Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([NH:10][CH3:11])[C:5]([CH:6]=O)=[CH:4][N:3]=1.[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21].[C:23](O[BH-](OC(=O)C)OC(=O)C)(=[O:25])C.[Na+].O=C(Cl)OC(Cl)(Cl)Cl>C(O)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][N:17]([C:16]3[CH:18]=[CH:19][C:13]([F:12])=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=3)[C:23](=[O:25])[N:10]([CH3:11])[C:8]=2[CH:9]=1
Reactant: CNc1cc(Cl)ncc1C=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1C(=O)N(c2ccc(F)c([N+](=O)[O-])c2)Cc2cnc(Cl)cc21

Procedure:
By analogy to Example A24, 6-chloro-4-(methylamino)nicotinaldehyde (from Example A24), 4-fluoro-3-nitroaniline and sodium triacetoxy borohydride are combined in glacial acetic acid to give crude 2-chloro-5-((4-fluoro-3-nitrophenylamino)methyl)-N-methylpyridin-4-amine, which is reacted with diphosgene by the procedure of Example A75 to give 7-chloro-3-(4-fluoro-3-nitrophenyl)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one. Zn Dust is reacted with a suspension of 7-chloro-3-(4-fluoro-3-nitrophenyl)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one and NH4Cl in MeOH/THF (1:1) to provide 3-(3-amino-4-fluorophenyl)-7-chloro-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one. By analogy to Example A25, 4-methoxybenzylamine and 3-(3-amino-4-fluorophenyl)-7-chloro-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one are combined and heated to 180° C. to provide 7-(4-methoxybenzylamino)-3-(3-amino-4-fluorophenyl)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one, which is further reacted with trifluoroacetic acid to provide 7-amino-3-(3-amino-4-fluorophenyl)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.C(O)(=O)C.[NH2:17][C:18]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[NH:31][CH:32]=[C:33]([C:35]#[N:36])[N:34]=2)=[O:29])=[C:23]([C:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]=2)[CH:22]=1)([CH3:20])[CH3:19].CC[N:45](C(C)C)C(C)C>C1COCC1>[C:37]1([C:23]2[CH:22]=[C:21]([C:18]([CH3:20])([NH:17][C:5]([NH2:45])=[O:11])[CH3:19])[CH:26]=[CH:25][C:24]=2[NH:27][C:28]([C:30]2[NH:31][CH:32]=[C:33]([C:35]#[N:36])[N:34]=2)=[O:29])[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(N)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(NC(N)=O)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.4 %

Procedure:
To a solution of triphosgene (7.2 mg, 0.024 mmol) in 2 mL of THF at 0° C. was added a solution of 4-cyano-1H-imidazole-2-carboxylic acid [4-(1-amino-1-methyl-ethyl)-2-cyclohex-1-enyl-phenyl]-amide acetic acid salt (as prepared in Example 3, step (b), 25.0 mg, 0.0611 mmol) and DIEA (32 μL, 0.18 mmol) in 2 mL of THF under Ar. The resulting mixture was stirred at RT for 20 min and cooled to 0° C. NH3 (g) was bubbled into the mixture for ca. 4 min and the reaction was then sealed and stirred at RT for 0.5 h. The mixture was treated with brine (10 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were concentrated in vacuo and the residue was purified by flash chromatography on silica gel (3-6% MeOH/DCM) to afford 7.2 mg (30%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.11 (d, 1H, J=8.6 Hz), 7.98 (s, 1H), 7.32 (dd, 1H, J=8.6, 2.1 Hz), 7.22 (d, 1H, J=2.1 Hz), 5.80 (m, 1H), 2.20-2.34 (m, 4H), 1.73-1.89 (m, 4H), 1.61 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C21H24N6O2, 393.2 (M+H). found 393.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH:14]([CH3:24])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].Br[CH2:29][CH:30](Br)[CH2:31][Cl:32]>CO>[Cl:32][CH2:31][CH:30]1[CH2:29][O:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:15][CH:14]([N:10]3[CH2:9][CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[O:12][C:11]3=[O:13])[CH3:24])=[CH:17][C:18]=2[O:23]1
Reactant: ClCC(Br)CBr
Reactant: CC(Cc1ccc(O)c(O)c1)N1CC(c2cccc(Cl)c2)OC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(Cc1ccc2c(c1)OC(CCl)CO2)N1CC(c2cccc(Cl)c2)OC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
One equivalent of 5-(3-chlorophenyl)-3-(2-(3,4-dihydroxyphenyl)-1-methylethyl)-2-oxazolidinone, prepared by the procedure of U.S. Pat. No. 5,061,727, Example 1, is combined with two equivalents of 2N sodium methoxide in methyl alcohol and the resulting slurry is stirred at room temperature for 30 minutes. One equivalent of 1,2-dibromo-3-chloropropane is added and the stirring is continued at room temperature for 24 hours. The solvent is evaporated in vacuo and the residue is dissolved in methylene chloride. The organic layer is dried, filtered through a pad of hydrous magnesium silicate and the filtrate is evaporated in vacuo to give 2-and 3- chloromethyl-6-(2-(5-(3-chloro-phenyl)-2-oxo-3-oxazolidinyl)propyl)-1,4-benzodioxane. The individual, 2- and 3- isomers, are separated by chromatography.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:22])[CH2:15][C:16]1[S:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH:32]([N:35]([CH2:43]OC)[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:34])[CH3:33]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:22])[C@@H:15]([C:16]1[S:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[CH2:43][N:35]([CH:32]([CH3:34])[CH3:33])[C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:41])[CH3:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)s1)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: COCN(C(=O)OC(C)(C)C)C(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N(C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Cl)s1)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
1.0M of titanium tetrachloride in DCM (30.9 mL, 30.9 mmol) was added dropwise to a solution of (R)-4-benzyl-3-(2-(5-chlorothiophen-2-yl)acetyl)oxazolidin-2-one (9.43 g, 28.1 mmol) in DCM (170 mL) at −78° C., followed by N,N-diisopropylethylamine (9.78 mL, 56.2 mmol). The resulting dark blue mixture was stirred at −78° C. for 1 hour. tert-Butyl isopropyl(methoxymethyl)carbamate (11.4 g, 56.2 mmol) was then added. The mixture was stirred at −78° C. for 1 hour, and then allowed to warm up to room temperature. The mixture was stirred at room temperature for 2 hours, quenched with saturated NH4Cl (300 mL), and extracted with DCM (3×200 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel chromatography eluting with EtOAc/hexane (0-20%) to give tert-butyl (S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(5-chlorothiophen-2-yl)-3-oxopropyl(isopropyl)carbamate (10.2 g, 72%). MS (APCI+) [M+H]+ 507.2. 1H NMR (CDCl3, 400 MHz) δ 7.36-7.22 (m, 5H), 6.79 (d, J=4.0 Hz, 1H), 6.75 (d, J=4.0 Hz, 1H). 4.67-4.62 (m, 1H), 4.15-4.09 (m, 4H), 3.45-3.38 (m, 2H), 2.80-2.72 (m, 1H), 1.49 (s, 9H), 1.12 (d, J=6.0 Hz, 3H), 1.05 (d, J=6.0 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15](=[O:28])[CH2:16][O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)[NH2:14]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15](=[O:28])[CH2:16][O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(OCC(=O)NN)cc1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(OCC(=O)NN=C2C(=O)Nc3ccc(Br)cc32)cc1
Temperature: 100 °C
Yield: 80 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-bromo-1H-indole-2,3-dione in acetic acid was added methyl 4(2-hydrazino-2-oxoethoxy)benzoate. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 86 mg of the title compound (80%) as a orange powder in 94% purity by HPLC (Rt: 4.17, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[CH2:20][NH2:21])[CH:6]=[CH:7][CH:8]=1.C(N(C(C)C)CC)(C)C.[CH:33]([S:36](Cl)(=[O:38])=[O:37])([CH3:35])[CH3:34]>ClCCl>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[CH2:20][NH:21][S:36]([CH:33]([CH3:35])[CH3:34])(=[O:38])=[O:37])[CH:6]=[CH:7][CH:8]=1
Reactant: NCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)S(=O)(=O)NCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.7 %

Procedure:
0.08 g (0.239 mmol) of (3-((3-(trifluoromethyl)phenyl) ethynyl) imidazo[1,2-a]pyridin-2-yl) methanamine (prepared according to steps 1 to 4 of Example 11) were solubilised in 2 ml of dichloromethane with magnetic stirring, 0.208 ml (1.193 mmol) of diisopropylethylamine and 0.083 ml (0.716 mmol) of isopropylsulfonyl chloride were added. The mixture was stirred at r.t. for 16 h. A supplement of 0.083 ml (0.716 mmol) of isopropylsulfonyl chloride was added and the mixture was stirred at r.t. for 1 h before being concentrated in vacuo. The crude residue was directly purified by flash chromatography on a silica gel cartridge (eluent: dichloromethane/methanol 95/5, v/v). 0.048 g (yield=22%) of N-((3-((3-(trifluoromethyl)phenyl)ethynyl) imidazo[1,2-a]pyridin-2-yl)methyl)propane-2-sulfonamide were obtained as a white solid. LC-MS: m/z=422 (MH+); UV purity at 254 nm=98%. 1H NMR (300 MHz, DMSO) δ 8.75 (d, J=6.8 Hz, 1H), 8.13 (s, 1H), 7.99 (d, J=7.5 Hz, 1H), 7.85-7.61 (m, 4H), 7.53-7.38 (m, 1H), 7.15 (t, J=6.8 Hz, 1H), 4.44 (d, J=5.9 Hz, 2H), 3.25 (dd, J=13.6, 6.8 Hz, 1H), 1.21 (d, J=6.8 Hz, 6H).
Reaction SMILES: N1NN=NC=1C1NN=C2C=1C[C@H]1C[C@H]12.[CH2:15]1[C@@H:17]2[CH2:18][C:19]3[C:23]([C@H:16]12)=[N:22][NH:21][C:20]=3[C:24]([OH:26])=[O:25]>>[N:22]1[NH:21][C:20]([C:24]([OH:26])=[O:25])=[C:19]2[C@@H:18]3[CH2:15][C@@H:17]3[CH2:16][C:23]=12
Reactant: O=C(O)c1[nH]nc2c1C[C@H]1C[C@@H]21
Agent: C1c2c(n[nH]c2-c2nn[nH]n2)[C@@H]2C[C@H]12
Product: O=C(O)c1[nH]nc2c1[C@@H]1C[C@@H]1C2

Procedure:
(1aR, 5aR)-4-(2H-Tetrazol-5-yl)-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene; and (1aR, 5aR)-1a,3,5,5a-Tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[C:3]=1[C:4]#[N:5].[C:11](=[O:14])([O-])[O-].[K+].[K+]>O1CCOCC1>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:2]2[CH:9]=[CH:8][CH:7]=[C:6]([O:14][CH3:11])[CH:3]=2)[C:3]=1[C:4]#[N:5]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1c(N)cccc1Br
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cccc(-c2cccc(N)c2C#N)c1
Yield: 160.5 %

Procedure:
To a stirred solution of 2-amino-6-bromobenzonitrile (195 mg, 1.0 mmol) and (3 acid (300 mg, 2 mmol) in dioxane (2 mL) was added aqueous potassium carbonate (2.0 mmol, 0.7 mL). The reaction solution was degassed by bubbling N2 for 2 minutes. Palladium tetrakistriphenylphosphine (5% mol) was added to the reaction mixture and the reaction vessel was placed in a microwave reactor and irradiated at 165° C. for 20 minutes. The precipitate was removed by filtration and the filtrate concentrated. The residue was purified by HPLC (acetonitrile/water; 10-90% gradient, 25 minutes) to give the title compound as an off-white solid (180 mg, 80%). MS 225 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([S:10](Cl)(=[O:12])=[O:11])[CH3:9]>ClCCl>[CH2:8]([S:10]([N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH2:3]1)(=[O:12])=[O:11])[CH3:9]
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1cccnc1
Solvent: ClCCl
Product: CCS(=O)(=O)N1C=CC=C(N)C1

Procedure:
A solution of 3-aminopyridine (2.15 g, 22.84 mmol) and ethanesulfonyl chloride (2.18 ml, 22.84 mmol) in dichloromethane (150 ml) was stirred for 20 h at room temperature. The mixture was washed with 30 ml saturated sodium bicarbonate solution and extracted with 15% isopropanol/dichloromethane. The organics were combined, dried over sodium sulfate, filtered, and concentrated in vacuo to give N-(ethanesulfonyl)-3-aminopyridine (2.15 g, as a crude solid. The solid was dissolved in N,N-dimethylformamide (50 ml) and treated with potassium carbonate (6.37 g, 22.8 mmol) and 3-iodobenzyl bromide (6.80 g, 22.8 mmol) with stirring at room temperature for 3 h. The mixture was diluted with ethyl acetate (150 ml) and washed four times with water (100 ml). The organics were separated, dried over sodium sulfate, filtered, and concentrated in vacuo to afford a crude residue. The residue was purified on a 200 g pad of silica eluting with 3% methanol/dichloromethane to afford the title compound. MS calcd. 402.3; MS (M+1) 403.1.
Reaction SMILES: ClC1C=C(C(CCO)C[NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)C=CC=1Cl.CC[O:25]CC.[OH-].[Na+]>O1CCCC1.Cl.O>[OH:25][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]([NH2:11])=[O:19]
Reactant: CCOCC
Reactant: O=C(NCC(CCO)c1ccc(Cl)c(Cl)c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1ccccc1O

Procedure:
N-[2-(3,4-Dichlorophenyl)-4-hydroxybutyl]benzamide. A solution of the above ether (4.0 g) in tetrahydrofuran (20 mL) and 3 N hydrochloric acid (20 mL) was stirred for 2 hours. The reaction mixture was diluted with water, neutralized with 1 N sodium hydroxide, and extracted with dichloromethane. The organic extracts were dried, evaporated, and chromatographed, with dichloromethane:methanol (95:5) as eluent, to give the hydroxy benzamide compound as a viscous oil (2.9 g); NMR: 7.63 (m,2), 7.47 (m,1), 7.37 (m,3), 7.32 (d,1, J=2.1), 7.06 (dd,1, J=2.1, 8.3), 6.46 (m,1), 3.82 (m,1), 3.69 (m,1), 3.57-3.39 (m,2), 3.12 (m,1), 2.60 (m,1), 1.97 (m,1), 1.82 (m,1); MS: m/z=338(M+1).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][O:18][C@@H:17]([C:21]2[CH:26]=[CH:25][C:24]([N:27]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[CH3:28])=[CH:23][CH:22]=2)[CH2:16]1)=O)(C)(C)C.[OH-].[Na+]>O.C(#N)C>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([N:27]([CH3:28])[C:24]2[CH:23]=[CH:22][C:21]([C@@H:17]3[O:18][CH2:19][CH2:20][NH:15][CH2:16]3)=[CH:26][CH:25]=2)=[CH:34][CH:33]=1
Reactant: CN(c1ccc(Cl)cc1)c1ccc([C@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: CN(c1ccc(Cl)cc1)c1ccc([C@H]2CNCCO2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 26.6 %

Procedure:
To a stirred solution of trifluoroacetic acid (51.3 μl) in water (4 ml) was added a solution of (S)-2-{4-[(4-chloro-phenyl)-methyl-amino]-phenyl}-morpholine-4-carboxylic acid tert-butyl ester (45 mg) in acetonitrile (2 ml). The reaction mixture was then capped and the mixture was shaken at 80° C. for 2 h. The reaction mixture was then cooled to room temperature and poured into 1 M aq. NaOH and the resulting mixture was extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis; gradient: 0% to 100% EtOAc in heptane, then 0% to 10% MeOH in EtOAc) to afford (4-chloro-phenyl)-methyl-((S)-4-morpholin-2-yl-phenyl)-amine (9 mg, 27%) as a colourless gum. MS (ISP): 305.3 ([{37Cl}M+H]+), 303.3 ([{35Cl}M+H]+).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([Cl:16])=[CH:14][N:13]=[C:12]([C:17]4[S:21][C:20]([C@@H:22]([OH:24])[CH3:23])=[CH:19][CH:18]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.C1(C2NN=C(NC3C(Cl)=CN=C(C4SC([C@H](O)C)=CC=4)N=3)C=2)CC1>>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([Cl:16])=[CH:14][N:13]=[C:12]([C:17]4[S:21][C:20]([CH:22]([OH:24])[CH3:23])=[CH:19][CH:18]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Agent: C[C@@H](O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Product: CC(O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1

Procedure:
Following the 5-fluoro analogs, (S)-1-(5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-chloropyrimidin-2-yl)thiophen-2-yl)ethanol (Compound 132) (4 mg) and (R)-1-(5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-chloropyrimidin-2-yl)thiophen-2-yl)ethanol (Compound 131) (3.7 mg) were prepared. Both had LC-MS: 362.1 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:16][C@@H:17]([CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19]>>[CH2:37]([O:36][CH2:35][C@H:17]([NH:16][C:13](=[O:15])[CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([Cl:2])[CH:4]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COc1ccc(CCC(=O)O)cc1Cl
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: COc1ccc(CCC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)cc1Cl
Yield: 43.3 %

Procedure:
Proceeding as in Example 1, but substituting 3-(3-chloro-4-methoxyphenyl)propanoic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 81, (S)-3-(benzyloxy)-2-(3-(3-chloro-4-methoxyphenyl)propanamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (3 mg, 43.3%). MS (EI) for C32H30ClFN2O5. found 578.1 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:12](Cl)=[O:13].[NH2:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([O:23][CH3:24])=[O:22]>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:6][C:12](=[O:13])[NH:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([O:23][CH3:24])=[O:22])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1ccccc1Br
Reactant: COC(=O)c1cccc(N)c1
Solvent: ClCCl
Product: COC(=O)c1cccc(NC(=O)NC(=O)c2ccccc2Br)c1

Procedure:
The 1-phenyl substituted compound can be prepared as illustrated by the exemplary reaction in Scheme 4. Reaction of 2-bromobenzamide with oxalyl chloride in DCM, followed by addition of methyl 3-aminobenzoate produced methyl 3-(3-(2-bromobenzoyl)ureido)benzoate. Reaction of the benzoate with potassium tert-butoxide in DMF produced 1-(3-methoxycarbonylphenyl)quinazoline-2,4(1H,3H)-dione. Hydrolysis of the ester with NaOH in water-methanol produced 1-(3-carboxyphenyl)quinazoline-2,4(1H,3H)-dione. Coupling of the acid with 2-(piperazin-1-yl)pyrimidine in the presence of coupling agents, such as HATU and DIPEA in DMF, produced the targeted compound 1-(3-(1-(pyrimidin-2-yl)piperazine-4-carbonyl)phenyl)quinazoline-2,4(1H,3H)-dione.
Reaction SMILES: Cl.CN[O:4][CH3:5].[CH3:6][N:7]1CCOCC1.Cl.CN(C)CCCN=C=NCC.[C:25]([O:29][C:30]([NH:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=O)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:28][C:25]([O:29][C:30](=[O:31])[NH:32][CH2:33][CH2:34][CH2:35][C:36]([NH:7][CH2:6][O:4][CH3:5])=[O:38])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: CN1CCOCC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COCNC(=O)CCCNC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 82.8 %

Procedure:
4-(Dimethylamino)pyridine (6.11 g), N,O-dimethylhydroxylamine hydrochloride(4.88 g), N-methylmorpholine (5.06 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.58 g) were added in quick succession to a solution of 4-(tert-butoxycarbonylamino)butyric acid (10.16 g) in dichloromethane (200 ml). The reaction mixture was then stirred under ambient conditions for 18 h. The solution was then washed with 2M hydrochloric acid solution, 10% sodium bicarbonate solution and brine. The organic layer was separated, dried over magnesium sulfate, filtered and the filtrate evaporated to dryness to give the subtitle compound as a colourless oil (10.2 g, 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.Cl.Cl[C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[N:19]=[C:18]2[CH2:29][CH2:30][CH2:31][C:17]=12>CO.ClCCl>[Cl:28][C:24]1[CH:23]=[C:22]([C:20]2[N:19]=[C:18]3[CH2:29][CH2:30][CH2:31][C:17]3=[C:16]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=3)[CH:21]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)COc1ccc(N)cc1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)COc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 150 °C
Yield: 43.7 %

Procedure:
An 18-mL vial was charged with methyl 2-(4-aminophenoxy)acetate (24 mg, 0.13 mmol, 2 eq.) and 4-Chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine HCl salt (20 mg, 0.066 mmol, 1 eq. See step 1 of EXAMPLE 1). The mixture was dissolved in a mixture of MeOH (1 ml) and dichloromethane (2 ml). After the volatile material was removed under reduced pressure, the residue was heated at 150° C. under argon for 1 hr. After cooling to room temperature, the reaction mixture was partitioned between NaHCO3 aq. (10 ml) and ethyl acetate (10 ml). The organics was separated and dried over MgSO4. The solvent was removed under reduced pressure to give a residue, which was purified by chromatography on silica gel using dichloromethane followed by 0.1˜0.3% methanol in dichloromethane as eluent to give the desired product methyl 2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenoxy]acetate as white solid (11.8 mg, 44% yield).
Reaction SMILES: FC(F)(F)C(O)=[O:4].C(OC(N[C@@H:16]([C:25]([OH:27])=[O:26])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O)(C)(C)C>ClCCl>[OH:4][C@H:16]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:25]([OH:27])=[O:26]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)O
Solvent: ClCCl
Product: O=C(O)[C@H](O)CCc1ccccc1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
Trifluoroacetic acid (40 mL) was added to a solution of N-tert-butoxycarbonyl-D-homophenylalanine (4.00 g) in dichloromethane (40 mL) at 0° C. After stirring at 0†° C. for 5 min and at room temperature for 40 min, the reaction mixture was evaporated in vacuo. The residue was dissolved in 10% sulfuric acid (80 mL), and the solution was warmed up to 60° C. After removing the bath, a solution of sodium nitrite (5.93 g) in water (5 mL) was added to the solution, and the solution was stirred at 60° C. for 7 hr. Then additional solution of sodium nitrite (1.98 g) in water (1.5 mL) was added, and the resulting solution was stirred at 60° C. for 2.5 hr. After cooling, urea (6.02 g) was added to the reaction mixture, and the whole was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogen carbonate. The aqueous phase was acidified with 1 N hydrochloric acid, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to afford the title compound (2.51 g) as a white solid: 1H NMR (400 MHz, CDCl3) δ 1.92-2.10 (m, 1H), 2.10-2.27 (m, 1H), 2.80 (t, J=7.8 Hz, 2H), 4.20-4.32 (m, 1H), 5.12 (br s, 2H), and 7.12-7.40 (m, 5H).