Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]2[NH:15][C:16]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]=[C:24]([C:29]3[CH:34]=[CH:33][C:32]([C:35]5[NH:39][C:38]([CH:40]6[CH2:45][C@@H:44]7[C@@H:42]([CH2:43]7)[N:41]6C(OCC6C=CC=CC=6)=O)=[N:37][CH:36]=5)=[CH:31][CH:30]=3)[CH:23]=[CH:22]4)=[CH:17][N:18]=2)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C@@H:42]12[CH2:43][C@@H:44]1[CH2:45][C@@H:40]([C:38]1[NH:37][CH:36]=[C:35]([C:32]3[CH:33]=[CH:34][C:29]([C:24]4[CH:25]=[C:26]5[C:21](=[CH:22][CH:23]=4)[CH:20]=[C:19]([C:16]4[NH:15][C:14]([C@@H:13]6[CH2:12][C@@H:11]7[C@@H:9]([CH2:10]7)[N:8]6[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:18][CH:17]=4)[CH:28]=[CH:27]5)=[CH:30][CH:31]=3)[N:39]=1)[NH:41]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6C[C@H]7C[C@H]7N6C(=O)OCc6ccccc6)[nH]5)cc4)ccc3c2)[nH]1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5c[nH]c([C@@H]6C[C@H]7C[C@H]7N6)n5)cc4)ccc3c2)[nH]1
Reaction time: 3 h

Procedure:
A reaction mixture of (1R,5R)-benzyl 3-(5-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (0.305 g, 0.416 mmol) and NaHCO2 (0.070 g, 0.832 mmol) in MeOH (15 mL) was charged with 10% Pd/C (0.022 g, 0.021 mmol). The resulting suspension was vacuum flushed with N2 (3×) and placed under 1 atm of H2 (balloon) for 3 h at room temperature. The mixture was then filtered though a pad of diatomaceous earth (CELITE®) and concentrated under vacuum. An off-white solid corresponding to (1R,3S,5R)-tert-butyl 3-(5-(6-(4-(2-((1R,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (0.235 g) was recovered and used without further purification. LC/MS [M+H]+=599; Rt=1.96 min is product. Column Luna 3u C18 2×50 mm; start % B: 0, final % B: 100 Solvent A: 10% Acetonitrile/90% H2O+1% TFA; Solvent B: 90% Acetonitrile/10% H2O+1% TFA; flow rate 4 ml/min. Run time: 5 min. Purity=94%. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.00 (2 H, br. s.), 8.11-8.32 (3 H, m), 7.88-8.02 (5 H, m), 7.72-7.88 (9 H, m), 7.63 (4 H, br. s.), 4.64 (2 H, br. s.), 4.42 (1 H, t, J=7.93 Hz), 3.97-4.18 (1 H, m), 3.45 (1 H, br. s.), 3.17 (3 H, s), 2.96 (1 H, dd, J=13.43, 6.71 Hz), 2.08-2.43 (6 H, m), 1.66 (2 H, br. s.), 1.07-1.50 (20 H, m), 0.81-0.89 (3 H, m), 0.77 (1 H, br. s.), 0.45-0.61 (3 H, m), 0.30 (1 H, br. s.).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][NH:8][CH2:7][CH2:6][NH:5]1)#[C:2][CH3:3].FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.C(C1CNCCN1)#CC.C(N(CC)CC)C.[S:40]1[CH:44]=[CH:43][CH:42]=[C:41]1[S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[C:1]([CH:4]1[NH:5][CH2:6][CH2:7][N:8]([S:45]([C:41]2[S:40][CH:44]=[CH:43][CH:42]=2)(=[O:47])=[O:46])[CH2:9]1)#[C:2][CH3:3]
Reactant: CC#CC1CNCCN1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CC1CN(S(=O)(=O)c2cccs2)CCN1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The 2-(1-propyn-1-yl)piperazine bis(trifluoroacetate (110 mg, 0.312 mmol) was dissolved in CH2Cl2 in a 50 mL round-bottomed flask and was then cooled to 0° C. To this solution was added an excess of triethylamine (152 μL, 1.093 mmol) followed by thiophene-2-sulfonyl chloride (57.0 mg, 0.312 mmol, Sigma-Aldrich, St. Louis, Mo.). The mixture was warmed slowly to room temperature and stirred for 2 h. Afterwards, the mixture was concentrated and absorbed onto silica gel. The crude material was purified via column chromatography (about 40 g silica gel, 0% to 10% MeOH in CH2Cl2) to give 3-(1-propyn-1-yl)-1-(2-thiophenylsulfonyl)piperazine (42 mg) as a foamy solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7]/[C:8](=[N:16]/[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])/S(C(F)(F)F)(=O)=O)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:42][CH:41]([OH:43])[CH2:40]2)=[CH:35][CH:34]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:24])[NH:7]/[C:8](/[NH:32][C:33]1[CH:34]=[CH:35][C:36]([N:39]2[CH2:40][CH:41]([OH:43])[CH2:42]2)=[CH:37][CH:38]=1)=[N:16]/[C:17](=[O:18])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)S(=O)(=O)C(F)(F)F
Reactant: Nc1ccc(N2CC(O)C2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)Nc1ccc(N2CC(O)C2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80 %

Procedure:
To a solution of {[(Z)-tert-butoxycarbonylimino]-trifluoromethanesulfonyl-methyl}-carbamic acid tert-butyl ester (13.62 g, 34.8 mM) and triethylamine (4.9 ml, 34.8 mM) in dry DCM (183 ml), 1-(4-aminophenyl)azetidin-3-ol (Method 37; 6.0 g, 36.5 mM) was added. The solution was stirred at room temperature under nitrogen for 48 hours. The reaction mixture was diluted with more DCM and washed with water (twice), saturated sodium bicarbonate solution (twice), water and saturated sodium chloride. The solution was then dried with anhydrous sodium sulphate, filtered and evaporated. The crude product was triturated with ether/isohexane (2:1), filtered washed with the same solvent and dried to give the title compound as a yellow solid (11.77 g, 83%). NMR 1.4 (s, 9H), 1.5 (s, 9H), 3.47 (t, 1H), 4.02 (t, 2H), 4.5 (m, 1H), 5.55 (d, 1H), 6.38 (d, 2H), 7.23 (d, 2H), 9.75 (s, 1H), 11.46 (m, 1H); m/z 407.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([OH:17])[CH2:12][CH2:13][CH2:14][C:15]#[CH:16].C(N(CC)CC)C>C(Cl)Cl>[C:4]1([C:3]2[CH:16]=[C:15]([CH2:14][CH2:13][CH2:12][CH2:11][OH:17])[O:1][N:2]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCCCO
Reactant: ON=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCCCCc1cc(-c2ccccc2)no1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 51 %

Procedure:
To N-hydroxybenzenecarboximidoyl chloride (622 mg, 4 mmol) in dry DCM (6 ml) was added 5-hexyn-1-ol (431 mg, 4.4 mmol). The mixture was cooled to 0° C. under nitrogen as triethylamine (0.612 ml, 4.4 mmol) was added dropwise over 10 min. Stirred for a further 20 min at 0° C. then at room temperature overnight. The mixture was washed with water and the organic phase evaporated. The product was purified by silica SPE (20 g) eluting with EtOAc-cyclohexane (1:2, then 3:1) to give a white waxy solid (443 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.Br[CH2:18][CH2:19][CH2:20][Cl:21].Cl>C1COCC1.CCCCCC.C(OCC)(=O)C>[Cl:21][CH2:20][CH2:19][CH2:18][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1cccc(F)c1
Reactant: ClCCCBr
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)C(CCCCl)c1cccc(F)c1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
A solution of 3-fluorophenylacetic acid (500 mg) in THF (15 mL) was stirred at −78° C. for 5 minutes. A 2.66 M solution of n-butyl lithium in hexane (2.44 mL) was added, and the reaction solution was stirred at −78° C. for three hours. Thereafter, the reaction solution was stirred at 0° C. for one hour, 1-bromo-3-chloropropane was added, and the reaction solution was stirred at room temperature for 17 hours. Thereafter, ethyl acetate and 1 N aqueous hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 734 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [H-].[Na+].[CH3:3][OH:4].Br[C:6]([CH3:11])([CH3:10])[C:7](Br)=[O:8].[O:12]1[CH2:16]CCC1>>[CH3:3][O:4][C:6]([CH3:11])([CH3:10])[C:7]([O:12][CH3:16])=[O:8].[CH3:16][O:12][C:6]([CH3:11])([CH3:10])[C:7]([OH:4])=[O:8]
Reactant: C1CCOC1
Reactant: CC(C)(Br)C(=O)Br
Reactant: CO
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C(C)(C)OC
Product: COC(C)(C)C(=O)O
Temperature: 25 °C

Procedure:
To a mixture of sodium hydride (3.13 g, 130.5 mmol) in tetrahydrofuran at 0° C. was added methanol (5.3 mL, 130.5 mmol) and allowed to warm to room temperature. The reaction was cooled to 0° C. and 2-bromo-2-methylpropionyl bromide (5.4 mL, 43.5 mmol) was added. After warming to room temperature, the reaction was heated to 45° C. for 42 hours and then cooled to room temperature. The resulting mixture was filtered through diatomaceous earth with ether wash and the solvent was distilled off. The pot residue was partitioned between ether and 1N hydrochloric acid. The organic layer was dried (magnesium sulfate), filtered and concentrated to give methyl 2-methoxy-2-methylpropionate and 2-methoxy-2-methylpropionic acid (2.47 g). This mixture of products was treated with methanolic sodium hydroxide, using a similar procedure to that described in Example 111b and distillation, the title compound was obtained as a colorless oil (650 mg, 12.6%), bp 85°-95° C./20 mm; MS(CI): 119(M+H): H-NMR (300 MHz, DMSO-d6): 1.29(s, 6H), 3.14(s, 3H), 12.52(s, 1H).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH3:32])[CH:30]=2)[NH:25][CH:24]=1>>[CH3:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH3:32])[CH:30]=2)[NH:25][C:24]=1[CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]1[C:3](=[O:7])[C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]=1[OH:6]
Reactant: Cc1ccc2[nH]cc(C)c2c1
Reactant: O=Cc1ccccc1
Reactant: CC1(c2ccccc2)C(=O)CC1=O
Product: Cc1ccc2[nH]c(C(C3=C(O)C(C)(c4ccccc4)C3=O)c3ccccc3)c(C)c2c1

Procedure:
Using general procedure C, 2-methyl-2-phenyl-cyclobutane-1,3-dione (Lit. 1) was reacted with benzaldehyde and 3,5-dimethyl-1H-indole (Lit. 3) to give the title compound as a colorless solid. MS: 406.5 ([M−H]−).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1>>[CH3:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([C:12]4[NH:20][C:19]5[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=5[CH:13]=4)[CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1cccc(N)c1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(Nc2ccc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)c1
Yield: 4 %

Procedure:
Prepared according to Example 102, using 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 50 mg, 0.168 mmol), 3-methylaniline (91 μl, 0.840 mmol, Sigma Aldrich), and 1.0 M LHMDS in THF (163 μl, 0.840 mmol, Sigma Aldrich) and stirring at 25° C. for 2.h. Purification by column chromatography (silica gel: 0 to 4% MeOH/DCM) provided 2-(2-((3-methylphenyl)amino)-8-quinolinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (2.5 mg, 4%). 1H NMR (400 MHz, MeOH-d4) δ ppm 7.84-7.90 (2H, m) 7.37-7.43 (1H, m) 7.27-7.32 (2H, m) 7.17 (3H, s) 6.88 (2H, m) 3.40 (2H, t, J=1.00 Hz) 2.50 (2H, t, J=1.00 Hz) 2.24 (3H, s). m/z (ESI, +ve) 369.2 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.[Cl:19][C:20]1[CH:36]=[CH:35][C:23]([CH2:24][N:25]2[C@H:29]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:33])[NH:27][C:26]2=[O:34])=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][N:25]2[C@H:29]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:33])[N:27]([CH2:2][C:3]3[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]4[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=4[CH:4]=3)[C:26]2=[O:34])=[CH:35][CH:36]=1
Reactant: CC(C)[C@@H]1C(=O)NC(=O)N1Cc1ccc(Cl)cc1
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)[C@@H]1C(=O)N(Cc2cc3cnc(C#N)nc3n2CC(C)(C)C)C(=O)N1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.1 %

Procedure:
To a solution of 0.5 g (1.63 mmoles) of 6-bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in DMF (5 ml) are added 0.653 g of (2.45 mmoles) of (R)-1-(4-chloro-benzyl)-5-isopropyl-imidazolidine-2,4-dione and 0.293 g (2.12 mmoles) of K2CO3 at ambient temperature under N2 atmosphere. The mixture is stirred at ambient temperature for 15 hours. The mixture is diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated. The crude product is purified by silica gel column chromatography to give 0.644 g of desired 6-[(R)-3-(4-chloro-benzyl)-4-isopropyl-2,5-dioxo-imidazolidin-1-ylmethyl]-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 78% yield.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C:8]2[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@@H:14]3[CH2:18][CH2:17][CH2:16][NH:15]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34]>CN(C=O)C.O.C(OCC)(=O)C>[CH3:36][O:35][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][N:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[CH2:13][O:12][C:11]1[CH:19]=[CH:20][C:8]([CH2:7][C:6]2[CH:21]=[CH:22][C:3]([Cl:2])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)CCCBr
Reactant: Clc1ccc(Cc2ccc(OC[C@@H]3CCCN3)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCN1CCC[C@H]1COc1ccc(Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
To a solution of the product from step 2 (1.50 g, 4.43 mmol) in DMF (20 mL) was added potassium carbonate (1.23 g, 8.90 mmol) and methyl 4-bromobutyrate (0.64 mL, 5.56 mmol). The resulting suspension was stirred at ambient temperature overnight. The reaction mixture diluted with water and ethyl acetate. The crude residue was extracted into ethyl acetate. The organic portion was washed with water, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography using hexane/EtOAc (gradient system) to give the title compound (1.22 g, 69%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C1C(=O)N([Br:22])C(=O)C1>C(O)(=O)C>[Br:22][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([N+:12]([O-:14])=[O:13])[C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)c(O)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 95.3 %

Procedure:
(I4A): Methyl 4-hydroxy-3-nitrobenzoate (15 g, 76 mmol) was suspended in acetic acid (152 ml) and then treated with NBS (20.31 g, 114 mmol). The mixture became a homogeneous yellow solution which was stirred for 2 h. The mixture was quenched with water and the suspension was filtered. Methyl 3-bromo-4-hydroxy-5-nitrobenzoate (20 g) was obtained as a yellow solid.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13](=[O:16])[N:12]([CH3:17])[C:11]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[F:26])=[O:9])=C.Cl.[OH-].[Na+]>C(O)C.CCOC(C)=O.O>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13](=[O:16])[N:12]([CH3:17])[C:11]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[F:26])=[O:9]
Reactant: C=COCCONC(=O)c1ccc(=O)n(C)c1Nc1ccc(C)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(Nc2c(C(=O)NOCCO)ccc(=O)n2C)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.9 %

Procedure:
To a solution of 2-(2-fluoro-4-methylphenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (2-vinyloxyethoxy)-amide (0.048 g, 0.13 mmol) in ethanol (5 mL) was added aqueous 2 M HCl (0.332 mL, 0.664 mmol). The reaction mixture was stirred for 16 hours at room temperature. The pH of the reaction mixture was adjusted with 1 M NaOH until 7. The reaction mixture was diluted with EtOAc and H2O. The organic layer was separated and washed with saturated NaCl, dried (Na2SO4), and concentrated under reduced pressure to yield 0.044 g (100%) pure desired product as a pale yellow foamy solid. MS ESI (+) m/z 336 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 10.3 (s, 1H), 8.46 (s, 1H), 7.38 (d, 1H), 6.96-6.87 (m, 2H), 6.76 (t, 1H), 6.18 (d, 1H), 4.04 (m, 2H), 3.93 (br s, 1H), 3.75 (br s, 2H), 3.20 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[O:16]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.C(N=C=NC(C)(C)CC)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:30](=[O:31])[CH2:29][C:26]3[CH:27]=[CH:28][C:23]([O:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:24][CH:25]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: O=C(O)Cc1ccc(Oc2ccccc2)cc1
Reactant: CN(C)CCn1ncc2cc(N)ccc21
Agent: CCN=C=NC(C)(C)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN(C)CCn1ncc2cc(NC(=O)Cc3ccc(Oc4ccccc4)cc3)ccc21
Reaction time: 6 h

Procedure:
A mixture of 1-(2-dimethylamino-ethyl)-1H-indazol-5-ylamine (42 mg, 0.20 mmol), 4-phenoxy-phenylacetic acid (47 mg, 0.21 mmol), ethyldimethylpropylcarbodiimide hydrochloride (43 mg g, 0.22 mmol), N-hydroxybenzotriazole (30 mg, 0.22 mmol), N-methyl morpholine (46 mg, 0.44 mmol) in 2 mL of DMF was shaken for 6 hours. The mixture was concentrated under reduced pressure, the residue taken up in 1.5 mL of a 1:1 mixture of DMSO/MeOH and purified by preparative reverse-phase HPLC. 1H NMR (300 MHz, DMSO-d6) ppm 2.84 (s, 6H), 3.65 (s, 2H), 3.62 (t, J=6.24, 2H), 4.76 (t, J=6.24, 2H), 6.97–7.00 (m, 4H), 7.11–7.14 (m, 1H), 7.36–7.40 (m, 4H), 7.64 (m, 1H), 7.69 (m, 1H), 8.12 (m, 1H), 8.15 (m, 1H), 9.58 (s, 1H); MS (DCI/NH3) m/z 415 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:6][CH:5]1[N:7]1[CH:14]=[CH:13][C:11](=O)[NH:10][C:8]1=[O:9].C[Si](C)(C)[NH:17][Si](C)(C)C.C(N)=O>CO>[OH:1][CH2:2][CH2:3][CH:4]1[CH2:6][CH:5]1[N:7]1[CH:14]=[CH:13][C:11]([NH2:17])=[N:10][C:8]1=[O:9]
Reactant: O=c1ccn(C2CC2CCO)c(=O)[nH]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Solvent: NC=O
Solvent: CO
Product: Nc1ccn(C2CC2CCO)c(=O)n1
Temperature: 140 °C
Reaction time: 85 h

Procedure:
To 79 mg (0.42 mmol) of 1-(2'-(2"-hydroxyethyl)cyclopropyl) uracil, the product of Step B of Example 8, is added 0.44 mL (2.1 mmol) of hexamethyldisilazane and 0.034 mL (0.82 mmol) of formamide and the resultant mixture is heated with stirring in a sealed tube at 140° C. After 85 h, 10 mL of methanol is added to the cooled reaction mixture, the tube resealed and heated to 65° C. After 3 h at 65° C., the cooled reaction mixture is concentrated under reduced pressure. The residue is dissolved in 10 mL of water and the resultant aqueous solution treated with 50 mg of Darco G-60 charcoal, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel eluted with a gradient of methanol in methylene chloride from 100% methylene chloride to 30% methanol affords the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>>[CH2:22]([NH:29][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(NCc3ccccc3)ncc21
Temperature: 140 °C
Yield: 53.7 %

Procedure:
To 2-Chloro-9-cyclopentyl-8,9-dihydro-5,7,7-trimethyl-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (50 mg, 0.162 mmol) in nbutanol (2 ml), was added benzylamine (71 μl, 0.648 mmol) and diisopropylethylamine (113 μl, 0.648 mmol). The reaction mixture was heated to 140° C. in a microwave for 90 minutes. The crude mixture was concentrated in vacuo and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min] to afford the title compound (33 mg) as an off-white powder. NMR DMSO D6 1.10 (6H, s), 1.46-1.58 (4H, m), 1.60-1.74 (4H, m), 3.13 (3H, s), 3.42 (2H, s), 4.52 (2H, d), 4.95-5.04 (1H, m), 7.24-7.30 (1H, m), 7.31-7.39 (4H, m), 7.83 (1H, s), 8.64 (1H, br s); HPLC rt(min): 10.36; MS (ES+) 380, (ES−) 378.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[C:14]1([N:20]2[C:24]3([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:23][N:22]([CH2:30][C:31](O)=[O:32])[CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C)CCCN=C=NCC.O>ClCCl>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:6][C:31](=[O:32])[CH2:30][N:22]1[CH2:23][C:24]2([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[N:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:21]1)([CH3:13])[CH3:12]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(O)CN1CN(c2ccccc2)C2(CCCCC2)C1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN1CN(c2ccccc2)C2(CCCCC2)C1
Temperature: -10 °C
Reaction time: 4 h
Yield: 8.9 %

Procedure:
130 μl (0.69 mmol) of 2,6-diisopropylaniline are added to a solution of 180 mg (0.65 mmol) of (1-phenyl-1,3-diazaspiro[4.5]dec-3-yl)acetic acid in 20 ml of dichloromethane. The solution is cooled to −10° C. and 132 mg (0.69 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide are added. The medium is allowed to return to room temperature and stirred for 4 h and then at reflux for one day and again at room temperature for 5 days. The medium is then poured into water and extracted with dichloromethane. The organic phases are collected and washed with water. They are dried over sodium sulfate. The solvents are evaporated. The residue is chromatographed on silica gel (heptane/ethyl acetate 90/10, v/v). 25 mg of N-(2,6-diisopropylphenyl)-2-(1-phenyl-1,3-diazaspiro[4.5]dec-3-yl)acetamide are obtained in the form of a white solid. M.p. 151-3° C., yield=8.8%.
Reaction SMILES: [C:1]([NH2:6])(=O)[CH:2]([CH3:4])[CH3:3].[N+:7]([C:10]1[CH:11]=[C:12]([NH2:19])[C:13](=[CH:17][CH:18]=1)[C:14]([OH:16])=O)([O-:9])=[O:8].[Cl:20][C:21]1[CH:27]=[CH:26][C:24](N)=[CH:23][CH:22]=1.P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH:21]([O:8][CH:2]([CH3:3])[CH3:4])([CH3:27])[CH3:22].[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([N:6]2[C:14](=[O:16])[C:13]3[C:12](=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:18][CH:17]=3)[N:19]=[C:1]2[CH:2]([CH3:4])[CH3:3])=[CH:23][CH:22]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: CC(C)C(N)=O
Solvent: Cc1ccccc1
Solvent: ClP(Cl)Cl
Product: CC(C)OC(C)C
Product: CC(C)c1nc2cc([N+](=O)[O-])ccc2c(=O)n1-c1ccc(Cl)cc1
Temperature: 150 °C

Procedure:
A suspension of 4-nitroanthranilic acid isobutyramide (4 g, 15.8 mmol), 4-chloroaniline (2.2 g, 17.2 mmol) and phosphorus trichloride (5.6 mL) in toluene (150 mL) is heated to reflux (bath temperature for 150° C.) for 2 hours. The reaction mixture is allowed to cool to room temperature and then evaporated to dryness. The residue is partitioned between water and EtOAc and the aqueous phase is extracted (2×) with EtOAc. The combined organic phases are washed with water, dried (Na2SO4) and evaporated in vacuo. Trituration with isopropyl ether provides the desired compound as a brown solid.