Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[C:29]1[S:37]([NH2:40])(=[O:39])=[O:38]>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:40][S:37]([C:29]3[S:28][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=3)(=[O:39])=[O:38])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)c1nc2ccccc2s1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2nc3ccccc3s2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 2-benzothiazolesulfonamide (J Org Chem, 1958, 1768) in accordance with Procedure 1, Method A described hereinabove. Yield (52%); 1H NMR (d6-DMSO) δ 8.07 (d, J=8.3 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.53-7.05 (m, 15H), 6.78 (d, J=8.1 Hz, 2H), 6.27 (d, J=15.7 Hz, 1H), 2.35 (q, J=7.3 Hz, 2H), 0.82 (t, J=7.3 Hz, 3H); APcI m/z: 551 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[N+:7]([C:10]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:11]=1[C:12](=[O:25])[C:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=1[C:19]2=[O:24])([O-])=O.[H][H]>[Pd].C(O)CCC>[NH2:7][C:10]1[C:11]2[C:12](=[O:25])[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19](=[O:24])[C:20]=2[CH:21]=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: O=C1C2=C(CCCC2)C(=O)c2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 100 °C
Yield: 91.3 %

Procedure:
0.07 Gram of 5% palladium on carbon catalyst and 8 grams of crystal sodium carbonate were added to a mixture of 7.7 grams of 5-nitrotetrahydroanthraquinone and 320 grams of butanol. The resultant mixture was heated to 70° C. and hydrogen was fed for hydrogenation under normal pressure to have hydrogen absorbed in the starting 5-nitro compound in an amount of 2 mols per mol of the 5-nitro compound. The resultant solution was heated to 100° C. and subjected to filtration under hot conditions for separation of the catalyst therefrom, followed by distilling off butanol for condensation. The condensed solution was allowed to cool to precipitate crystals, which were then separated by filtration, washed with water and dried to obtain 6.1 grams of 1-aminoanthraquinone having a purity of 98.5%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:39])[NH:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:41][O:42][C:43](=[O:68])[NH:44][CH:45]([C:49]([N:51]1[CH2:55][CH2:54][CH2:53][CH:52]1[C:56]1[NH:57][C:58]([C:61]2[CH:66]=[CH:65][C:64](Br)=[CH:63][CH:62]=2)=[CH:59][N:60]=1)=[O:50])[CH:46]([CH3:48])[CH3:47].C(=O)([O-])[O-].[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:40])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:39])[NH:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:25]=[CH:26][C:27]([C:64]3[CH:65]=[CH:66][C:61]([C:58]4[NH:57][C:56]([CH:52]5[CH2:53][CH2:54][CH2:55][N:51]5[C:49](=[O:50])[CH:45]([NH:44][C:43]([O:42][CH3:41])=[O:68])[CH:46]([CH3:48])[CH3:47])=[N:60][CH:59]=4)=[CH:62][CH:63]=3)=[CH:28][CH:29]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1C(=O)Nc1cccc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CCCC1C(=O)Nc1cccc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)c1)C(C)C
Temperature: 85 °C
Yield: 5.1 %

Procedure:
(2-Methyl-1-{2-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-3-ylcarbamoyl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (135 mg, 0.246 mmol), (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (110 mg, 0.246 mmol), Pd(PPh3)4 (14 mg, 0.0123 mmol) and a 2 M aqueous solution of potassium carbonate (0.246 mL, 0.492 mmol) were degassed in 1,2-dimethoxyethane (2.5 mL) for 13 min. The stirred suspension was heated to 85° C. for 3 hours then concentrated, brought up in DMF/water and purified by reverse phase preparative HPLC to provide {1-[2-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-[1,1′;4′,1″]terphenyl-3″-ylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (10 mg, 5%). (MeOH-d4, 400 MHz) 7.90 (s, 1H), 7.82-7.66 (m, 8H), 7.54-7.51 (m, 1H), 7.40-7.37 (m, 2H), 4.59 (m, 1H), 4.24 (m, 1H), 4.02-3.73 (m, 4H), 3.66 (s, 3H), 3.65 (s, 3H), 2.36-2.02 (m, 10H), 1.15-0.88 (m, 12H); MS (ESI) m/z 792 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][N:4]2[N:8]=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=[C:3]12.S(=O)(=O)(O)O.[CH3:19][CH2:20]O>>[CH2:19]([O:12][C:11]([C:9]1[CH:10]=[C:3]2[C:2](=[O:1])[CH2:7][CH2:6][CH2:5][N:4]2[N:8]=1)=[O:13])[CH3:20]
Reactant: CCO
Reactant: O=C(O)c1cc2n(n1)CCCC2=O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc2n(n1)CCCC2=O
Temperature: 100 °C

Procedure:
To a mixture of 4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridine-2-carboxylic acid (16 g, 89 mmol) in 170 mL EtOH is added slowly 12 mL concentrated sulphuric acid and the reaction mixture is heated to 100° C. for 2 h. The reaction mixture is cooled to RT and concentrated under reduced pressure. The residue is poured on ice, neutralized by the addition of an aqueous saturated solution of NaHCO3 and extracted with DCM. The combined organic phases are washed with water and brine, dried on MgSO4 and the solvent are removed under reduced pressure. Yield: 17 g. HPLC-MS: Rt=1.79 min, (M+H)+=209.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][O:30][C:31]([CH:33]1[CH2:38][CH2:37][CH:36]([CH2:39][NH:40][C:41](N2C=CN=C2)=[O:42])[CH2:35][CH2:34]1)=[O:32]>C(Cl)Cl>[CH3:29][O:30][C:31]([CH:33]1[CH2:38][CH2:37][CH:36]([CH2:39][NH:40][C:41]([N:9]2[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:42])[CH2:35][CH2:34]1)=[O:32]
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)C1CCC(CNC(=O)n2ccnc2)CC1
Solvent: ClCCl
Product: COC(=O)C1CCC(CNC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 85.7 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (70.2 mg, 0.165 mmol) and 4-{[(imidazole-1-carbonyl)-amino]-methyl}cyclohexanecarboxylic acid methyl ester (509.6 mg, 1.921 mmol) in CH2Cl2 (9 mL) was stirred at rt for 17 hrs and at reflux for 7 hrs. The reaction mixture was then purified by flash column to give rac 4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-cyclohexanecarboxylic acid methyl ester (87.7 mg, 85.1%). HRMS (ES+) m/z Calcd for C32H37Cl2F2N3O3+H [(M+H)+]: 620.2253; Found: 620.2254.
Reaction SMILES: O.[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][C:16]3[C:21]([N:22]=2)=[CH:20][CH:19]=[C:18]([C:23]2([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:28][CH2:27][CH:26]=[CH:25][CH2:24]2)[N:17]=3)=[C:10]([F:35])[CH:9]=1>[Pd].C1COCC1>[O:4]1[CH2:5][CH2:6][CH2:7][O:2][CH:3]1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][C:16]3[C:21]([N:22]=2)=[CH:20][CH:19]=[C:18]([C:23]2([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[N:17]=3)=[C:10]([F:35])[CH:9]=1
Reactant: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(c4ccccc4)CC=CCC3)nc2s1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(c4ccccc4)CCCCC3)nc2s1
Reaction time: 36 h

Procedure:
A mixture of 10% palladium on carbon, 50% water wet (0.33 g, 0.31 mmol) and 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylcyclohex-3-enyl)thiazolo[5,4-b]pyridine (0.492 g, 1.0 mmol) under nitrogen was treated with 10 mL THF and exposed to 1 atm H2 gas via balloon. The reaction mixture was allowed to stir 36 h, then flush with nitrogen, filter, rinsing with DCM. The filtrate was concentrated in vacuo to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylcyclohexyl)thiazolo[5,4-b]pyridine as a light yellow solid. MS (ESI) m/z: Calculated: 474.2; Observed: 475.1 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[NH:10][N:11]=[C:12]([I:13])[C:5]=12)[CH3:2].[H-].[Na+].[C:16](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:1]([O:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:11]=[C:12]([I:13])[C:5]=12)[CH3:2]
Reactant: CCOc1ncnc2[nH]nc(I)c12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ncnc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
To a solution of iodo mixture-4-ethoxy-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (1.40 g, 4.823 mmol) in DMF (20 mL) cooled to 0° C., was added NaH (212.2 mg, 5.31 mmol, 60% dispersion in oil). The reaction mixture was stirred at this temperature for 30 minutes and then trityl chloride (1.41 g, 5.06 mmol) was added in one portion. The reaction mixture was allowed to warm to ambient temperature over 18 hours. After this time, the reaction mixture was concentrated in vacuo, diluted with DCM and water. The organic layer was separated and washed with saturated aqueous brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude mixture was purified by column chromatography (ISCO Companion™, 120 g column, eluting with DCM) to give the sub title compound as a mixture of regioisomers (592 mg, 23% Yield). 1H NMR (400 MHz, DMSO) δ 8.27 (1H, s), 7.34-7.12 (15H, m), 4.55 (3H, q) and 1.40 (2H, t).
Reaction SMILES: C(O[CH:4](OCC)[C:5]#[C:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10]2)C.[C:20]1([NH:26][NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>C(#N)C.O>[C:20]1([N:26]2[C:6]([C:7]3[CH:8]=[C:9]4[C:13](=[CH:14][CH:15]=3)[NH:12][C:11](=[O:16])[CH2:10]4)=[CH:5][CH:4]=[N:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(C#Cc1ccc2c(c1)CC(=O)N2)OCC
Reactant: NNc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1Cc2cc(-c3ccnn3-c3ccccc3)ccc2N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
To a solution of 5-(3,3-diethoxyprop-1-ynyl)indolin-2-one (100 mg, 0.39 mmol) in acetonitrile (5 ml) were added phenyl hydrazine (38 μL, 0.38 mmol) and sulfuric acid (52 μL, 0.98 mmol), and the mixture was stirred for 3 h at room temperature, then the mixture was stirred for 2 h at 50° C. The reaction mixture was poured into water (50 mL), and the resulting precipitate was filtered and dried. The precipitated was dissolved in acetonitrile (5 mL), then water (52 μL, 3.9 mmol) and sulfuric acid (93 μL, 1.75 mmol) were added. The mixture was heated at 80 C for 4 h. The mixture was cooled to room temperature, and then neutralized with sat. NaHCO3. The mixture was extracted with CHCl3/EtOAc 3 times. The combined organic extracts were washed with sat. NaCl, dried over Na2SO4, and evaporated in vacuo. The residue purified by column chromatography (EtOAc/n-hexane) to give the title compound as a brown solid (44 mg, 41%).
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=4)=[N:22][CH:23]=3)=[CH:13][CH:14]=2)[C:9]([C:36]([F:39])([F:38])[F:37])=[N:8]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:35][C:32]([F:33])([F:34])[O:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:21]2[N:22]=[CH:23][C:18]([CH2:17][O:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[NH:7][N:8]=[C:9]4[C:36]([F:38])([F:39])[F:37])=[CH:19][N:20]=2)=[CH:26][CH:27]=1
Reactant: FC(F)(F)Oc1ccc(Nc2ncc(COc3ccc4c(c3)c(C(F)(F)F)nn4C3CCCCO3)cn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)Oc1ccc(Nc2ncc(COc3ccc4[nH]nc(C(F)(F)F)c4c3)cn2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 39.5 %

Procedure:
To a solution of 5-(((1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-indazol-5-yl)oxy)methyl)-N-(4-(trifluoromethoxy)phenyl)pyrimidin-2-amine (0.03 g, 0.054 mmol) in DCM (5 mL) at 0° C., TFA (2 mL, 26.0 mmol) was added. The reaction mixture was stirred at room temperature for 5 h. Solvent was removed under vacuum and the crude product was purified by preparative HPLC on an Inertsil ODS column (19×250 mm, 5μ) using 0-65% mobile phase B (ACN) in mobile phase A (0.1% TFA) over 6 min to give N-(4-(trifluoromethoxy)phenyl)-5-(((3-(trifluoromethyl)-1H-indazol-5-yl)oxy)methyl)pyrimidin-2-amine as an off-white solid (10 mg, 39%). 1HNMR 400 MHz, DMSO-d6: δ ppm 5.11 (s, 1H), 7.22-7.22 (m, 1H), 7.29-7.30 (m, 3H), 7.65 (d, J=9.20 Hz, 1H), 7.86-7.87 (m, 2H), 8.67 (s, 2H), 10.00 (s, 1H), 13.90-0.00 (m, 1H). LCMS: R.T.=2.13 min; [M+H]+=468.0.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[N:10]=[C:9]([CH2:11][C:12]([OH:14])=O)[S:8][C:6]=2[N:7]=1.[CH3:21][C:22]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:25])[CH2:23][OH:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[N:10]=[C:9]([CH2:11][C:12]([N:29]3[CH2:30][CH2:31][N:26]([C:22]([CH3:25])([CH3:21])[CH2:23][OH:24])[CH2:27][CH2:28]3)=[O:14])[S:8][C:6]=2[N:7]=1
Reactant: CC(C)(CO)N1CCNCC1
Reactant: O=C(O)Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(CO)N1CCN(C(=O)Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Temperature: 25 °C
Reaction time: 65 h
Yield: 57.1 %

Procedure:
A mixture of (5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-yl)acetic acid (80 mg, 0.25 mmol), 2-methyl-2-piperazin-1-ylpropan-1-ol (48 mg, 0.31 mmol), HATU (116 mg, 0.31 mmol) and DIPEA (133 μL, 0.76 mmol) in DMF (3 mL) was stirred at r.t. for 65 h then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH/DCM. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording the title compound as an orange solid (65 mg, 56%)._LCMS (method H): RT 2.02 min [M+H]+ 455.3
Reaction SMILES: Cl.[F:2][C:3]([CH3:8])([CH3:7])[CH2:4][CH2:5][NH2:6].CN1CCCC1.[F:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([C:23]2[CH:34]=[N:33][C:26]3[N:27]=[C:28]([NH:31][CH3:32])[N:29]=[CH:30][C:25]=3[CH:24]=2)=[CH:18][C:17]=1[NH:35][C:36](=O)[O:37]C(C)=C>O1CCOCC1>[F:2][C:3]([CH3:8])([CH3:7])[CH2:4][CH2:5][NH:6][C:36]([NH:35][C:17]1[CH:18]=[C:19]([C:23]2[CH:34]=[N:33][C:26]3[N:27]=[C:28]([NH:31][CH3:32])[N:29]=[CH:30][C:25]=3[CH:24]=2)[C:20]([CH3:22])=[CH:21][C:16]=1[F:15])=[O:37]
Reactant: C=C(C)OC(=O)Nc1cc(-c2cnc3nc(NC)ncc3c2)c(C)cc1F
Reactant: CC(C)(F)CCN
Agent: CN1CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: CNc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)F)c(F)cc3C)cnc2n1
Temperature: 80 °C
Yield: 105.7 %

Procedure:
Add 3-fluoro-3-methyl-butan-1-amine hydrochloride (88 mg, 0.62 mmol) followed by N-methylpyrrolidine (0.065 mL, 0.62 mmol) to a stirred solution of isopropenyl N-[2-fluoro-4-methyl-5-(2-methylaminopyrido[2,3-d]pyrimidin-6-yl)phenyl]carbamate (184 mg, 0.50 mmol) in 1,4-dioxane (5 mL) and heat at 80° C. under N2 overnight. Concentrate and purify on silica eluting with 0-5% MeOH (2N NH3)/DCM. Purify on SCX column eluting with NH3/MeOH to obtain the title compound (219 mg, 70%). MS (m/z): 414.8 (M+1).
Reaction SMILES: [CH:1]([CH:8]1[CH:13]2[CH:9]1[CH2:10][CH:11]([OH:24])[CH:12]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]C)=[O:21])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(=O)([O-])[O-].[Na+].[Na+].Cl>CO>[CH:1]([CH:8]1[CH:13]2[CH:9]1[CH2:10][CH:11]([OH:24])[CH:12]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC=CC1C2CC(O)C(CCCCCCC(=O)OC)C12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCC=CC1C2CC(O)C(CCCCCCC(=O)O)C12
Temperature: 0 °C

Procedure:
A solution of methyl 6-(1-heptenyl)-3-hydroxybicyclo[3.1.0]hexane-2-heptanoate (17 mg.) from Example 25 in 5 ml. of methanol containing 0.5 ml. of 10% aqueous sodium carbonate solution is heated at 55° C. for 2 hours. The resulting mixture is then cooled to 0° C., acidified with hydrochloric acid to pH 2, and extracted with diethyl ether. The diethyl ether solution is washed, dried with anhydrous sodium sulfate, and evaporated to give 6-(1-heptenyl)-3-hydroxybicyclo[3.1.0]hexane-2-heptanoic acid. I. R. 1745 and 1700 cm-1.
Reaction SMILES: C([NH:4][C:5]1[CH:14]=[C:13]2[C:8]([NH:9][C:10](=[O:22])[C:11](=[O:21])[N:12]2[CH2:15][C:16]([O:18]CC)=[O:17])=[CH:7][CH:6]=1)(=O)C.[N+:23]([O-])([O-:25])=[O:24].[K+]>S(=O)(=O)(O)O>[NH2:4][C:5]1[CH:14]=[C:13]2[C:8]([NH:9][C:10](=[O:22])[C:11](=[O:21])[N:12]2[CH2:15][C:16]([OH:18])=[O:17])=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2ccc(NC(C)=O)cc21
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Nc1cc2c(cc1[N+](=O)[O-])[nH]c(=O)c(=O)n2CC(=O)O
Temperature: 0 °C
Yield: 69.3 %

Procedure:
57.5 g (0.19 mol) of 7-acetamido-1-(ethoxycarbonylmethyl)-2,3(1H,4H)-quinoxalinedione were dissolved in 575 mi of concentrated sulfuric acid. The solution was cooled to 0° C., and 19.0 g (0.19 mol) of potassium nitrate were added a little at a time. The cooling was then removed and the mixture was stirred until the reaction was complete and was then poured into 2 1 of ice-water and heated on a water bath for 2 h. The pH was then adjusted with aqueous ammonia solution to about 4-5, and the precipitate was filtered off with suction. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (mobile phase: methanol/tetrahydrofuran/water=5:4:1+2.5% glacial acetic acid). The resulting product was combined with the first precipitate to yield 36.9 g (70%) of product.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C:13]1([CH3:23])[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[CH3:29][NH:30][CH3:31].C(N(CC)CC)C>C(#N)C>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C:13]1([CH3:23])[CH2:17][CH2:16][CH:15]([C:18]([N:30]([CH3:31])[CH3:29])=[O:20])[C:14]1([CH3:21])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CNC
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(C)CCC(C(=O)O)C1(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(C)CCC(C(=O)N(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
To a 20-mL scintillation vial were added the product from Example 96 (118 mg, 0.300 mmol), dimethylamine hydrochloride (Aldrich, 36.7 mg, 0.450 mmol), and 2-(1H-benzo[d][1,2,3]tria-zol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (TBTU, Bachem, 144 mg, 0.450 mmol). Anhydrous acetonitrile (3 mL) was added to form a yellow slurry. Neat triethylamine (Aldrich, 182 mg, 1.80 mmol) was added to form a tan solution. The reaction was stirred at 25° C. in a shaker block for 24 hr. The volatiles removed by rotary evaporator to give a brown oil. The product was purified by flash chromatography (silica gel: 10-45% ethyl acetate in hexanes). The product was recrystallized from hexanes to afford 67.0 mg (53%) of the title compound. 1H NMR (DMSO-d6) δ ppm 0.49 (s, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.25 (s, 3H), 1.26 (s, 3H), 1.28-1.33 (m, 2H), 1.37-1.46 (m, 1H), 1.57 (s, 9H), 1.57-1.70 (m, 3H), 2.01-2.10 (m, 1H), 2.62-2.67 (m, 2H), 2.74-2.83 (m, 1H), 2.83 (s, 3H), 3.05 (s, 3H), 3.33-3.39 (m, 1H), 8.49 (s., 1H). MS (ESI+) m/z 422 (M+H)+. Anal. calcd. for C23H39N3O2S: C, 65.52; H, 9.32; N, 9.97. Found: C, 65.13; H, 9.22; N, 9.55.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=2[CH2:11]1.[C:21](OC(=O)CC)(=O)[CH2:22][CH3:23]>>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([CH:10]2[CH2:19][CH2:18][C:17]3[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=3[CH2:11]2)=[C:2]([NH:1][CH2:21][CH2:22][CH3:23])[CH:7]=1
Reactant: CCC(=O)OC(=O)CC
Reactant: COc1ccc(C2CCc3cc(O)ccc3C2)c(N)c1
Product: CCCNc1cc(OC)ccc1C1CCc2cc(O)ccc2C1

Procedure:
Synthesized from 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (500 mg) and propionic anhydride (1 ml) according to an analogous synthetic method to Example 36, the title compound (270 mg) was obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].C(=O)(O)[O-].[Na+].C1(C)C=CC=CC=1.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(OCC)(=O)C>[CH2:27]([O:26][C:24]([NH:1][CH:2]([CH2:3][CH2:4][C:5](=[O:7])[NH2:6])[C:8]([OH:10])=[O:9])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: NC(=O)CCC(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
Glutamine (36.5 g, 0.25 mol) was stirred with 1M sodium bicarbonate (750 ml) and toluene (200 ml). Benzyl chloroformate (50 ml, 59.75 g, 0.35 mol, 1.4 equiv.) was added drop-wise over 20 min. and the resulting mixture was stirred under nitrogen at room temperature overnight. Ethyl acetate (400 ml) was added and phases were separated. The organic phase was extracted with water (50 ml) and discarded. The aqueous phase was acidified with 6N hydrochloric acid and extracted with ethyl acetate (2×600 ml). The combined extracts were washed with water (100 ml) and stripped. The residue was dried in a vacuum oven (50° C.) to produce (1) (64 g, 91.4%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:19])=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.Cl.Cl.[C:22]1([CH:28]([NH2:38])[CH2:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:19])[N:3]=[C:2]([NH:38][CH:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:29][CH2:30][CH2:31][N:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:10]2
Reactant: NC(CCCN1CCCCC1)c1ccccc1
Reactant: Clc1cc2nc(Cl)c(-c3ccccn3)nc2cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Clc1cc2nc(NC(CCCN3CCCCC3)c3ccccc3)c(-c3ccccn3)nc2cc1Cl
Yield: 63.3 %

Procedure:
To a solution 2,6,7-trichloro-3-pyridin-2-yl-quinoxaline (0.31 g) and alpha-phenyl-1-piperdine-butylamine dihydrochloride (0.31 g) in toluene (25 mL) was added triethylamine (0.50 mL). The resulting mixture was refluxed under nitrogen atmosphere for 36 hours. After refluxing, the reaction mixture was cooled, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 1:9 methanol/dichloromethane) to give a yellow solid. Recrystallization from methanol and water gave the product as a fluffy yellow powder (0.32 g); mp 125-127° C.