Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N+:32]([O-])=O)(=[O:24])=[O:23])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:35])[CH:11]=2)[CH:6]=1.[Cl-].[NH4+].CO.O>[Zn].CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:36])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:17][CH2:18][N:19]([S:22]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[NH2:32])(=[O:24])=[O:23])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:35])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)Cc3ccccc3[N+](=O)[O-])CC2)c1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)Cc3ccccc3N)CC2)c1C
Temperature: 45 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A mixture of {6-fluoro-3-methyl-4-[1-(2-nitro-phenylmethanesulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (505 mg, 0.981 mmol), zinc dust (325 mesh) (642 mg, 9.82 mmol), and ammonium chloride (787 mg, 14.7 mmol, was combined with methanol (10 mL) and water (5 mL) under nitrogen to create a suspension. Moderate heating using a heat gun was used to bring more of the starting material into solution, and more methanol (5 mL) was added. The suspension was stirred for two hours at which time LCMS and TLC analysis (1:1 hexane-ethyl acetate) analysis indicated the presence of unreacted starting material and a more polar product. Another 20 equivalents of zinc dust (1.02 g) was added and the reaction mixture was stirred for two hours with some heating with a heat gun during this time period. TLC analysis indicated that the reaction was not complete. Another 30 equivalents of ammonium chloride (1.4 g) was added and the resulting suspension was heated to 40-50° C. with a heating mantle. The reaction mixture was cooled to room temperature and the zinc was filtered-off and washed with methanol. The filtrate was concentrated and the residue was diluted with water. The suspension was extracted with ethyl acetate (2×75 mL) and the combined extracts were washed with brine, dried over MgSO4, filtered, and concentrated. Flash chromatography (80 g ISCO column, eluting with 0-70% ethyl acetate/hexanes) provided {4-[1-(2-amino-phenylmethanesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (385 mg, 81%) as a white solid. MS cald. for C26H30FN2O4S [(M+H)+] 484, obsd. 485.2.
Reaction SMILES: C([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[F:20])C1C=CC=CC=1.CO.[H][H]>[C].[Pd].C(OCC)(=O)C>[F:20][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([O:18][CH3:19])[C:9]=1[OH:8])[C:13]([OH:15])=[O:14]
Reactant: [H][H]
Reactant: COc1cc(C(=O)O)cc(F)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)O)cc(F)c1O

Procedure:
To 4-benzyloxy-3-fluoro-5-methoxybenzoic acid were added 20 ml of methanol, 20 ml of ethyl acetate and 50 mg of 10% palladium-carbon, and the mixture was stirred at room temperature for 4 hours under the hydrogen atmosphere. Thereafter, the reaction mixture was filtered through Celite (registered trade mark). The filtrate was concentrated under reduced pressure, and 4.5 g of 3-fluoro-4-hydroxy-5-methoxybenzoic acid was obtained.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[O:5]=[C:6]1[NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]2[CH2:17][CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH:8]2[CH2:7]1.O>C(O)(=O)C>[N+:1]([C:14]1[CH:15]=[CH:16][C:10]2[N:9]3[CH2:17][CH2:18][N:19]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:20][CH:8]3[CH2:7][C:6](=[O:5])[NH:12][C:11]=2[CH:13]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)OC(=O)N1CCN2c3ccccc3NC(=O)CC2C1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN2c3ccc([N+](=O)[O-])cc3NC(=O)CC2C1
Reaction time: 3 h

Procedure:
Nitric acid (65% solution, 0.20 mL, 3.2 mmol) was added to a solution of Example 1C (1.0 g, 3.2 mmol) in acetic acid (5 mL) at room temperature. The solution was stirred for 3 hours, and then the reaction mixture was poured into water (200 mL). The precipitate was collected by filtration from the aqueous solution to afford the title compound. 1H NMR (300 MHz, DMSO-d6) d ppm 8.00 (dd, J=8.92, 2.58 Hz, 1 H), 7.79 (d, J=2.78 Hz, 1 H), 7.24 (d, J=9.12 Hz, 1 H), 3.86-4.10 (m, 2 H), 3.36-3.50 (m, 1 H), 3.20-3.29 (m, 1 H), 2.81-2.99 (m, 1 H), 2.62-2.77 (m, 1 H), 2.18 (d, J=13.48 Hz, 1 H); MS (APCI+) m/z 307 (M+H-tBu)+.
Reaction SMILES: [C:1]([CH2:14][C:15]([CH2:18][CH2:19][S:20](Cl)(=[O:22])=[O:21])([F:17])[F:16])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[CH3:24][N:25]([CH2:27][CH2:28][CH2:29][NH2:30])[CH3:26]>>[C:1]([CH2:14][C:15]([CH2:18][CH2:19][S:20]([NH:30][CH2:29][CH2:28][CH2:27][N:25]([CH3:26])[CH3:24])(=[O:22])=[O:21])([F:17])[F:16])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: O=S(=O)(Cl)CCC(F)(F)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CN(C)CCCN
Product: CN(C)CCCNS(=O)(=O)CCC(F)(F)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 75 °C
Yield: 96.8 %

Procedure:
C4F9CH2CF2CH2CH2SO2Cl (100 g, 0.23 mol, 70.3% in toluene) was added dropwise to a mixture of dimethylaminopropylamine (DMAPA) at 45° C. After the addition, the reaction was heated at 75° C. overnight. The reaction mass was filtered and the wet cake was washed with 60° C. toluene. After stripping off the toluene, the concentrated organic product was washed with 200 mL of 95° C. deionized water. The product Intermediate 2, C4F9CH2CF2CH2CH2SO2N(H)—CH2CH2CH2N(CH3)2 (106 g, 96.8%) was obtained as a brown colored solids after removing water under reduced pressure.
Reaction SMILES: COC1C=CC(C([O:22][C@@H:23]2[C:27]([CH2:30][OH:31])([CH2:28][OH:29])[O:26][C@@H:25]([N:32]3[CH:40]=[C:38]([CH3:39])[C:36](=[O:37])[NH:35][C:33]3=[O:34])[CH2:24]2)(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1>C(O)(=O)C.O>[OH:29][CH2:28][C:27]1([CH2:30][OH:31])[O:26][C@@H:25]([N:32]2[CH:40]=[C:38]([CH3:39])[C:36](=[O:37])[NH:35][C:33]2=[O:34])[CH2:24][C@@H:23]1[OH:22]
Reactant: COc1ccc(C(O[C@H]2C[C@H](n3cc(C)c(=O)[nH]c3=O)OC2(CO)CO)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1cn([C@H]2C[C@H](O)C(CO)(CO)O2)c(=O)[nH]c1=O
Yield: 90.8 %

Procedure:
A solution of 3′-O-(4,4′-dimethoxytrityl)-4′-C-hydroxymethylthymidine (6.32 g, 11.o mmol) in 80% acetic acid in water (50 ml) stood at room temperature fro 4 h. Solvents were removed under reduced pressure and water (200 ml) added. The resulting cloudy mixture was washed with ether (3×80 ml) and water was evaporated. The residue was dissolved in methanol and toluene and the resulting solution was concentrated. This process was repeated twice. 4′-C-hydroxymethylthymidine (2.72 g, 91%) was obtained as a foam.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)=[O:8])[CH2:3][CH2:2]1.[NH2:18][C@@H:19]1[CH2:28][CH2:27][C:26]2[C:21](=[C:22]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[CH:23]=[CH:24][CH:25]=2)[CH2:20]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:35][N:32]1[CH2:33][CH2:34][N:29]([C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[C:21]=2[CH2:20][C@H:19]([NH:18][C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[O:8])=[CH:17][CH:16]=2)[CH2:28][CH2:27]3)[CH2:30][CH2:31]1
Reactant: O=C(O)c1ccc(C(=O)N2CCOCC2)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(C(=O)N4CCOCC4)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Morpholinocarbonylbenzoic acid (130 mg, 0.54 mmol; described in: J. Med Chem. 1994, 37(26), 4538-4554) was dissolved in thionyl chloride (5 mL). When the acid was dissolved, the excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. The crude acid chloride was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazine-1-yl)-1,2,3,4-tetrahydronaphthalene (120 mg, 0.49 mmol) and triethylamine (100 μL, 0.73 mmol) in methylene chloride (20 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using using chloroform/methanol/concentrated ammonium hydroxide (95:4:0.5) as the eluent. Yield: 160 mg (72%) of the title compound as white crystals: mp 124-127° C.; [α]21D −40° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 462 (2, M+).
Reaction SMILES: [CH:1]1([C@H:7]([NH:12][C:13]([C@@H:15]([NH:20][C:21]([C@@H:23]2[CH2:28][C@@H:27]3[CH2:29][C@H:24]2[C:25](=[O:30])[O:26]3)=[O:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:8]([NH:10][CH3:11])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl.[CH2:34]([O:36][C:37]([C:39]1([NH2:44])[CH2:41][CH:40]1[CH:42]=[CH2:43])=[O:38])[CH3:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCOCC1.O>[CH2:34]([O:36][C:37]([C@@:39]1([NH:44][C:25]([C@@H:24]2[CH2:29][C@H:27]([OH:26])[CH2:28][C@H:23]2[C:21]([NH:20][C@H:15]([C:13]([NH:12][C@@H:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]([NH:10][CH3:11])=[O:9])=[O:14])[C:16]([CH3:19])([CH3:17])[CH3:18])=[O:22])=[O:30])[CH2:41][CH:40]1[CH:42]=[CH2:43])=[O:38])[CH3:35]
Reactant: C=CC1CC1(N)C(=O)OCC
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H]1C[C@@H]2C[C@H]1C(=O)O2)C(C)(C)C)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C=CC1C[C@]1(NC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)NC)C1CCCCC1)C(C)(C)C)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 83 %

Procedure:
Compound 72 (60 mg, 0.14 mmol) was dissolved in dioxane (3.5 mL) and H2O (2.5 mL) and the solution was cooled to 0° C. LiOH (1 M, 280 □L, 0.28 mmol) was added dropwise during 5 min, after which the reaction mixture was stirred at 0° C. for 40 min. The pH was adjusted to 7 using 1 M HCl, and the solvents were evaporated. The residue was suspended in DMF (5 mL) and 1-amino-2-vinyl-cyclopropanecarboxylic acid ethyl ester (32 mg, 0.17 mmol), and DIEA (146 □L, 0.84 mmol) were added. After cooling to 0° C. HATU (64 mg, 0.17 mmol) was added and the mixture was stirred at 0° C. for 1 h and at rt for 1 h. The solvent was evaporated and the product was purified using flash column chromatography (EtOAc/MeOH 9:1) to give compound 73 (67 mg, 82%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.ON1C2C=CC=CC=2N=N1.[NH2:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][CH2:29][N:30]([CH3:36])[CH2:31]2>CN(C=O)C>[CH3:36][N:30]1[CH2:29][CH2:28][C:27]2[C:32](=[CH:33][CH:34]=[CH:35][C:26]=2[NH:25][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[C:3]([O:13][CH3:14])=[CH:4][C:5]=2[O:11][CH3:12])[CH2:31]1
Reactant: COc1cc(OC)c(C(=O)O)cc1Br
Reactant: CN1CCc2c(N)cccc2C1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc(OC)c(C(=O)Nc2cccc3c2CCN(C)C3)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
5-Bromo-2,4-dimethoxybenzoic acid (0.296 g, 1.1 mmol), 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimide hydrochloride (0.186 g, 0.94 mmol) and 1-hydroxybenzotriazole (0.144 g, 0.94 mmol) were dissolved in dry DMF (10 ml) and stirred at room temperature under argon for 25 mins before 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (0.153 g, 0.94 mmol) was added. The mixture was then stirred overnight under argon at room temperature. The DMF was removed in vacuo and the residue taken up into ethyl acethate and washed with water. The organic layer was dried over magnesium sulfate, concentrated in vacuo and the residue recrystallised from ethyl acethate/hexane to afford the title compound as a solid (0.106 g)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[CH:15]/[C:16]([OH:18])=[O:17])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: COc1ccc(C=O)c([N+](=O)[O-])c1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ccc(/C=C/C(=O)O)c([N+](=O)[O-])c1
Temperature: 125 °C
Yield: 65.2 %

Procedure:
To a mixture of 4-methoxy-2-nitrobenzaldehyde (20 g, 0.11 mol) and malonic acid (28.8 g, 0.28 mol) in pyridine (200 mL) is added piperidine (1 mL, catalytic amount) and the mixture is refluxed at 125° C. under nitrogen for 12 h. After cooling to room temperature, the solvent is removed under reduced pressure and the residue is acidified with 1.5 N HCl. The product is extracted with EtOAc and the organic layer is washed with water and brine then dried over Na2SO4. The solvent is removed under reduced pressure to afford 16 g (65%) of the title compound as a pale brown solid. 1H NMR (DMSO-d6, 400 MHz) δ 12.59 (bs, 1H), 7.91-7.93 (m, 1H), 7.68-7.72 (m, 1H), 7.56 (s, 1H), 7.31-7.33 (m, 1H), 7.46-7.50 (m, 1H), 3.87 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[N:12][C:5]2[NH:6][C:7](=O)[CH2:8][O:9][CH2:10][C:4]=2[CH:3]=1.[BH4-].[Na+].[NH4+].[Cl-].C([O-])(O)=O.[Na+]>C1COCC1>[Br:1][C:2]1[CH:13]=[N:12][C:5]2[NH:6][CH2:7][CH2:8][O:9][CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1COCc2cc(Br)cnc2N1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Brc1cnc2c(c1)COCCN2
Temperature: 0 °C
Reaction time: 3 h
Yield: 40.5 %

Procedure:
3-Bromo-5,9-dihydro-6-oxa-1,9-diaza-benzocyclohepten-8-one (205 mg, 0.84 mmol) and sodium borohydride (160 mg, 4.2 mmol) are dissolved in 1.0 mL of THF and the mixture is cooled down to 0° C. Neat BF3 Et2O (0.74 mL, 5.9 mmol) is added dropwise and the mixture is stirred for 3 hr at room temperature. Then saturated aqueous NH4Cl solution (15 mL) is added carefully and the mixture is further basified by adding solid NaHCO3. The mixture is then extracted with EtOAc (3×35 mL). The organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography affords 78 mg of 3-bromo-5,7,8,9-tetrahydro-6-oxa-1,9-diaza-benzocycloheptene
Reaction SMILES: [F:1][C:2]1[CH:41]=[CH:40][C:5]2[NH:6][C:7]([CH:9]([O:32][CH:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)[C:10]3[CH:11]=[C:12]([C:16]#[C:17][CH2:18][CH2:19][CH2:20][N:21]4C(=O)C5C(=CC=CC=5)C4=O)[CH:13]=[CH:14][CH:15]=3)=[N:8][C:4]=2[CH:3]=1.O.NN.O.[C:46]([OH:51])(=[O:50])[C:47]([OH:49])=[O:48]>C(O)C.CC(C)=O>[C:46]([OH:51])(=[O:50])[C:47]([OH:49])=[O:48].[F:1][C:2]1[CH:41]=[CH:40][C:5]2[NH:6][C:7]([CH:9]([O:32][CH:33]3[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]3)[C:10]3[CH:11]=[C:12]([C:16]#[C:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH:13]=[CH:14][CH:15]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CN1CCC(OC(c2cccc(C#CCCCN3C(=O)c4ccccc4C3=O)c2)c2nc3cc(F)ccc3[nH]2)CC1
Agent: NN
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CC(C)=O
Solvent: CCO
Product: CN1CCC(OC(c2cccc(C#CCCCN)c2)c2nc3cc(F)ccc3[nH]2)CC1

Procedure:
A solution of 2-(5-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)isoindole-1,3-dione (example 438B, 170 mg) and hydrazine hydrate (200 μL) in ethanol (2.5 mL) is stirred a room temperature overnight. Water is added and the aqueous phase is extracted by diethyl ether. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (dichloromethane/methanol/ammonia from 95/5/0.5 to 90/10/1)) to afford the free base. One equivalent of oxalic acid in acetone is added to the free base to afford 5-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine oxalate as a white crystalline solid melting at 150° C.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([CH:9]2[C:14](=O)[CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10]2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][C:24]1[N:25]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH2:38])=[NH:37])=[CH:31][CH:30]=2)[CH:26]=[CH:27][N:28]=1>>[CH:1]1([CH2:6][C:7]2[C:9]3[CH2:10][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:13][C:14]=3[N:38]=[C:36]([NH:35][C:32]3[CH:33]=[CH:34][C:29]([N:25]4[CH:26]=[CH:27][N:28]=[C:24]4[CH3:23])=[CH:30][CH:31]=3)[N:37]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C(=O)CC2CCCC2)C1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(CC4CCCC4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Yield: 39 %

Procedure:
tert-Butyl 4-(cyclopentylmethyl)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (199 mg, 39%) was synthesised from tert-butyl 3-(2-cyclopentylacetyl)-4-oxopiperidine-1-carboxylate and 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine (Example 41c) according to the general procedure for the synthesis of pyrimidines. MS (ES+) m/z 489.1 (M+H)+
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)CB([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)C1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CCCCO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][C:7](=[O:11])[NH:8]3)=[CH:4][CH:3]=2)[CH:21]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CC1(C)CB(c2cccnc2)CC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCCCO
Product: O=C1Cc2ccc(-c3cccnc3)cc2N1
Temperature: 100 °C
Reaction time: 1.65 h
Yield: 79.3 %

Procedure:
A mixture 6-chloroindolin-2-one (100 mg, 0.60 mmol), 3-(3,3,4,4-tetramethylborolan-1-yl)pyridine (184 mg, 0.90 mmol), Pd2dba3 (5.4 mg, 0.0060 mmol) and powdered K3PO4 (252 mg, 1.2 mmol) in n-BuOH (2 mL) was degassed by evacuation and refilling with Ar. Dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (11.4 mg, 0.024 mmol) was added under the atmosphere of Ar. The reaction mixture was sealed and heated with stirring under microwave irradiation at 100° C. for 99 min. Later the reaction was cooled to rt and treated with degassed H2O (0.25 mL). The mixture was reheated under microwave irradiation at 110° C. for 1 h. The crude reaction mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel using MeOH (0 to 6%) in DCM as the eluent to provide the title compound as a pale yellow solid (100 mg, 80%). %). 1H NMR (400 MHz, CD3OD) δ ppm 8.77 (d, J=1.52 Hz, 1H), 8.52 (dd, J4.80, 1.52 Hz, 1H), 8.05-8.10 (m, 1H), 7.52 (dd, J7.33, 4.80 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.30 (dd, J=7.71, 1.39 Hz, 1H), 7.17 (s, 1H), 3.59 (s, 2H); MS ESI 211.0 (100) [M+H]+, calcd for [C13H10N2O+H]+ 211.2.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][CH2:16][C@@H:17]([C:19]([NH:21][CH2:22][C:23]([O:25]C)=O)=[O:20])[NH2:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO.C(N(CC)CC)C>[CH2:8]([O:15][CH2:16][CH:17]1[NH:18][C:23](=[O:25])[CH2:22][NH:21][C:19]1=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)CNC(=O)[C@@H](N)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C1CNC(=O)C(COCc2ccccc2)N1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A 250 ml, round-bottomed flask was charged with methyl O-benzyl-L-serylglycinate trifluoroacetate (9.37 g, 24.64 mmol) and 3:1 MeOH/triethylamine (50 mL). The mixture was then heated to reflux for 16 h. The reaction was then cooled to room temperature, concentrated, and diluted with ice cold 50% aqueous EtOH (50 mL). The resulting precipitate was collected by filtration and dried under reduced pressure to give 3-(benzyloxymethyl)piperazine-2,5-dione (3.95 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([C:8]2[N:13]=[C:12]([CH3:14])[NH:11][C:10](=O)[CH:9]=2)[CH:7]=1.CN(C)C=O.C(Cl)(=O)C([Cl:26])=O>ClCCl.O1CCOCC1>[Cl:26][C:10]1[CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:16][CH3:17])[N:13]=[C:12]([CH3:14])[N:11]=1
Reactant: COc1ccc(Cl)cc1-c1cc(=O)[nH]c(C)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(Cl)cc1-c1cc(Cl)nc(C)n1
Reaction time: 1 h
Yield: 94 %

Procedure:
To a suspension of 6-(5-chloro-2-methoxy-phenyl)-2-methyl-3H-pyrimidin-4-one (520 mg, 2.1 mmol) in dichloromethane (20 ml) and 1,4-dioxane (20 ml) was added N,N-dimethylformamide (0.2 ml) followed by a solution of oxalyl chloride in dichloromethane (2 M, 4.2 ml). After stirring for 1 hour, the mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate solution (60 ml). The organic phase was dried over magnesium sulfate and concentrated under vacuum to give 4-chloro-6-(5-chloro-2-methoxy-phenyl)-2-methyl-pyrimidine (530 mg, 94% yield) as a white powder. 1H NMR (DMSO-d6) δ 2.67 (s, 3H, CH3), 3.91 (s, 3H, CH3), 7.26 (d, 1H, J=9.2 Hz, Ar), 7.59 (dd, 1H, J=8.8 Hz, J=2.6 Hz, Ar), 7.95 (s, 1H, Ar), 7.96 (d, 1H, J=2.9 Hz, Ar).
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]2[N:24]=[C:25]([NH:28][C:29](=[O:31])[CH3:30])[S:26][CH:27]=2)=[CH:17][CH:16]=1)=[O:11])[NH:2]C(OC(C)(C)C)=O.O1CCOCC1.[ClH:38].C(OCC)(=O)C>ClCCl.CO>[ClH:38].[NH:1]([C:10]([O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]2[N:24]=[C:25]([NH:28][C:29](=[O:31])[CH3:30])[S:26][CH:27]=2)=[CH:17][CH:16]=1)=[O:11])[NH2:2]
Reactant: CC(=O)Nc1nc(CCc2ccc(CCOC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(CCc2ccc(CCOC(=O)NN)cc2)cs1
Temperature: 25 °C
Reaction time: 13 h
Yield: 89.3 %

Procedure:
To a suspension of 2-(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)ethyl tert-butyl hydrazine-1,2-dicarboxylate (620.0 mg, 1.382 mmol) in anhydrous dichloromethane (6.9 ml) was added 4M hydrogen chloride dioxane solution (6.9 ml, 27.6 mmol). After stirring at room temperature for 13 hr, the reaction mixture was concentrated under reduced pressure. Dichloromethane was added to the residue, and the mixture was concentrated again under reduced pressure. The operation was performed twice. Ethyl acetate was further added to the residue, and the mixture was concentrated under reduced pressure. This operation was performed 3 times to remove hydrogen chloride gas azeotropically. The residue was dried under reduced pressure to give a crude product (570.4 mg). The crude product was dissolved in methanol (18 ml) and ethyl acetate (144 ml) was added to recrystallize the crude product. The crystals were collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the title compound (474.8 mg, 1.234 mmol, yield 89.3%) as a white solid.