Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:29])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:20](O)[C:21]4[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:28]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[Br:1][C:2]1[C:3]([F:29])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH2:20][C:21]4[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:28]=1
Reactant: COC(=O)c1nc2n(c1C(O)c1ccnn1C)C1CC(C1)c1cc(F)c(Br)cc1-2
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1nc2n(c1Cc1ccnn1C)C1CC(C1)c1cc(F)c(Br)cc1-2
Temperature: 25 °C

Procedure:
To a solution of methyl 10-bromo-9-fluoro-3-(hydroxy(1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate (140 mg, 0.3035 mmol) in dichloromethane (0.91 mL) was added triethylamine (4.0 equiv., 0.171 mL, 1.214 mmol) followed by methanesulfonyl chloride (1.2 equiv., 0.029 mL, 0.3642 mmol). The reaction was stirred at room temperature until LC/MS analysis indicated complete consumption of starting material.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:27]4[C@H:26]([CH3:25])[CH2:30][O:29][C:28]4=[O:31])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[O:24])=[CH:18][CH:19]=1
Reactant: C[C@@H]1COC(=O)N1
Reactant: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(Br)nc2)CC1
Product: C[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCC(C(=O)c3ccc(Cl)cc3)CC2)cn1
Yield: 41.8 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 31 and using (6-bromopyridin-3-yl)[4-(4-chlorobenzoyl)piperidin-1-yl]methanone (2 g) described in Preparation Example 23 and (R)-4-methyloxazolidin-2-one (288 mg) described in Preparation Example 25, the title compound (510 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[N:5][C:4](=[O:7])[N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](Cl)=[O:18]>[N+](C1C=CC=CC=1)([O-])=O>[CH3:1][C:2]1[NH:3][C:4](=[O:7])[NH:5][C:6]=1[C:17]([C:13]1[S:12][CH:16]=[CH:15][CH:14]=1)=[O:18]
Reactant: O=C(Cl)c1cccs1
Reactant: CC1=NC(=O)N=C1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1[nH]c(=O)[nH]c1C(=O)c1cccs1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 7.3 g of 4-methylimidazol-2-one and 10.8 g of aluminum chloride in 150 ml of nitrobenzene is added 12.0 g of 2-thienoyl chloride. The mixture is stirred at 60° C. for 3 hours, cooled and poured over ice water. The organic portion is extracted into ethyl acetate, dried and the organic solvent evaporated to give the title compound. M.P. 212°-215° C.
Reaction SMILES: C(ON=O)(C)(C)C.[C:8]1([C:14]([CH2:16]Br)=[CH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N+:18]([C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=1)N)([O-:20])=[O:19].NC1C=CC=CC=1>CC#N>[N+:18]([C:21]1[CH:22]=[C:23]([CH2:16][C:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH2:15])[CH:25]=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=1)([O-:20])=[O:19]
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: C=C(CBr)c1ccccc1
Agent: CC(C)(C)ON=O
Solvent: Nc1ccccc1
Solvent: CC#N
Product: C=C(Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1ccccc1
Temperature: 25.5 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a solution of t-butylnitrite (119 μl, 1.0 mmol) and 2-phenyl-3-brompropene (0.99 g, 5.0 mmol) in CH3CN (0.5 ml) was 3,5-dinitroaniline (92 mg, 0.5 mmol) added during 10 minutes, while maintaining the temperature of the reaction mixture at 23-28° C. At the end of the addition of the aniline extra t-butylnitrite (119 μl, 1.0 mmol) was added to the reaction mixture which then was heated to 35° C. for 5 minutes. The reaction mixture was stirred at 22° C. for one hour. The volatile material in the reaction mixture was removed at reduced pressure. Column chromatography (heptane-ethyl acetate 23:2) succeeded by crystallization from heptane gave 50 mg (35%) of 3,5-dinitro-1-(2-phenyl-2-propenyl)benzene as bright yellow needles. 1H NMR (CDCl3, 400 MHz) δ 8.88, (t, 1H, J=2.1 Hz), 8.42, (d, 2H, J=2.1 Hz), 7.42-7.37, (m, 2H), 7.36-7.24, (m, 3H), 5.65, (s, 1H), 5.22, (d, 1H, J=0.8 Hz), 4.08, (s, 2H).
Reaction SMILES: O.[OH-].[Li+].[CH3:4][N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][C:14]([O:16][C:17]3[CH:18]=[C:19]([CH:24]=[C:25]([O:27][C@H:28]4[CH2:32][CH2:31][O:30][CH2:29]4)[CH:26]=3)[C:20]([O:22]C)=[O:21])=[CH:15][C:8]=2[O:7][CH2:6]1>O.C1COCC1>[CH3:4][N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][C:14]([O:16][C:17]3[CH:18]=[C:19]([CH:24]=[C:25]([O:27][C@H:28]4[CH2:32][CH2:31][O:30][CH2:29]4)[CH:26]=3)[C:20]([OH:22])=[O:21])=[CH:15][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)c1cc(Oc2ccc3c(c2)OCN(C)C3=O)cc(O[C@H]2CCOC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1COc2cc(Oc3cc(O[C@H]4CCOC4)cc(C(=O)O)c3)ccc2C1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.1 %

Procedure:
Lithium hydroxide monohydrate (13 mg, 0.3 mmol) in water (2.5 mL) was added to a solution of methyl 3-[(3-methyl-4-oxo-3,4-dihydro-2H-1,3-benzoxazin-7-yl)oxy]-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate (0.12 g, 0.3 mmol) in THF (5 mL) and stirred at RT for 20 hours. The THF was removed in vacuo and the aqueous layer was washed with ethyl acetate (50 mL) to remove any impurities. The aqueous layer was acidified and extracted into ethyl acetate (2×50 mL), washed with brine (50 mL), dried (MgSO4), and the solvent removed in vacuo to give the desired compound as a white solid (110 mg).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@:8]([NH:19][S@@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])([CH2:17][F:18])[CH2:9][C:10](OC(C)(C)C)=[O:11])[C:5]([F:26])=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([C@@:8]([NH:19][S@@:20]([C:22]([CH3:24])([CH3:23])[CH3:25])=[O:21])([CH2:9][CH:10]=[O:11])[CH2:17][F:18])[C:5]([F:26])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C[C@](CF)(N[S@](=O)C(C)(C)C)c1nc(Br)ccc1F
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)N[C@@](CF)(CC=O)c1nc(Br)ccc1F
Temperature: -78 °C
Reaction time: 1.25 h
Yield: 67.8 %

Procedure:
To a 500 mL 3-neck round-bottomed flask equipped with internal temperature monitoring and a magnetic stir bar was added (5)-tert-butyl 3-(6-bromo-3-fluoropyridin-2-yl)-3-((R)-1,1-dimethylethylsulfinamido)-4-fluorobutanoate (8.90 g, 19.55 mmol) and DCM (200 mL). The solution was cooled to −78° C. and DIBAL-H (Aldrich; 48.9 mL, 48.9 mmol, 1.0 M in hexane) was added over 30 min with the solution running down the side of the flask to precool it. The solution did not go above −74° C. during the addition. After 75 min at −78° C., an additional 5 mL of the DIBALH solution was added. After 10 min the solution was quenched with MeOH (4 mL) dropwise with the MeOH running down the inside of the flask. The solution was allowed to warm to rt and 4 mL of sat NaHCO3 was added. This was stirred for 10 min and then solid Na2SO4 was added (˜20 g). This was stirred for 10 min and then filtered through Celite and the filtercake was washed with DCM. The filtrate was concentrated onto silica. Purification by silica gel chromatography (Gradient: 0.0 to 60% EtOAc/hexane) afforded (R)-N-((S)-2-(6-bromo-3-fluoropyridin-2-yl)-1-fluoro-4-oxobutan-2-yl)-2-methylpropane-2-sulfinamide (5.08 g, 13.25 mmol, 67.8% yield) as a pale yellow oil. MS m/z=383.0 [M+H]+. Calculated for C13H17BrF2N2O2S: 382.0.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:15][C:16]([O:18]CC3C=CC=CC=3)=O)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+].C1(COC2C=C(CC(O)=O)C=CC=2)C=CC=CC=1.C(Cl)(=O)C([Cl:50])=O>O.ClCCl.CN(C=O)C.C1COCC1.O>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:15][C:16]([Cl:50])=[O:18])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1cccc(OCc2ccccc2)c1)OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C(O)Cc1cccc(OCc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cl)Cc1cccc(OCc2ccccc2)c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 98.4 %

Procedure:
To a solution of phenylmethyl 2-[3-(phenylmethoxy)phenyl]acetate (9.97 g, 0.03 mol) in a 5:1 mixture of THF/water was added a solution of lithium hydroxide monohydrate (2.5 g, 0.06 mol) in water. The reaction was allowed to stir at 50° C. for 6 hours and then at room temperature overnight. Solvent was removed and the reaction was acidified with 4 N HCl solution while on ice. 2-[3-(Phenylmethoxy)phenyl]acetic acid precipitated from the solution and was collected by filtration. The 2-[3-(phenylmethoxy)phenyl]acetic acid (7.0 g, 0.03 mol) was dissolved in dichloromethane (100 ml) and a small amount of DMF (4 drops) was added. To the reaction was added oxalyl chloride (5.23 ml, 0.06 mol). The reaction was allowed to stir for 6 hours, and solvents were removed to yield the title compound (7.7 g, 99% yield): ES-MS (m/z) 386 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([CH:12]3[CH2:14][CH2:13]3)=[O:11])[S:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[S:33][C:32]([S:34](Cl)(=[O:36])=[O:35])=[CH:31][CH:30]=1>CN(C)C1C=CN=CC=1.CC(C)=O>[CH:12]1([C:10]([NH:9][C:7]2[S:8][C:4]3[CH:3]=[C:2]([O:1][S:34]([C:32]4[S:33][C:29]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=5)=[CH:30][CH:31]=4)(=[O:35])=[O:36])[CH:16]=[CH:15][C:5]=3[N:6]=2)=[O:11])[CH2:13][CH2:14]1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Reactant: O=C(Nc1nc2ccc(O)cc2s1)C1CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(-c4ccccn4)s3)cc2s1)C1CC1
Yield: 8.5 %

Procedure:
A solution of cyclopropanecarboxylic acid (6-hydroxybenzothiazol-2-yl)amide (intermediate 6) (60 mg, 0.256 mmol), pyridine (80 μl, 0.991 mmol), 4-dimethylaminopyridine (3 mg, 0.025 mmol) and 5-(2-pyridyl)thiophene-2-sulfonyl chloride (99 mg, 0.384 mmol) in 2 ml of acetone is stirred for 24 hours at 40° C. The reaction medium is concentrated to dryness, taken up in 2 ml of DMSO and purified 4 times by preparative LC/MS (method B) to give 10 mg of 5-pyridin-2-ylthiophene-2-sulfonic acid 2-(cyclopropanecarbonyl-amino)benzothiazol-6-yl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:18]([OH:20])[C:17]3[C:12](=[C:13]([CH2:24][CH2:25][C:26]([OH:28])=O)[CH:14]=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].COC(=O)CCC1C=C([N+]([O-])=O)C=C2C=1N=C(Cl)N=C2O.Cl[C:51]1[CH:52]=[C:53]([CH:55]=[CH:56][C:57]=1[Cl:58])[NH2:54].[OH-].[Li+].Cl>CN1CCCC1=O.O1CCCC1.O>[Cl:58][C:57]1[CH:56]=[CH:55][C:53]([NH:54][C:26](=[O:28])[CH2:25][CH2:24][C:13]2[CH:14]=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=[C:17]3[C:12]=2[N:11]=[C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[N:19]=[C:18]3[OH:20])=[CH:52][CH:51]=1
Reactant: O=C(O)CCc1cc([N+](=O)[O-])cc2c(O)nc(Nc3ccc(Cl)c(Cl)c3)nc12
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: COC(=O)CCc1cc([N+](=O)[O-])cc2c(O)nc(Cl)nc12
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(CCc1cc([N+](=O)[O-])cc2c(O)nc(Nc3ccc(Cl)c(Cl)c3)nc12)Nc1ccc(Cl)cc1
Temperature: 125 °C
Reaction time: 48 h

Procedure:
3-[2-(3,4-Dichlorophenylamino)-4-hydroxy-6-nitro-quinazolin-8-yl]propionicacid. To a solution of 3-(2-chloro-4-hydroxy-6-nitroquinazolin-8-yl)propionic acid methyl ester (0.536 g) in 1-methyl-2-pyrrolidinone (10 mL) was added 3,4-dichloroaniline (0.890 g). The reaction mixture was heated to 125° C. for 6 h, then cooled to room temperature and stirred for 48 h. The solvent was removed in vacuo and the residue was diluted with water (20 mL). The precipitate that formed was collected via filtration, washed with water and dried to give a brown solid which was dissolved in tetrahydrofuran (30 mL) and water (30 mL). To this solution was added lithium hydroxide (0.507 g) and the resulting mixture was stirred at room temperature for 17 h. The pH of the solution was adjusted to ca. 3 using 1.2 M hydrochloric acid and the solvent was removed in vacuo. The residue was triturated with water and dried to afford the title compound as a solid (0.744 g). 1H NMR (300 MHz, DMSO-d6): 12.20 (s, 1H), 11.58 (s, 1H), 9.85 (s, 1H), 8.58 (d, J=2.8 Hz, 1H), 8.34 (d, J=2.8 Hz, 1H), 8.24 (D, J=2.8 Hz, 1H), 7.67-6.55 (m, 2H), 3.18 (t, J=7.5 Hz, 2H), 2.67 (t, J=7.3 Hz, 2H); HPLC (Method D): 7.68 min; MS (ES−): m/z 421.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([S:14][CH3:15])[C:3]=1[C:16]#[N:17].[CH:18]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1B(O)O)=[O:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH:18]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([S:14][CH3:15])[C:3]=1[C:16]#[N:17])=[O:19]
Reactant: COc1ccc(B(O)O)c(C=O)c1
Reactant: CSc1cc(-c2cccnc2)nc(Cl)c1C#N
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(-c2nc(-c3cccnc3)cc(SC)c2C#N)c(C=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
A mixture of 6-chloro-4-(methylthio)-2,3′-bipyridine-5-carbonitrile (57.7 mg, 0.220 mmol), 2-formyl-4-methoxyphenylboronic acid (83.4 mg, 0.463 mmol), aqueous potassium phosphate (550 μL, 1.100 mmol) and palladium tetrakis(triphenylphosphine) (16.1 mg, 0.014 mmol) in N,N-dimethylformamide (1 mL) was pumped under vacuum and backfilled with nitrogen twice. After 2 h at 90° C., the mixture was cooled to room temperature, diluted with methanol (2 mL) and filtered to give 6-(2-formyl-4-methoxyphenyl)-4-(methylthio)-2,3′-bipyridine-5-carbonitrile as brown solid (56.9 mg, 62% yield). 1H NMR (500 MHz, CDCl3) δ ppm 9.99 (1H, s), 9.20 (1H, δ, J=1.92 Hz), 8.72 (1H, dd, J=4.67, 1.65 Hz), 8.34 (1H, dt, J=7.97, 1.92 Hz), 7.71 (1H, δ, J=8.52 Hz), 7.57 (1H, δ, J=2.75 Hz), 7.56 (1H, s), 7.45-7.49 (1H, m), 7.44 (1H, dd, J=8.11, 4.81 Hz), 3.95 (3H, s), 2.74 (3H, s); MS (ES+) m/z: 362 (M+H); LC retention time: 3.088 min (analytical HPLC Method A).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([CH3:27])[CH:21]=1>>[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[C:22]([CH3:27])[CH:21]=1
Reactant: Cc1cc(F)ccc1N
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: Cc1cc(F)ccc1NC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 34.7 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 200 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 and 278 mg of 4-fluoro-2-methylaniline in place of the 2,4-difluoroaniline. 92 mg of N-(4-fluoro-2-methylphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a pinkish solid, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][C:15]3([C:25]([O:27][CH3:28])=[O:26])[CH2:17][O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH:14]3[NH:13]2)=[O:11])=[CH:5][CH:4]=1.[CH3:31][N:32]=[C:33]=[O:34]>CCOCC.C(N(CC)CC)C>[CH3:31][NH:32][C:33]([N:13]1[CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][CH2:17][C:15]2([C:25]([O:27][CH3:28])=[O:26])[CH2:16][N:12]1[C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:29])[F:30])=[CH:4][CH:5]=1)=[O:11])=[O:34]
Reactant: COC(=O)C12COc3ccccc3C1NN(C(=O)Nc1ccc(C(F)(F)F)cc1)C2
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CNC(=O)N1C2c3ccccc3OCC2(C(=O)OC)CN1C(=O)Nc1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 53 %

Procedure:
The product (0.125 g, 0.000296 mol) of Example 6, Step B was dissolved in 5 mL ether and 0.023 g of methyl isocyanate was added and stirred for 30 min. Three drops of triethylamine was added and the reaction was stirred for 18 hours at room temperature. A white precipitate had formed, was filtered, rinsed with ether and dried to afford 0.075 g of a white solid; mp 208°-209° C.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]2[C:9]3[C:14]([N:15]=[C:16]4[C:21]=2[C:20](=[O:22])[CH2:19][CH2:18][CH2:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[H-].[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[C:9]3[C:14]([N:15]=[C:16]4[C:21]=2[CH:20]([OH:22])[CH2:19][CH2:18][CH2:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:23][CH:24]=1
Reactant: O=C1CCCc2nc3ccccc3c(NCc3ccc(F)cc3)c21
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: OC1CCCc2nc3ccccc3c(NCc3ccc(F)cc3)c21
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
In 100 ml of dry THF was dissolved 3.00 g of 3,4-dihydro-9-(4-fluorobenzyl)aminoacridin-1(2H)-one. The mechanically stirred solution was cooled in ice and 4.68 ml of 1M LiAlH4 in THF was added over 5 minutes. After 1/2 hour the reaction was complete by TLC. The excess hydride was neutralized with 1 ml of saturated ammonium chloride solution and the resulting salts were filtered. The THF filtrate was evaporated to a solid which was recrystallized from 1:1 dichloromethane/pentane to yield 2.47 g of solid, mp 169.5°-170° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([OH:17])=O)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[C:20]([O:24][C:25]([N:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([NH2:37])[CH:33]=2)[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:20]([O:24][C:25]([N:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([NH:37][C:15]([C:10]3[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:8][CH:7]=4)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:17])[CH:33]=2)[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2C1

Procedure:
A 7.6 g (29 mmol) sample of 4'-trifluoromethyl-biphenyl-2-carboxylic acid, 7.1 g (29 mmol) of 6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester, 100 mg of DMAP and 6.1 g (32 mmol) of EDCl were reacted in 130 mL of methylene chloride for 12 hrs. The reaction mixture was extracted with 2×150 mL 1N HCl, 2×150 mL 1N NaOH, 150 mL water, brine and then concentrated to yield 14 g of a beige foam.
Reaction SMILES: C([O-])(O)=O.[Na+].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([NH:16][C:17]([NH2:19])=[NH:18])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[C:30](=O)[C:29](=[CH:32]N(C)C)[CH2:28][C:27](=[O:36])[N:26]([CH2:37][CH2:38][CH2:39][N:40]3[C:48](=[O:49])[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:41]3=[O:50])[C:25]=2[CH:51]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[C:30]3[N:18]=[C:17]([NH:16][C:10]4[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([O:7][CH3:6])[CH:9]=4)[N:19]=[CH:32][C:29]=3[CH2:28][C:27](=[O:36])[N:26]([CH2:37][CH2:38][CH2:39][N:40]3[C:41](=[O:50])[C:42]4[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:48]3=[O:49])[C:25]=2[CH:51]=1
Reactant: CN(C)C=C1CC(=O)N(CCCN2C(=O)c3ccccc3C2=O)c2cc(Cl)ccc2C1=O
Reactant: COc1ccc(NC(=N)N)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2N(CCCN2C(=O)c4ccccc4C2=O)C(=O)C3)cc1OC

Procedure:
In a manner similar to that described for method I (NaHCO3 used instead of K2CO3), 1-(3,4-dimethoxyphenyl)guanidine and 8-chloro-4-((dimethylamino)-methylene)-1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (I-40-b) were converted to I-40-c and carried on crude: MS m/z═584 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:24][CH2:23][O:22][C:8]=3[CH:9]=2)[N:4]=1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CCO>[CH2:23]1[O:24][C:7]2[CH:6]=[C:5]3[C:10]([C:11]([C:13]4[CH:18]=[CH:17][C:16]5[O:19][CH2:20][O:21][C:15]=5[CH:14]=4)=[N:12][C:3]([CH2:2][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[N:4]3)=[CH:9][C:8]=2[O:22]1
Reactant: C1CNCCN1
Reactant: ClCc1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Solvent: CCO
Product: c1cc2c(cc1-c1nc(CN3CCNCC3)nc3cc4c(cc13)OCO4)OCO2
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.9 %

Procedure:
A suspension of 2-chloromethyl-6,7-methylenedioxy-4-(3,4-methylenedioxy-phenyl)quinazoline (96 mg, 0.3 mmol) in EtOH (9 mL) was treated with piperazine (860 mg, 10 mmol). The mixture was stirred at rt for 15 h, then it was poured into ice cold dilute NaHCO3 solution. On standing at rt for 72 h the title compound was crystallized out as colorless plates. It was collected by filtration, washed with water, and dried to give 74 mg of solid; mp 73-76° C. 1H NMR (CDCl3) 7.37 (d, J=8.4, 1H), 7.16-7.24 (m, 3H), 6.97 (d, J=8.4, 1H), 6.14 (s, 2H), 6.07 (s, 2H), 3.95 (s, 2H), 2.97 (bs, 4H), 2.65 (bs, 4H).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]([OH:15])=O)[S:10][C:6]=2[C:5]([F:16])=[CH:4][C:3]=1[F:17].CCN=C=NCCCN(C)C.Cl.[CH2:30]([O:32][C:33](=[O:43])[CH2:34][NH:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:31]>C(Cl)Cl>[CH2:30]([O:32][C:33](=[O:43])[CH2:34][N:35]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:13](=[O:15])[CH2:12][CH2:11][C:9]1[S:10][C:6]2[C:5]([F:16])=[CH:4][C:3]([F:17])=[C:2]([F:1])[C:7]=2[N:8]=1)[CH3:31]
Reactant: O=C(O)CCc1nc2c(F)c(F)cc(F)c2s1
Reactant: CCOC(=O)CNCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)CCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.9 %

Procedure:
To methylene chloride (10 ml) was added 3-(4,5,7-trifluorobenzothiazol-2-yl)propionic acid (522 mg, 2 mmol) obtained in Example 3-i), WSC.HCl (422 mg, 2.2 mmol) and N-benzylglycine ethyl ester (386 mg, 2 mmol) and the mixture was stirred for 15 hours at room temperature. The reaction mixture was washed with 7% hydrochloric acid and water successively. The organic layer was dried and evaporated. The resulting residue was purified on a silica gel column to give N-benzyl-N-[3-(4,5,7-trifluorobenzothiazol-2-yl)propionyl]-glycine ethyl ester (680 mg, 78%) as an oil.