Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH3:11])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]([C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:4]1.[F:22][C:23]([F:36])([C:32]([F:35])([F:34])[F:33])[CH2:24][NH:25][C:26](=[O:31])[CH2:27][C:28](O)=[O:29]>>[CH3:19][C:17]([CH3:18])([CH3:20])[C:16]([N:5]1[CH2:4][C@H:3]([NH:2][C:28](=[O:29])[CH2:27][C:26]([NH:25][CH2:24][C:23]([F:36])([F:22])[C:32]([F:33])([F:35])[F:34])=[O:31])[C:9](=[O:10])[N:8]([CH3:11])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]1=2)=[O:21]
Reactant: O=C(O)CC(=O)NCC(F)(F)C(F)(F)F
Reactant: CN1C(=O)[C@@H](N)CN(C(=O)C(C)(C)C)c2ccccc21
Agent: Cl
Product: CN1C(=O)[C@@H](NC(=O)CC(=O)NCC(F)(F)C(F)(F)F)CN(C(=O)C(C)(C)C)c2ccccc21

Procedure:
In an analogous manner to that described in Example 20 d), the condensation of (S)-3-amino-5-(2,2-dimethyl-propionyl)-1-methyl-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one hydrochloride and N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid yielded the title compound as a white foam;
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.CC[O:10][C:11]([CH:13]([C:17]([CH3:19])=O)[C:14]([CH3:16])=O)=[O:12]>C(O)(=O)C>[CH3:7][C:5]1[CH:6]=[C:2]2[N:1]=[C:14]([CH3:16])[C:13]([C:11]([OH:12])=[O:10])=[C:17]([CH3:19])[N:3]2[N:4]=1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: Cc1cc(N)n[nH]1
Solvent: CC(=O)O
Product: Cc1cc2nc(C)c(C(=O)O)c(C)n2n1
Temperature: 120 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
3-Amino-5-methylpyrazole (970 mg) and ethyl diacetoacetate (1.7 g) were dissolved in acetic acid (5 ml) and stirred at 120° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Ethanol (5 ml) and 5 N sodium hydroxide solution (2 ml) were added to the residue and stirred at 70° C. for 1 hour. The reaction mixture was cooled to room temperature, and water was added to the reaction mixture which was then washed with ethyl acetate. 2 N Hydrochloric acid was added to the aqueous phase until it became acidic, and precipitated crystals were collected by filtration and washed with water and n-hexane. The crystals were dried under reduced pressure to give the title compound (1.6 g, Y.:80%) as white crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:13])([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:14].O1CCCC1.C([Li])CCC.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>CCCCCC>[CH2:9]([C:8]([C:5]1[CH:6]=[CH:7][C:2]([B:25]([OH:30])[OH:26])=[C:3]([CH3:14])[CH:4]=1)([OH:13])[CH2:11][CH3:12])[CH3:10]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCC(O)(CC)c1ccc(Br)c(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(O)(CC)c1ccc(B(O)O)c(C)c1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
In a three-necked flask, introduce under nitrogen 5 g of 3-(4-bromo-3-methylphenyl)pentan-3-ol (19.4 mmol) and 50 cm3 of tetrahydrofuran. Cool the mixture to −70° C. and add dropwise 23.3 cm3 (58 mmol) of a 2.5M solution of n-butyllithium in hexane, over 30 minutes. Leave the mixture for approximately 2 h with stirring at −70° C. and then add dropwise 13.5 cm3 of triisopropyl borate (58 mmol), over 20 minutes. Leave the mixture with stirring for 3 h, allowing the temperature to increase to −10° C. Hydrolyse the mixture with saturated NH4Cl solution and extract two times with ethyl acetate. Wash the combined organic phases with saturated sodium chloride solution and dry them over sodium sulfate. Evaporate the solvents under vacuum. This gives 5 g of a colorless oil, which is chromatographed on silica gel (heptane/ethyl acetate=9/1) to give 4-(1-ethyl-1-hydroxypropyl)-2-methylphenylboronic acid in the form of a highly viscous oil. (Yield=71%)
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11](Br)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[CH3:27][C:28]1[O:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11]([C:31]2[O:32][C:28]([CH3:27])=[CH:29][CH:30]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)nc1
Reactant: Cc1ccc(B(O)O)o1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2ccc(C)o2)nc1

Procedure:
By carrying out the operation analogously to example 1, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 5-methyl-2-furanboronic acid, the desired product is obtained in the form of an ecru solid (yield=74%).
Reaction SMILES: [C:1]1([CH:7]([CH2:12][C:13](O)=[O:14])[CH2:8][C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCCC1>[C:1]1([CH:7]([CH2:8][CH2:9][OH:10])[CH2:12][CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(CC(=O)O)c1ccccc1
Solvent: C1CCOC1
Product: OCCC(CCO)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
3-Phenylglutaric acid (3.39 g, 16.3 mmol) was dissolved in tetrahydrofuran (163 mL) and cooled to 0° C. A 1.0 M tetrahydrofuran solution of borane tetrahydrofuran complex (65 mL, 65 mmol) was added dropwise, and the reaction was allowed to warm to room temperature overnight. The reaction was cooled to 0° C., quenched with methanol slowly, followed by water, and concentrated in vacuo. The resulting solid was stirred with 1N hydrochloric acid for 20 minutes. The solution was extracted into ethyl acetate. The combined organic layers were dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate to give the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 1.75-1.86 (m, 2H), 1.86-1.96 (m, 2H), 2.45 (br s, 2H), 2.87-2.95 (m, 1H), 3.39-3.48 (m, 2H), 3.49-3.57 (m, 2H), 7.15-7.22 (m, 3H), 7.25-7.31 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Cl)=[CH:4][CH:3]=1.Br[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]2[CH:18]=[CH:17][CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(Br)c1
Reactant: Cc1ccc([Mg]Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(C#N)c2)cc1
Yield: 89 %

Procedure:
4-methylphenylmagnesium chloride (49 g, 20% solution in tetrahydrofuran) is added dropwise over eight hours to a refluxing solution of 3-bromobenzonitrile (10 g), palladium (II) acetate (2.4 g) and triphenylphosphine (5.8 g) in tetrahydrofuran (200 ml). [HPLC: yield 89-91%]. After cooling to room temperature tetrahydrofuran is removed under vacuum. The residue is taken up in toluene/water (3:1) (200 ml ) and the aqueous phase separated off. The solvent is removed by distillation and the crude product purified by column chromatrography (Kieselgel 60; n-hezane/acetone 3:1) to give 4'-methylbiphenyl-3-carbonitrile as a solid, m.pt. 59-61° C. 1H NMR (CDCl3): 2.41(s,3H), 7.29(d,2H), 7.46(d,2H), 7.49-7.63(m,2H) 7.77-7.85(m,2H).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9])(=[O:3])[CH3:2].S(Cl)([Cl:13])(=O)=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:1]([N:4]1[CH2:8][CH:7]([Cl:13])[O:6][C:5]1=[O:9])(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)N1CCOC1=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)N1CC(Cl)OC1=O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
5.00 g of 3-acetyloxazolidin-2-one were initially charged in 25 ml of carbon tetrachloride and heated to 70° C. under an argon atmosphere. Then, alternately, a solution of 3.46 ml of sulfuryl chloride in 5 ml of carbon tetrachloride and 0.10 g of 2,2′-azobis(2-methylpropionitrile) were added, and then the mixture was stirred at the same temperature for 2 hours. After cooling to room temperature, the clear solution was decanted off from the solid residues, and the solvent was removed under reduced pressure. This gave the product (6.80 g) with a molecular weight of 163.6 g/mol (C5H6ClNO3).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:10]([CH3:21])[C:9]=3[O:22][C:4]=2[CH:3]=1.[I:23]C1C=CC2OC3C(C)NCCC=3C=2C=1>>[I:23][C:7]1[CH:2]=[CH:3][C:4]2[O:22][C:9]3[CH:10]([CH3:21])[N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:12][CH2:13][C:8]=3[C:5]=2[CH:6]=1
Reactant: CC1c2oc3cc(I)ccc3c2CCN1C(=O)OC(C)(C)C
Reactant: CC1NCCc2c1oc1ccc(I)cc21
Product: CC1c2oc3ccc(I)cc3c2CCN1C(=O)OC(C)(C)C

Procedure:
Synthesized as described for tert-butyl 7-iodo-1-methyl-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate starting from 6-iodo-1-methyl-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine. MS m/z 414 [M+H]+. 1H-NMR (400 MHz, CDCl3): δ 1.47 (d, J=6.8 Hz, 3H), 1.51 (s, 9H), 2.57 (m, 1H), 2.71 (m, 1H), 3.05 (m, 1H), 4.38 (m, 1H), 5.21 (m, 1H), 7.20 (d, J=8.6 Hz, 1H), 7.51 (dd, J=8.6, 1.8 Hz, 1H), 7.76 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C[Al](C)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH2:21][CH2:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: C1COCCN1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1C
Agent: C[Al](C)C
Product: Cc1cc(F)ccc1-c1nc(N2CCOCC2)nc2c1CCC(=O)N2c1ccccc1C

Procedure:
Following the general procedure outlined in Example 193, the product of Example 121 (100 mg, 0.22 mmol), morpholine (58 mg, 0.66 mmol) and trimethylaluminum (0.33 mL, 0.66 mmol) were reacted to give the desired product, 61 mg (64%). LC-MS: 431.2 (MH+, m/z), 2.46 (Rt, min).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[C:14]([OH:25])(=O)[CH2:15][CH2:16][S:17][S:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]>C(C(C)=O)C(C)C>[C:21]([O:23][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH2:6])(=[O:22])[CH2:20][CH2:19][S:18][S:17][CH2:16][CH2:15][C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH2:6])=[O:25]
Reactant: NCCCCCCO
Reactant: O=C(O)CCSSCCC(=O)O
Agent: CS(=O)(=O)O
Solvent: CC(=O)CC(C)C
Product: NCCCCCCOC(=O)CCSSCCC(=O)OCCCCCCN
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
2.0 g of methanesulfonic acid (manufactured by Wako Pure Chemical Industries, Ltd.) was added dropwise, under an atmosphere of nitrogen and at 70° C., to 2.3 g of 6-amino-1-hexanol (manufactured by Tokyo Chemical Industry Co., Ltd.). After stirring for 10 minutes, 2.1 g of 3,3′-dithiodipropionic acid (manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the resulting mixture was heated to 120° C. and then stirred at 110° C. for 3 hours. Following completion of the reaction, the reaction mixture was cooled to room temperature and then added gradually to 50 mL of methyl isobutyl ketone (manufactured by Wako Pure Chemical Industries, Ltd.). After stirring for 2 hours, the precipitated crystals were collected by vacuum filtration and washed with acetone, yielding the methanesulfonate salt of di(6-aminohexyl) 3,3′-dithiodipropionate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]2=[N:14][C:15]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[N:17]=[C:12]2[CH2:11][CH:10](OC(=O)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>O>[N:36]1([CH:10]2[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:13]3=[N:14][C:15]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=4)=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=4)[N:17]=[C:12]3[CH2:11]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: C1CCNCC1
Reactant: CC(=O)OC1Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2N(C(=O)OC(C)(C)C)C1
Solvent: O
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(C(=O)OC(C)(C)C)CC(N2CCCCC2)C3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl-7-acetoxy-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (step 5)(210 mg, 0.443 mmol) was treated with piperidine (4380 μl, 44.3 mmol). The resulting pale yellow suspension was sonicated and then stirred at room temperature overnight. The resulting solution was added to water (100 ml) and extracted with DCM (×3), passing the organic extracts through a phase separating column. The filtrate was concentrated under reduced pressure and purification of the crude material by chromatography on silica eluting with 0-40% EtOAc in iso-hexane afforded the titled compound;
Reaction SMILES: [O:1]([CH:8]([CH3:12])[C:9](=O)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.Cl.[NH2:17][OH:18]>O>[O:1]([CH:8]([CH3:12])[C:9](=[N:17][OH:18])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(C)Oc1ccccc1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(=NO)C(C)Oc1ccccc1

Procedure:
3-Phenoxybutan-2-one (69.6 g.) and ethanol (300 ml.) were added to a solution of hydroxylamine hydrochloride (70 g.) and fused sodium acetate (70 g.) in water (130 ml.). The resulting solution was refluxed for 31/2 hours and evaporated to near dryness under reduced pressure. The residue was partitioned between water and ether. The ether extract was washed with water, dried over anhydrous potassium carbonate and evaporated. The residue was distilled to give a fraction, b.p. 154°-155°/14 mm. which crystallised. Recrystallisation from petroleum ether (b.p. 60°-80°) gave pure 3-phenoxybutan-2-one oxime, m.p. 65°-67°.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1OC)[N:9]=[CH:8][N:7]=C2OC1C=C(C=CC=1)N.C1(N=C=[O:31])C=CC=CC=1>C1COCC1>[C:10]1([NH:9][C:8](=[O:31])[NH2:7])[CH:5]=[CH:4][CH:3]=[CH:12][CH:11]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Product: NC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg, 0.3 mmol) in THF (3 mL) was added phenyl isocyanate (33 uL, 0.3 mmol) and the solution stirred at room temperature overnight. The reaction was concentrated in vacuo, diluted with EtOAc, and filtered to give 14346,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-phenylurea (63 mg, 0.15 mmol, 50%). 1H NMR (300 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.74 (s, 1H), 8.57 (s, 1H), 7.61-7.56 (m, 2H), 7.48-7.35 (m, 4H), 7.32-7.21 (m, 3H), 7.02-7.89 (m, 2H), 3.99 (s, 6H); LC-MS (ESI) m/z 417 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)=[N:4][N:3]=1.[CH2:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][NH:37][C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:26][CH2:25]1)[CH3:23]>>[CH2:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][N:37]([C:19]([C:16]5[CH:15]=[CH:14][C:13]([C:10]6[CH:11]=[CH:12][C:7]([C:5]7[O:6][C:2]([CH3:1])=[N:3][N:4]=7)=[CH:8][CH:9]=6)=[CH:18][CH:17]=5)=[O:20])[C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:26][CH2:25]1)[CH3:23]
Reactant: CCN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reactant: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3)cc2)o1
Product: CCN1CCC2(CC1)COc1cc3c(cc12)N(C(=O)c1ccc(-c2ccc(-c4nnc(C)o4)cc2)cc1)CC3
Yield: 31 %

Procedure:
The title compound was prepared from 4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-carboxylic acid (D11) and 1'-ethyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D109) using a similar procedure as that outlined in Example 1, to afford the title compound as a yellow gum (31%). This was converted to its hydrochloride salt to yield an off white solid m.p. 245-249° C.
Reaction SMILES: Cl.Cl.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][N:21]4[CH:25]=[CH:24][N:23]=[N:22]4)[O:17][C:16]3=[O:26])=[CH:11][C:10]=2[F:27])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:35][CH2:36][C:37](Cl)=[O:38]>ClCCl>[Cl:35][CH2:36][C:37]([N:6]1[CH2:5][CH2:4][N:3]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][N:21]4[CH:25]=[CH:24][N:23]=[N:22]4)[O:17][C:16]3=[O:26])=[CH:11][C:10]=2[F:27])[CH2:8][CH2:7]1)=[O:38]
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(N2CCNCC2)c(F)c1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)CC1
Reaction time: 0.25 h
Yield: 67.7 %

Procedure:
(5R)-3-(4-(piperazin-1-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one dihydrochloride (4.19 g, 10 mM) was suspended in dry dichloromethane (100 ml) under nitrogen and treated with triethylamine (3.03 g, 30 mM) to give a solution. After cooling to 4°, chloroacetyl chloride (1.14 g, 10 mM) was added and the mixture stirred for 15 minutes. The volume was reduced to 20 ml, and the solution chromatographed on silica, eluting with dichloromethane (30 ml). Relevant fractions were combined, washed with water (50 ml) and dried (magnesium sulfate). Evaporation gave the desired product (2.86 g).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]1[CH:11]1[CH2:15][C:14](=[O:16])[O:13][C:12]1=O.[CH3:18][NH2:19]>O>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]1[CH:11]1[CH2:15][C:14](=[O:16])[N:19]([CH3:18])[C:12]1=[O:13]
Reactant: O=C1CC(C2C=Cc3ccccc3C2)C(=O)O1
Reactant: CN
Solvent: O
Product: CN1C(=O)CC(C2C=Cc3ccccc3C2)C1=O

Procedure:
60 g of the above anhydride is added portionwise to a stirred 500 ml portion of aqueous methylamine. After addition is complete, the mixture is heated to boil off water and excess amine, ultimately to 210°-220° to complete the cyclization and form the title A compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[I:1][C:2]1[CH:3]=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)[CH:6]=1
Reactant: Ic1cn[nH]c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2cc(I)cn2)nc1
Temperature: 80 °C
Yield: 100.1 %

Procedure:
A mixture of the 4-iodo-1H-pyrazole (4.59 g, 23.7 mmol) and 2-chloro-5-nitropyridine (3.75 g, 23.7 mmol) in N,N-dimethylformamide (11.8 ml) was treated with potassium carbonate (3.76 g, 27.2 mmol). The mixture was heated to 80° C. for 12 hours. The reaction mixture was diluted with excess water resulting in the precipitation of a solid that was collected by filtration. Further drying in vacuo afforded the product (7.5 g, 100%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 9.27 (d, J=2.3 Hz, 1H), 8.70 (s, 1H), 8.62 (dd, J=9.0, 2.5 Hz, 1H), 8.12 (d, J=9.0 Hz, 1H), 7.80 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:3]([CH:17]2[CH2:20][CH2:19][CH2:18]2)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[N:7]=1.[OH-].[Na+].[O:23]1CCOCC1>O>[CH:17]1([C:3]2[C:2](=[O:23])[NH:7][N:6]3[C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: C1COCCO1
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]n2c(-c3ccccc3)nnc2cc1C1CCC1

Procedure:
6-Chloro-7-cyclobutyl-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (2.0 g, 7.0 mmol), 2 N NaOH (50 ml) and 1,4-dioxane (10 ml) were heated at reflux for 16 hours. Cooled and water (150 ml) added. Precipitate filtered, suspended in H2O, acidified (2 N HCl), filtered and dried to give a white solid. 1H NMR (250 MHz, CDCl3) δ1.89-2.02 (1 H, m), 2.08-2.25 (3 H, m), 2.36-2.48 (1 H, m), 3.56-3.70 (1 H, m), 7.48-7.60 (3 H, m), 7.88 (1 H, s), 8.38 (1 H, m). Mass spec ES+ (M+1)=267.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[CH3:15][O:16][CH2:17][CH2:18][NH2:19]>O>[Cl:8][C:6]1[CH:7]=[C:2]([NH:19][CH2:18][CH2:17][O:16][CH3:15])[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=1
Reactant: COCCN
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Solvent: O
Product: COCCNc1cc(Cl)nc(-c2ccccc2)n1

Procedure:
Seven grams of 4,6-dichloro-2-phenylpyrimidine is added in small portions to 30 ml. of β-methoxyethylamine with slight warming and stirring. The resulting mixture is heated on a steam bath for several minutes and then poured into 500 ml. of water. The product thus obtained (5.1 g.) is recrystallized from n-heptane to afford 4-chloro-6-(2-methoxyethylamino)-2-phenylpyrimidine, 48.5°-50°C.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:14][C@@H:13]2[C@@H:8]([S:9][C:10]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:11]=3[N:12]2[CH2:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C@@H:7]([O:27]C(=O)C)[C@@H:6]1[O:31]C(=O)C)=[N+:2]=[N-:3]>N>[N:1]([CH2:4][C@H:5]1[O:14][C@@H:13]2[C@@H:8]([S:9][C:10]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:11]=3[N:12]2[CH2:15][CH2:16][N:17]([CH2:18][CH3:19])[CH2:20][CH3:21])[C@@H:7]([OH:27])[C@@H:6]1[OH:31])=[N+:2]=[N-:3]
Reactant: CCN(CC)CCN1c2cc(Cl)ccc2S[C@H]2[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](CN=[N+]=[N-])O[C@H]21
Agent: N
Product: CCN(CC)CCN1c2cc(Cl)ccc2S[C@H]2[C@@H](O)[C@H](O)[C@@H](CN=[N+]=[N-])O[C@H]21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The compound (37) 10.1 g obtained in Example 36 was dissolved in 250 ml of ammonia-saturated methanol, and the solution was stirred for 6 hours at room temperature. The solvent was removed under reduced pressure to obtain the title compound quantitatively.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[NH2:5][CH2:6][CH2:7][C:8]1[C:9](=[N:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[NH:10][C:11](=[O:26])[N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([O:24][CH3:25])=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]=12.[OH-].[Na+]>O.Cl>[C:2]([N:10]1[C:9](=[N:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[C:8]([CH2:7][CH2:6][NH2:5])=[C:13]2[C:14]3[C:19]([CH2:20][CH2:21][N:12]2[C:11]1=[O:26])=[CH:18][C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)(=[O:1])[NH2:3]
Reactant: COc1cc2c(cc1OC)-c1c(CCN)c(=Nc3ccccc3C)[nH]c(=O)n1CC2
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c(cc1OC)-c1c(CCN)c(=Nc3ccccc3C)n(C(N)=O)c(=O)n1CC2
Temperature: 80 °C
Reaction time: 3 h
Yield: 45.4 %

Procedure:
Sodium cyanate (0.64 g, 9.8 mmol) in water (13 ml) was added dropwise to a stirred solution of amine 3 (2 g, 4.9 mmol) in water (63 ml) and 1M HCl (9.8 ml) at 80° C. After stirring for 3 h at 80° C. the mixture was cooled and basified with 2M NaOH. The mixture was extracted with CH2Cl2 until no more product remained in the organic phase. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography [dichloromethane/methanol (97:3)] and the product triturated with ether to afford the title compound (1.0 g, 45%) as a pale yellow solid.
Reaction SMILES: C([O:8][C:9]([C:11]1[N:12]=[C:13]([C:29](=[O:33])[N:30]([CH3:32])[CH3:31])[C:14]2[C:19]([C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])C1C=CC=CC=1.[OH-].[K+]>CCO>[CH2:22]([O:21][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:29](=[O:33])[N:30]([CH3:32])[CH3:31])=[N:12][C:11]=1[C:9]([OH:10])=[O:8])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN(C)C(=O)c1nc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)C(=O)c1nc(C(=O)O)c(OCc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
A mixture of 4-benzyloxy-1-dimethylcarbamoyl-isoquinoline-3-carboxylic acid benzyl ester (308 mg, 0.7 mmol), KOH (325 mg, 5 mmol) and EtOH (10 ml) was stirred at ambient temperature for 18 h before the solvent was evaporated in vacuo. To the residue was added water (25 ml) and the mixture was washed with Et2O (2×25 ml). Then the solution was acidified by addition of aqueous 6N HCl and extracted with EtOAc (2×25 ml). The combined organic phases were dried over MgSO4 and concentrated in vacuo to give the title compound as a yellowish gum (220 mg); MS-(+)-ion: M+1=351.0.