Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.[O:21]=[C:22]1[CH2:27][CH2:26][CH2:25][CH2:24][N:23]1[CH2:28][CH2:29][CH:30]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:6]2[CH:7]=[C:2]([NH:1][CH2:30][CH2:29][CH2:28][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][C:22]3=[O:21])[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=2)=[CH:14][CH:13]=1
Reactant: O=CCCN1CCCCC1=O
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCCN1CCCCC1=O
Reaction time: 0.5 h

Procedure:
A solution of ethyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate (0.79 g, 2.9 mmol) and 3-(2-oxo-1-piperidinyl)propanal (0.56 g, 3.6 mmol) under nitrogen in glacial acetic acid (10 mL) was treated with sodium triacetoxyborohydride (1.21 g, 5.7 mmol) at 0° C. for 30 min. After stirring for an additional 30 min., an additional 0.23 g of 3-(2-oxo-1-piperidinyl)propanal and 0.36 g sodium triacetoxyborohydride were added. After stirring another 1 h, an additional 0.145 g of 3-(2-oxo-1-piperidinyl)propanal and 0.3 g sodium triacetoxyborohydride were added and stirred at 0° C. for another ½ hour. The reaction was evaporated in vacuo and the residue was dissolved in CH2Cl2, washed with 2N Na2CO3, and back extracted the aqueous 2× with CH2Cl2. The organics were combined, washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The residue was dissolved in CH2Cl2 and chromatographed on silica gel eluting with 10-100% acetone in hexanes to provide, after combining pure fractions and concentrating them in vacuo, the product as a clear viscous oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.25-1.31 (m, 3 H), 1.63-1.77 (m, 6 H), 2.19 (t, J=5.90 Hz, 2 H), 3.12-3.25 (m, 4 H), 3.24-3.39 (m, 2 H), 3.94 (s, 2 H), 4.26 (q, J=7.11 Hz, 2 H), 7.08-7.16 (m, 3 H), 7.31 (ddd, J=12.00, 5.33, 3.02 Hz, 2 H), 7.61 (t, J=5.69 Hz, 1 H), 7.76 (d, J=1.82 Hz, 1 H); ES+ MS: 414 (M+H+).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=2)[CH2:6][CH2:5]1)(=O)C.Cl.[OH-].[Na+]>>[CH3:17][O:16][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[N+:13]([O-:15])=[O:14])[NH:4][CH2:5][CH2:6]2
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(C)=O)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(cc1[N+](=O)[O-])NCC2
Temperature: 25 °C
Yield: 93.9 %

Procedure:
A roundbottom flask equipped with a reflux condenser, mechanical stirrer and thermowell was charged with 1-acetyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (954 g, 4.04 mol) produced in accordance with Step C, immediately above, and aqueous 6N hydrochloric acid (9.5 L). The resulting suspension was heated to reflux for 4 hrs (became clear solution after 2 hrs). The reaction mixture was allowed to cool to room temperature then sodium hydroxide (50% w/w) was added to adjust the pH to 10. The resulting mixture was extracted with ethyl acetate (3×10L). The combined organic layers were washed with saturated potassium carbonate solution (10 L) and brine (10 L), then dried over sodium sulfate, evaporated in vacuo to afford 5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (737 g, 94%), which was used for the next step without further purification. 1H-NMR (DMSO, 300 MHz) δ 7.11 (s, 1H), 6.87 (s, 1H), 5.59 (brs, 1H), 3.78 (s, 3H), 3.43 (t, 2H), 2.97 (t, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])=[O:14])[CH3:11]>>[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[C:17]([NH:18][C:2]2[N:7]=[C:6]([NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[C:15]([C:13]([O:12][CH2:10][CH3:11])=[O:14])[CH:16]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:19]=[CH:20][CH:21]=1)=[O:14])[CH3:11]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CCOC(=O)c1cccc(N)c1
Product: CCOC(=O)c1cccc(Nc2ncc(F)c(Nc3cccc(C(=O)OCC)c3)n2)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-ethoxycarbonylaniline gave N2,N4-bis(3-ethoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 26.55 min.; purity: 100%; MS (m/e): 425 (MH+).
Reaction SMILES: C([NH:5][C:6]1[S:7][CH2:8][C:9]2([N:35]=1)[C:22]1[CH:21]=[C:20]([C:23]#[C:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:18][C:17]=1[O:16][C:15]1[C:10]2=[CH:11][C:12]([C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)=[CH:13][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=[O:37]>>[NH2:5][C:6]1[S:7][CH2:8][C@:9]2([N:35]=1)[C:10]1[CH:11]=[C:12]([C:29]3[CH:30]=[N:31][CH:32]=[N:33][CH:34]=3)[CH:13]=[CH:14][C:15]=1[O:16][C:17]1[C:22]2=[CH:21][C:20]([C:23](=[O:37])[CH2:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[CH:19][CH:18]=1
Reactant: CC(C)(C)C#Cc1ccc2c(c1)C1(CSC(NC(C)(C)C)=N1)c1cc(-c3cncnc3)ccc1O2
Reactant: O=C(O)C(F)(F)F
Product: CC(C)(C)CC(=O)c1ccc2c(c1)[C@]1(CSC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 160 °C
Reaction time: 3 h

Procedure:
A resealable tube charged with N-tert-butyl-2′-(3,3-dimethylbut-1-ynyl)-7′-(pyrimidin-5-yl)-5H-spiro[thiazole-4,9′-xanthen]-2-amine (0.113 g, 0.234 mmol) and TFA (2 mL) was sealed and heated to 160° C. After 3 hrs, the solvent was removed in vacuo and the residue taken up in 2 mL DCM. TEA (ca. 0.1 mL) was added and the solution was loaded onto a silica gel plug and purified by silica gel chromatography using 2-4% MeOH:DCM w/1% NH4OH to afford crude, racemic product that was resolved by chiral column chromatography to give both (R) and (S)-1-(2-amino-2′-(pyrimidin-5-yl)-5H-spiro[thiazole-4,9′-xanthene]-7′-yl)-3,3-dimethylbutan-1-one. MS Found: MH+=445.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C:9]=2[N:10]=[CH:11][N:12]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]2[CH2:16][CH2:15][NH:14][CH2:13][C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncnc2-c2ccccn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(-c2ncnc3c2CCNC3)nc1
Reaction time: 3 h
Yield: 83 %

Procedure:
To the product of Example 11, step a (157 mg, 0.50 mmol) in DCM (3 mL) was added TFA (1.00 mL). After stirring 3 h the mixture was concentrated in vacuo and loaded directly on a Prep Agilent system with a XBridge C18 OBD 50×100 mm column eluting with 5 to 99% 0.05% NH4OH in H2O/ACN over 17 min to afford the desired product as a tan solid (89 mg, 83%). MS (ESI) mass calcd. C12H12N4, 212.11. m/z found 213.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 9.05 (s, 1H), 8.71 (s, 1H), 8.06-7.94 (m, 1H), 7.93-7.81 (m, 1H), 7.45-7.32 (m, 1H), 4.17 (s, 2H), 3.16 (s, 4H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[CH2:18]([NH:25][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a suspension of P-HOBT 6 (1.01 g, 0.49 mmol) in CH2Cl2 (5 mL) was added p-toluenesulfonyl chloride (0.280 g, 1.47 mmol, 3.00 equiv.) and pyridine (0.155 g, 0.160 mL, 1.98 mmol, 4.04 equiv.). The suspension was subsequently rocked for 60 minutes at 25° C. The polymer was then filtered and washed with CH2Cl2 (3×5 mL), MeCN (3×5 mL), and MeOH (3×5 mL). The polymer was re-suspended in CH2Cl2 (5 mL), followed by the addition of benzylamine (0.026 g, 0.027 mL, 0.24 mmol, 0.49 equiv. based on P-HOBT 6). The suspension was rocked at 25° C. for 2 h. The polymer was then filtered and washed with CH2Cl2 (2×5 mL). The filtrate and washings were combined and concentrated to yield 0.050 g (77%) of N-benzyl-p-toluenesulfonarnide as a light yellow crystalline solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.Cl.[NH:27]1[CH2:32][CH2:31][CH2:30][CH:29]([NH2:33])[CH2:28]1.C(N(CC)C(C)C)(C)C>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([N:27]3[CH2:32][CH2:31][CH2:30][CH:29]([NH2:33])[CH2:28]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NC1CCCNC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CCCC(N)C3)c2c1
Temperature: 160 °C
Yield: 22.3 %

Procedure:
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (0.2 g, 0.54 mmol, prepared in analogy to the one in Example 2-1), piperidin-3-ylamine hydrochloric acid salt (0.275 g, 1.6 mmol) and N,N-diisopropylethylamine (1 mL) was heated at 160° C. under microwave irradiation for 1 hour. After being cooled to room temperature, the mixture was purified by preparative HPLC and SPE. After SPE separation, the eluent was concentrated in vacuo to remove the organic solution. The residue was dried by lyophylization to give 52.3 mg of the desired product (yield was 22.3%). MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 8.09-8.07 (d, J=8 Hz, 1 H), 7.87-7.85 (q, J=7.2 Hz, 1 H), 7.85-7.82 (m, 1 H), 7.73-7.68 (q, J=14 Hz, 2 H), 7.62-7.55 (m, 2 H), 6.56 (s, 1 H), 5.37 (s, 2 H), 4.57 (s, 2 H), 3.90-3.88 (d, J=9.6 Hz, 1 H), 3.75 (s, 2 H), 3.67-3.66 (m, 1 H), 3.51-3.48 (d, J=11.6 Hz, 1 H), 3.26-3.24 (d, J=9.6 Hz, 1 H), 3.24-3.14 (m, 1 H), 2.49 (s, 3 H), 2.26-2.22 (m, 1 H), 2.14-2.10 (m, 1 H), 1.99-1.92 (m, 1 H), 1.91-1.78 (m, 1 H).
Reaction SMILES: [Br:1][C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:5]2[N:6]=[C:7](Cl)[NH:8][C:4]=2[CH:3]=1.[F:16][C:17]([F:31])([F:30])[C:18]1[C:19]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1>>[Br:1][C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:5]2[NH:6][C:7]([N:27]3[CH2:28][CH2:29][N:24]([C:19]4[C:18]([C:17]([F:31])([F:16])[F:30])=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:25][CH2:26]3)=[N:8][C:4]=2[CH:3]=1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: FC(F)(F)c1cc2nc(Cl)[nH]c2cc1Br
Product: FC(F)(F)c1cc2[nH]c(N3CCN(c4ncccc4C(F)(F)F)CC3)nc2cc1Br

Procedure:
The benzoimidazole from step (f) above (1.2 g, 4.0 mmol) reacted with 1-(3-trifluoromethylpyridin-2-yl)piperazine (1.4 g, 6.0 mmol, Oakwood) under the conditions of Example 3c to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 496.0 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([S:25]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([CH3:15])([CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:17][CH:18]=2)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCNS(=O)(=O)c2ccccc2)cc1

Procedure:
from ethyl 2-[4-(2-aminoethyl)-phenoxy]-2-methylpropionate and benzenesulphonyl chloride;
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].[S:29](N)([NH2:32])(=[O:31])=[O:30]>O1CCOCC1>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([S:29]([NH2:32])(=[O:31])=[O:30])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(S(N)(=O)=O)CC3)coc12)c1c(Cl)ccc(F)c1Cl

Procedure:
A mixture of 7-[(R)-1-(2,6-Dichloro-3-fluorophenyl)-ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (0.0300 g, 0.071 mmol) and Sulfamide (0.00819 g, 0.0852 mmol) in 1,4-Dioxane (2 mL) was stirred under reflux for 7 h. The reaction mixture was directly loaded onto prep TLC for purification (silica gel, eluting with 4% MeOH in DCM) to afford the title compound as a yellow solid. 1H-NMR (CD3OD, 400 MHz): δ=1.87 (d, J=6.6 Hz, 3H), 2.60 (d, J=1.5 Hz, 2H), 3.36 (t, J=5.7 Hz, 2H), 3.85 (d, J=2.8 Hz, 2H), 6.29 (br. s., 1H), 6.49 (q, 1H), 7.21 (t, J=8.7 Hz, 1H), 7.39 (dd, J=9.0, 4.9 Hz, 1H), 7.64 (s, 1H), 8.19 (s, 1H). MS (ES+): m/z 500.98 (MH+, 35Cl, 37Cl), 502.88 (MH+, 37Cl, 37Cl). HPLC: tR=2.92 min (polar—5 min, ZQ3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[CH3:13][C:14]1[CH:15]=[C:16]([NH:23][C:24]([C:26]2([CH3:29])[CH2:28][O:27]2)=[O:25])[CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:29][C:26]([OH:27])([CH3:28])[C:24]([NH:23][C:16]2[CH:17]=[CH:18][C:19]([N+:20]([O-:22])=[O:21])=[C:14]([CH3:13])[CH:15]=2)=[O:25])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Product: Cc1cc(NC(=O)C(C)(O)COc2ccc(F)c(C(F)(F)F)c2)ccc1[N+](=O)[O-]

Procedure:
3-(4-Fluoro-3-trifluoromethylphenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1 starting from 4-fluoro-3-(trifluoromethyl)phenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane-1% methanol). 1H NMR (400 MHz, DMSO-d6): 1.44 (3H, s), 2.53 (3H, s), 4.06 (1H, d, J=9.9 Hz), 4.32 (1H, d, J=9.9 Hz), 6.23 (1H, s), 7.24-7.31 (2H, m), 7.38-7.43 (1H, m), 7.87 (1H, dd, J=9.0 Hz, J=2.1 Hz), 7.91 (1H, d, J=2.0 Hz), 8.03 (1H, d, J=9.0 Hz), 10.14 (1H, s).
Reaction SMILES: C1(O[C:8](=[O:22])[NH:9][C:10]2[C:11]([O:20][CH3:21])=[N:12][C:13]([CH3:19])=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>>[CH:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[CH:25]=3)[CH2:35][CH2:34]2)=[O:22])[C:11]([O:20][CH3:21])=[N:12][C:13]=1[CH3:19])([CH3:17])[CH3:18]
Reactant: COc1nc(C)c(C(C)C)cc1NC(=O)Oc1ccccc1
Reactant: Clc1cccc(N2CCNCC2)c1
Product: COc1nc(C)c(C(C)C)cc1NC(=O)N1CCN(c2cccc(Cl)c2)CC1
Yield: 63 %

Procedure:
Phenyl-N-(5-isopropyl-2-methoxy-6-methylpyridine-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:26]#[N:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>COCCO>[C:26]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:7])[N:9]=1)#[N:27]
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccccc3)cc2c1O
Reactant: NCCCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)NCCCCC(=O)O)c(O)c2cc(Oc3ccccc3)ccc12
Yield: 47.9 %

Procedure:
A mixture of 1-cyano-4-hydroxy-6-phenoxy-isoquinoline-3-carboxylic acid butyl ester (60 mg, 0.17 mmol) (prepared according to U.S. Pat. No. 7,928,120), 5-aminovaleric acid (970 mg, 8.28 mmol) and NaOMe (360 mg, 6.62 mmol) in 2-methoxyethanol (15 mL) was refluxed for 1.5 h. Solvent was evaporated, and the residue was partitioned between EtOAc and water. 1 M HCl was added with stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by preparative TLC (40% EtOAc/hexanes+2% AcOH) to give 33 mg of the title compound. MS: (+) m/z 406.13 (M+1).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:3]1.Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(N(C(C)C)CC)(C)C>CC#N>[CH3:1][C@@H:2]1[CH2:3][N:4]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:5][CH2:6][N:7]1[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C[C@@H]1CN(C2CCCCC2c2ccccc2)CCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(C2CCCCC2c2ccccc2)CCN1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.5 %

Procedure:
To a solution of (3R)-3-methyl-1-(2-phenylcyclohexyl)piperazine (900 mg, 3.48 mmol) (crude) in MeCN was added tert-butyl 2-bromoacetate (0.815 g, 4.18 mmol) followed by diisopropylethylamine (1.21 ml, 6.97 mmol). The reaction was stirred at RT for 5 h. The solvent was evaporated under high vacuum and the residue was loaded on column (SiO2, hexane to hexane/EtOAc=100:10 to 100:20 to 100:30 to 100:40) to give tert-butyl 2-((R)-2-methyl-4-(2-phenylcyclohexyl)piperazin-1-yl)acetate (1.16 g, 89.4% yield) as a gum.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=O)=[O:9])=[CH:4][CH:3]=1.O>CN1C(=O)CCC1>[CH:7]1[C:2]([NH2:1])=[CH:3][CH:4]=[C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[O:9])[CH:6]=1
Reactant: Nc1ccc(S(=O)(=O)c2ccc(N)cc2)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1ccc(S(=O)c2ccc(N)cc2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
At room temperature, 10.85 g (20 mmol) of bis[4-(3,4-dicarboxyphenoxy)phenyl]sulfonic acid dianhydride (SOPOP) was added to a solution of 4.966 g (20 mmol) of bis(4-aminophenyl) sulfone (DDSO) in 68 ml of NMP. The resulting mixture was stirred at room temperature for 10 hours. The reaction mixture was dropwise added to 1.5 liters of water to obtain a polyamic acid (SOPOP/DDSO) as a solid product in a yield of 14.2 g.
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].[Cl:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[C:26](Cl)=[N:25][N:24]=1.[I-].[K+]>>[Cl:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[C:26]([N:18]2[CH2:19][CH2:20][CH:15]([N:5]3[C:6](=[O:14])[C:7]4[C:12](=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=4)[N:3]([CH3:2])[C:4]3=[O:21])[CH2:16][CH2:17]2)=[N:25][N:24]=1
Reactant: COc1cc2c(Cl)nnc(Cl)c2cc1OC
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Agent: Br
Agent: [I-]
Agent: [K+]
Product: COc1cc2c(Cl)nnc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OC
Yield: 49 %

Procedure:
The procedure similar to that described in Example 15 was repeated, except that 354.0 mg (1.0 mmol) of 1,2,3,4tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazoline hydrobromide (Compound v) obtained in Example 41 was used, 1,4-dichloro-6,7-dimethoxyphthalazine was used in place of 4-chloro-6,7-dimethoxyquinazoline, and a catalytic amount of potassium iodide was added. As a result, 243.7 mg (yield: 49%) of Compound 76 was obtained as white crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:13]1([C:9]2[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6](=[O:21])[N:5]3[C:10]=2[C:11]([CH3:12])=[C:2]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[CH:3]=[CH:4]3)[CH2:15][CH2:14]1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(F)cc3)ccn2c1=O
Temperature: 80 °C
Yield: 82.1 %

Procedure:
A mixture of ethyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (120 mg, 0.400 mmol), 4-fluoro-phenyl boronic acid (67 mg, 0.48 mmol), (Ph3P)2PdCl2 (28 mg, 0.040 mmol), and Na2CO3 (190 mg in 0.8 mL of water, 1.80 mmol) in THF (5 mL) was degassed 3 times under N2 and heated to 80° C. overnight. The reaction mixture was diluted with ethyl acetate (50 mL), and washed with water (2×20 mL). The organic phase was separated, dried, and concentrated. The residue was purified by flash silica column chromatography (hexane:ethyl acetate, 1:2) to afford the title compound as a yellow solid (120 mg, 82%). ESI-MS m/z: 366 (M+H)+.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][N:59]([CH3:64])[CH2:60][CH2:61][CH2:62][NH2:63]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:63][CH2:62][CH2:61][CH2:60][N:59]([CH3:64])[CH3:58])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)CCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NCCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and N,N-dimethyl-1,3-propanediamine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14-1.49 (m, 3H) 1.53-1.87 (m., 9H) 2.13 (s, 6H) 2.25 (t, J=6.44 Hz, 2H) 3.29 (m, 2H) 3.31 (s, 3H) 3.93 (s, 3H) 4.06 (t, J=13.26 Hz, 2H) 4.46 (m, 1H) 7.46 (d, J=8.0 Hz, 1H) 7.51 (s, 1H) 7.90 (s, 1H) 8.21 (s, 1H) 8.27 (d, J=8.08 Hz, 1H) 8.48 (br. s., 1H). [M+H] calculated for C27H37F2N7O3, 546. found 546.
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([OH:40])[C:36](OC)=[O:37])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O>[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([OH:40])[C:36]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][N:10]=1)=[O:37])([C:26]([CH3:29])([CH3:27])[CH3:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: C[Al](C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)[Si](OCCOC[C@H](O)C(=O)Nc1ccc(Cl)cn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61.3 %

Procedure:
Trimethylaluminium (2M in toluene) (4.97 mL, 9.94 mmol) was added carefully to 5-chloropyridin-2-amine (1.277 g, 9.94 mmol) in toluene (10 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 15 minutes. (S)-Methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) (2 g, 4.97 mmol) in toluene (2 mL) was added. The reaction was heated to 120° C. for 2 hours in the microwave reactor. The reaction mixture was allowed to cool. The residue was neutralised with citric acid (1M, aq) and then diluted with water and extracted with EtOAc. The combined organics were dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane to afford the product (1.52 g, 61.3%). 1H NMR (400 MHz, CDCl3) δ 1.04 (9H, s), 3.63-3.68 (3H, m), 3.79-3.83 (2H, m), 3.85 (2H, d), 4.33 (1H, q), 7.34-7.46 (6H, m), 7.63-7.69 (5H, m), 8.18-8.25 (2H, m), 9.19 (1H, s); m/z (ES+) (M+H)+=499.55; HPLC tR=3.43 min.