc) to give the title compound as an off-white solid (2.1 g, 54.2%). mp 112–113° C.; 1H NMR (CDCl3): δ 1.38 (d, 6H, 2×CH3), 3.95 (s, 3H, OCH3), 4.24 (m, 1H, CH), 5.0 (br s, 2H, NH2), 7.02 (d, 1H, Ar-H, J=9 Hz), 7.55 (d, 1H, Ar-H, J=9 Hz), 8.87 (s, 1H, Ar-H); MS m/z 218.05, C12H15N3O (M++1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[CH:17]=1)=[O:14].[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[CH2:12][C:7]2[C:8]3[C:3](=[C:2]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH3:31])[CH:11]=[CH:10][CH:9]=3)[CH:4]=[CH:5][CH:6]=2)=[CH:17][C:18]=1[N:24]1[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]1
Reactant: COc1ccc(NC(=O)Cc2cccc3c(Br)cccc23)cc1N1CCN(C)CC1
Reactant: Cc1ccccc1B(O)O
Product: COc1ccc(NC(=O)Cc2cccc3c(-c4ccccc4C)cccc23)cc1N1CCN(C)CC1

Procedure:
The title compound was prepared from 5-bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]naphth-1-ylacetamide (E20) and 2-methylphenylboronic acid using a similar procedure to Example 4 (48%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:14][CH:13]2[CH2:12][NH:11][CH:10]3[CH3:15])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:16]CN(C(C)C)C(C)C.CI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:14][CH:13]2[CH2:12][N:11]([CH3:16])[CH:10]3[CH3:15])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1NCC2CC21c1ccc(Cl)c(Cl)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: CN(C)C=O
Product: CC1N(C)CC2CC21c1ccc(Cl)c(Cl)c1

Procedure:
To a dried, 5 mL round-bottomed flask was added (±)-1-(3,4-dichlorophenyl)-(R/S)-2-methyl-3-aza-bicyclo[3.1.0]hexane, Hunig's Base, and DMF under Ar (g) with stirring. Methyl iodide was added drop wise with stirring over 5 min and the resulting solution stirred under ambient temperature overnight. The solution was concentrated under reduced pressure and purified after drying. The residue was purified by HPLC which failed to remove the impurities. This was further purified on a prep TLC plate eluting with 20/1 CHCl3/MeOH (v/v). The desired band was collected, extracted with CHCl3/MeOH, and concentrated after filtration to afford the desired free base. Yield: 0.005 g 15%; LCMS (+)ESI: m/z=256 [MH]+ (100); 258 [MH+2]+; (65); 1H NMR (300 MHz, CDCl3) δ□: 7.33 (d, H, J=12 Hz, ArH), 7.32 (d, 1H, J=2 Hz, ArH), 7.08 (dd, 1H, J=9 Hz, J=2 Hz, ArH), 3.31 (q, 1H, J=6 Hz, CHNH2), 2.83 (s, 2H, CH2N), 2.32 (s, 3H, NCH3), 1.79 (m, 1H, CH2CH), 1.40 (t(br), 1H, ArCCH2), 0.73 (d, 3H, J=7 Hz, CHCH3)., 0.60 (dd, 21-1, J=8 Hz, 4 Hz, ArCCH2); 13C NMR (75 MHz, CDCl3) δ□: 131.2, 130.1, 128.9, 61.1, 53.8, 36.5, 21.9, 18.4, 11.6.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: BrCCCCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCCCCOc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with (5-bromopentoxy)benzene (1.4 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material from dichloromethane extraction was purified by HPLC (dichloromethane-hexane; 4:1) to provide 0.9 g of analytically pure alpha-oxo-4-[[(5-phenoxy)pentyl]oxy]benzeneacetic acid methyl ester which failed to crystallize.