Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:27])[N:16]([CH3:26])[C:17]3[C:22]([C:23]=2[O:24][CH3:25])=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:30]=1[C:31](O)=[O:32]>>[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:30]=1[C:31]([NH:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:27])[N:16]([CH3:26])[C:17]3[C:22]([C:23]=2[O:24][CH3:25])=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4])=[O:32]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(OC)c3ccccc3n(C)c2=O)cc1
Reactant: Cc1cccc(Cl)c1C(=O)O
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)c3ccccc3n(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl

Procedure:
The compound obtained as an intermediate in Process 3 of Example 6, that is, methyl (2S)-2-amino-3-[4-(4-methoxy-1-methyl-2-oxo-1,2-dihydro-3-quinolinyl)phenyl]propionate (50 mg) was acylated with 2-chloro-6-methylbenzoic acid by the same procedure as that of Process 1 of Example 17 to obtain methyl (2S)-2-[(2-chloro-6-methylbenzoyl)amino]-3-[4-(4-methoxy-1-methyl-2-oxo-1,2-dihydro-3-quinolinyl)phenyl]propionate (38 mg).
Reaction SMILES: C[O:2][C:3](=[O:14])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH:6]=1.O.[OH-].[Li+].CO.Cl>O1CCCC1.O.C(OCC)C.CCCCCCC>[O:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:5]([CH2:4][C:3]([OH:14])=[O:2])=[CH:6]1
Reactant: COC(=O)Cc1coc2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)Cc1coc2ccccc12
Reaction time: 8 h

Procedure:
A solution of Example 6 (6.23 g, 33 mmol) and lithium hydroxide monohydrate (1.45 g, 35 mmol) in tetrahydrofuran (50 mL), water (35 mL), and methanol (14 mL) was stirred for 6.5 hours at room temperature. Water (70 mL) was added, and the reaction mixture was acidified to pH 4 using 2 M HCl and extracted with dichloromethane (5×200 mL). The organics were dried (MgSO4) and the solvent removed in vacuo to give a brown solid. This was dissolved in diethyl ether, heptane was added, and the mixture was stirred overnight. Solvent was removed by syringe to give product as a pale brown solid, 27 mmol, 80%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.N1C=CC=CC=1.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@:4]([CH2:3][CH2:2][NH:1][C:40](=[O:42])[CH3:41])([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:18][CH:17]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCN)(c2ccc(F)cc2)OC1=O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NCC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
To a solution of (R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (120 mg, 0.264 mmol) and pyridine (41 mg, 0.528 mmol) in anhydrous CH2Cl2 (5 mL) was dropwise added acetic anhydride (30 mg, 0.291 mmol) in anhydrous CH2Cl2 (5 mL) at 0° C. under nitrogen. The above mixture was allowed to stir for overnight at ambient temperature. The mixture was diluted with CH2Cl2 and washed with water. The organic layer was dried over Na2SO4 and concentrate to give the crude product, which was purified by preparative TLC to give N-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)acetamide (60 mg, 46%).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:15]([C:26]2[N:27]=[N:28][N:29]([CH3:31])[N:30]=2)[CH:14]=1)[CH2:4][CH2:5][CH3:6].C=O.O.[C:42](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[ClH:1].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:32][CH:33]2[CH2:38][CH2:37][N:36]([CH3:42])[CH2:35][CH2:34]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[C:15]([C:26]2[N:27]=[N:28][N:29]([CH3:31])[N:30]=2)[CH:14]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(-c2nnn(C)n2)c1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2nnn(C)n2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 158.2 %

Procedure:
To a solution of 3-butyl-4-[4-cyclohexyloxy-3-(2-methyl-2H-tetrazol-5-yl)-phenyl]-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.09 mmol, 50.6 mg) in DCM (1 mL) was added formaldehyde solution in water (37%, 0.27 mmol, 0.020 mL) and 1 drop of acetic acid. Sodium triacetoxyborohydride (0.36 mmol, 80.3 mg, 95%) was added. The reaction mixture was stirred at room temperature for 1.5 h and partitioned between ethyl acetate (10 mL) and saturated aq. sodium bicarbonate solution (10 mL). The ethyl acetate layer was separated and dried over sodium sulfate. The crude product was purified by column chromatography on silica gel using 2 M ammonia in MeOH/DCM 1:19 to 1:14, dissolved in MeOH and treated with 4 N HCl in dioxane. The organic solvents were removed in vacuo and the residue was triturated with anhydrous diethyl ether. The light yellow solid was dried overnight under high vacuum to provide the title compound (41.2 mg). LCMS: m/z 508 [M+1] 1H NMR (400 MHz, CD3OD) δ 8.00 and 8.03 (1H, d), 7.77-7.86 (1H, m), 7.63-7.69 (1H, m), 7.39-7.43 (1H, m), 5.38-5.56 (1H, m), 4.65-4.68 (1H, m), 4.44 and 4.44 (3H, s), 3.13-3.69 (6H, m), 2.94 (3H, s), 1.29-2.58 (18H, m), 0.82 (3H, t).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[BH4-].[Na+]>C(O)(C)C>[CH3:1][N:2]([CH3:17])[C:3]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccc(Cl)cc2)CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CN(C)C1(c2ccc(Cl)cc2)CCC(O)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A suspension of 4.0 g. (0.016 mole) of 4-dimethylamino-4-(p-chlorophenyl)cyclohexanone in 60 ml. 95% isopropanol is warmed to dissolve the solid. Sodium borohydride (0.61 g.) is then added and the mixture stirred at room temperature for six hours. The bulk of the solvent is then removed in vacuum. The residue is taken up in water and methylene chloride. The organic layer is washed with water and brine and taken to dryness. The residual solid is recrystallized twice from acetone to afford 1.21 g. (30%) of product, melting point 148°-150.5° C.
Reaction SMILES: [Si]([O:8][C@@H:9]([CH3:42])[C@@H:10]([NH:31][C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([Cl:40])[C:33]=1[CH3:41])[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([O:23][Si](C(C)(C)C)(C)C)[CH:17]=2)=[N:14][N:15]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[NH4+].[Cl-]>C1COCC1>[Cl:40][C:34]1[C:33]([CH3:41])=[C:32]([NH:31][C@@H:10]([C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([OH:23])[CH:17]=3)=[N:14][N:15]=2)[C@@H:9]([OH:8])[CH3:42])[CH:39]=[CH:38][C:35]=1[C:36]#[N:37]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(F)c(O[Si](C)(C)C(C)(C)C)c3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(F)c(O)c3)o2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: -55 °C
Yield: 90.6 %

Procedure:
4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(3-(tert-butyldimethylsilyloxy)-4-fluorophenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-chloro-3-methylbenzonitrile (400 mg, 0.63 mmol) was dissolved in THF (10 mL) and cooled to −55° C. under N2 atmosphere. TBAF (1.0M solution in THF, 1.52 mL, 1.52 mmol) was added to the pre-cooled solution slowly and the temperature allowed to rise gradually. After the reaction was complete, sat. NH4Cl (200 mL) was added and the mixture was extracted with EtOAc (3×100 mL). Purification by flash chromatography over silica gel provided the desired product (230 mg). Mp 103-108° C., 1H NMR (500 MHz, acetone-d6, δ in ppm): 7.64 (d, J=9 Hz, 1H), 7.49 (m, 1H), 7.30 (t, J=9 Hz, 1H), 6.86 (d, J=9 Hz, 1H), 5.69 (d, J=9 Hz, 1H), 5.09 (m, 1H), 4.60 (m, 1H), 2.40 (s, 3H), 1.40 (d, J=6 Hz, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([CH2:16][CH2:17][O:18][CH2:19]CC)[C:6]1[C:11]([CH2:12]C)=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:14][CH3:15])=[O:4].Cl[C:23]1C=C(NC(=O)CC)C=CC=1Cl.ClC1C=C(NC(=O)C(C)=C)C=CC=1Cl.ClC1C=C(NC(=O)C(C)CCC)C=CC=1C.ClC1C=C(NC(=O)C(C)(C)C)C=CC=1Cl.C(N(C1C=CC=CC=1)C(=O)CCl)(C)C.C(OCN(C1C(CC)=CC=CC=1CC)C(=O)CCl)CCC.COCN(C1C(CC)=CC=CC=1CC)C(=O)CCl>>[Cl:1][CH2:2][C:3]([N:5]([C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:14][CH3:15])[CH:16]([CH3:23])[CH2:17][O:18][CH3:19])=[O:4]
Reactant: CCC(=O)Nc1ccc(Cl)c(Cl)c1
Reactant: CCCOCCN(C(=O)CCl)c1c(CC)cccc1CC
Agent: C=C(C)C(=O)Nc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)C(=O)Nc1ccc(Cl)c(Cl)c1
Agent: CC(C)N(C(=O)CCl)c1ccccc1
Product: CCc1cccc(C)c1N(C(=O)CCl)C(C)COC

Procedure:
2-chloro-2',6'-diethyl-N-(2-propyloxyethyl)acetanilide; N-(3,4-dichlorophenyl)propionamide; N-(3,4-dichlorophenyl)methacrylamide; N-(3-chloro-4-methylphenyl)-2-methylpentanamide; N-(3,4-dichlorophenyl)trimethylacetamide; N-(3,4-dichlorophenyl)-alpha, alpha-dimethylvaleramide; N-isopropyl-N-phenylchloroacetamide; N-n-butoxymethyl-N-(2,6-diethylphenyl)chloroacetamide; N-methoxymethyl-N-(2,6-diethylphenyl)chloroacetamide;
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:12][C:13](=[O:24])[C:14]2[N:19]([CH3:20])[N:18]=[C:17]([CH2:21][CH2:22][CH3:23])[C:15]=2[N:16]=1)C=C.C1(O)C=CC=CC=1.N1CCCCC1>C(O)C.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>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:12][C:13](=[O:24])[C:14]2[N:19]([CH3:20])[N:18]=[C:17]([CH2:21][CH2:22][CH3:23])[C:15]=2[N:16]=1
Reactant: C=CCOc1ccccc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Oc1ccccc1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3ccccc3O)nc12
Yield: 9.2 %

Procedure:
A mixture of 5-(2-allyloxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (0.25 g, 0.0008 mol), phenol (0.145 g, 0.0015 mol), piperidine (0.131 g, 0.0015 mol) and tetrakis(triphenylphosphine)palladium(0) (0.046 g, 0.00004 mol) in absolute ethanol (5ml) was refluxed overnight under nitrogen. The mixture was allowed to cool, the solvent evaporated under vacuum and the residue dissolved in ethyl acetate (40 ml). This solution was washed with water (3×10 ml), 1M HCl (3×10 ml) and brine (1×10 ml). After drying (Na2SO4) and filtration, the filtrate was evaporated under vacuum to give the crude product. The title phenol (0.021 g, 10%) was obtained after trituration with diethyl ether and crystallisation from ethyl acetate/pentane, m.p. 233°-238° C. Found: C,63.17; H,5.65; N,19.52. C15H16N4O2 requires C,63.36; H,5.67; N,19.71%.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=[C:9]3[C:10]=2[N:5]([CH2:6][CH2:7][S:8]3)[C:4](=[O:17])[C:3]=1[C:18](=[O:27])[N:19]([CH3:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.ClC1C=C(C=CC=1)C(OO)=[O:33]>ClCCl>[OH:1][C:2]1[C:11]2[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=[C:9]3[C:10]=2[N:5]([CH2:6][CH2:7][S:8]3=[O:33])[C:4](=[O:17])[C:3]=1[C:18](=[O:27])[N:19]([CH3:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc2c3c(c1)c(O)c(C(=O)N(C)c1ccccc1)c(=O)n3CCS2
Solvent: ClCCl
Product: COc1cc2c3c(c1)c(O)c(C(=O)N(C)c1ccccc1)c(=O)n3CCS2=O
Temperature: 5 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A mixture of 2,3-dihydro-7-hydroxy-9-methoxy-6-(N-methyl-N-phenylcarbamoyl)-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzothiazine (1 g) and m-chloroperoxybenzoic acid (0.5 g) in dichloromethane (50 ml) was stirred at 5° C. for 1 hour. The insoluble material was filtered and the filtrate was concentrated in vacuo. The residue (1.5 g) was recrystallized from acetone to give pale yellow crystals of 2,3-dihydro-7-hydroxy-9-methoxy-6-(N-methyl-N-phenylcarbamoyl)-5-oxo-5H-pyrido[1,2,3-de]-1,4- benzothiazine 1-oxide (0.86 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]2[O:11][CH2:10][CH:9]([NH:12][CH3:13])[CH2:8][CH:7](O)[C:6]=2[CH:15]=1.[ClH:17]>CO>[ClH:17].[CH3:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]2[O:11][CH2:10][CH:9]([NH:12][CH3:13])[CH:8]=[CH:7][C:6]=2[CH:15]=1
Reactant: CNC1COc2cc(C)c(C)cc2C(O)C1
Agent: Cl
Solvent: CO
Product: CNC1C=Cc2cc(C)c(C)cc2OC1

Procedure:
10.0 g of 7,8-dimethyl-3-methylamino-2,3,4,5-tetrahydro-1benzoxepin-5-ol were dissolved in 50 ml of methanol saturated with hydrogen chloride, and the solution was heated at reflux for two hours with stirring. Subsequently, the solution was evaporated under vacuum; the residue was dissolved in a 25 percent aqueous ammonia solution, and the alkaline ammonia solution was worked up as described in Example 1. 7.9 g of 7,8-dimethyl-3-methylamino-2,3-dihydro-1-benzoxepine hydrochloride were obtained. Melting point: 216-218 degrees C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]([O:12]CC)=[O:11])=[N:2]1>OS(O)(=O)=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]([OH:12])=[O:11])=[N:2]1
Reactant: CCOC(=O)c1noc2ccccc12
Agent: O=S(=O)(O)O
Product: O=C(O)c1noc2ccccc12
Temperature: 80 °C
Yield: 57.2 %

Procedure:
To ethyl benzo(d)isoxazole-3-carboxylate (2.0 g, 10.5 mmol) was added 50 ml of 70% H2SO4. The mixture was heated at 80° C. for 4 hours. The reaction mixture was poured in ice, followed by extraction with ether. The extract was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, whereby benzo(d)isoxazole-3-carboxylic acid (980 mg, 57%) was obtained as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[C:20]#[N:21])=[CH:15][CH:14]=1)=[CH:9][C:8]([Cl:24])=[CH:7][CH:6]=2.C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:24][C:8]1[CH:7]=[CH:6][C:5]2[N:4]=[CH:3][C:2]3[NH:1][C:33](=[O:35])[N:12]([C:13]4[CH:14]=[CH:15][C:16]([C:19]([CH3:22])([CH3:23])[C:20]#[N:21])=[CH:17][CH:18]=4)[C:11]=3[C:10]=2[CH:9]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C#N)c1ccc(Nc2c(N)cnc3ccc(Cl)cc23)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Cl)cc4c32)cc1
Reaction time: 0.33 h

Procedure:
A solution of 2-(4-(3-amino-6-Chloroquinolin-4-ylamino)phenyl)-2-methylpropanenitrile (Compound of Preparation G, 3.3 g, 9.8214 mmol) and triethylamine (1.34 g, 12.74 mmol) in CH2Cl2 (120 mL) was added over 40 min to a solution of triphosgene (3.5 g, 11.7852 mmol) in 80 mL of CH2Cl2 at 0° C. with an ice-bath. The reaction mixture was stirred for 20 min at this temperature then quenched with saturated aqueous NaHCO3, stirred for 5 min and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to obtain the title compound. Yield: 1.2 g (34%); 1H NMR (DMSO-d6, 300 MHz): δ 12.190 (s, 1H), 8.921 (s, 1H), 8.069-8.100 (d, 1H, J=8.7 Hz), 7.807-7.835 (d, 2H, J=8.4 Hz), 7.641-7.694 (m, 3H), 6.808-6.815 (d, 1H, J=2.1 Hz), 1.766 (s, 6H); MS: m/z 363 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][N:9]=[C:10]([CH3:12])[CH3:11])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>O1CCCC1>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([N:8]([C:22](=[O:24])[CH3:23])[N:9]=[C:10]([CH3:11])[CH3:12])=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)=NNC(=O)c1ccc(Cl)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N(N=C(C)C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 82 %

Procedure:
10.5 g of 1-p-chlorobenzoyl-2-isopropylidene hydrazine, 5.3 g of triethylamine and 100 ml of tetrahydrofuran were placed in a 200 ml round-bottom flask, and while stirring with ice-water cooling, 3.9 of acetylchloride was dropped gradually. After dropping, the mixture was heated at reflux for one hour so as to complete the reaction. The reaction mixture was cooled to room temperature and the separated salts were filtered off, and then the filtrate was concentrated to obtain yellow brown crystals, which were then recrystallized from a mixed solvent of hexane/acetone to yield 10.4 g (82%) of yellow crystalline 1-p-chlorobenzoyl-1-acetyl-2-isopropylidene hydrazine having a melting point of 73°-74° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([NH:20][C:21]([NH2:23])=[S:22])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:4][CH:3]=1.[CH2:24](I)[CH3:25]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([NH:20][C:21](=[NH:23])[S:22][CH2:24][CH3:25])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:4][CH:3]=1
Reactant: CCI
Reactant: NC(=S)Nc1ccc2nc(NCCc3ccc(Br)cc3)sc2c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCSC(=N)Nc1ccc2nc(NCCc3ccc(Br)cc3)sc2c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 23 %

Procedure:
{2-[2-(4-Bromo-phenyl)-ethylamino]-benzothiazol-6-yl}-thiourea (Example 39, 51.3 mg, 0.126 mmol) was dissolved in dry DMF (0.5 mL). Ethyl iodide (11 μl, 1.1 eq) was added and the yellow solution stirred at room temperature for 23 hours. The solution was diluted with ethyl acetate (10 mL) and extracted with ice water (2 mL) followed by ice cold brine (3×2 mL). The product was dried over MgSO4, filtered and concentrated to give a yellow oil. The product was purified by chromatography on silica gel (5% 2M ammonia/methanol in CH2Cl2) to give the isothiourea (12.5 mg, 23%). The product was dissolved in methanol (1.0 mL) and acidified with 1.0 M HCl in ether (4 mL). The orange precipitate was collected by filtration and washed with hexanes (6.0 mg, 10%). MS (M+1, 435, 437).
Reaction SMILES: [NH2:1][C@H:2]([C:15]([NH:17][C@H:18]([C:31]([OH:33])=O)[CH2:19][CH2:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(Cl)(Cl)Cl.CO.CC(O)=O>N1C=CC=CC=1>[NH:1]1[C:31](=[O:33])[C@H:18]([CH2:19][CH2:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:17][C:15](=[O:16])[C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCC[C@@H]1NC(=O)[C@H](CCC(=O)OCc2ccccc2)NC1=O

Procedure:
H-L-Lys(Boc)-L-Glu(OBzl)-OH (23.0, 0.05 mol) was dissolved in 100 ml of pyridine and refluxed for 4 hours. The reaction was monitored by TLC using the system of CHCl3:MeOH: 32% AcOH=5:3:1. After completion of the reaction, the mixture was evaporated in vacuum and 500 ml of 0.1% AcOH was added. The cyclo-L-Lys(Boc)-L-Glu(OBzl) was precipitated. The precipitate was filtered off, washed with water and dried in a vacuum oven at 40° C. The yield was 20.9 (86%). Rf=0.75 (CHCl3:MeOH: 32% AcOH=5:3:1); HPLC data: retention time 19.2 min.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:10])=[C:6]([CH3:9])[C:7]=1[CH3:8].[Br:11]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:8][C:7]1[C:6]([CH3:9])=[C:5]([Cl:10])[N:4]=[N:3][C:2]=1[Cl:1]
Reactant: Cc1c(Cl)nnc(Cl)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1c(Cl)nnc(Cl)c1CBr

Procedure:
To a stirred solution of 3,6-dichloro-4,5-dimethylpyridazine (500 mg, 2.82 mmol) in carbon tetrachloride (10 mL) was added N-bromosuccinimide (503 mg, 2.82 mmol), and AIBN (2.3 mg, 0.014 mmol) in a round bottom flask equipped with condenser. The reaction was continuously irradiated with a 300 W light and refluxed for 5 h. The formed succimide was filtered and the filtrate was concentrated to afford 4-(bromomethyl)-3,6-dichloro-5-methylpyridazine as a brown solid. To a solution of 4-(bromomethyl)-3,6-dichloro-5-methylpyridazine (400 mg, 1.56 mmol) in DMF was added with benzyl amine (188 μL, 1.72 mmol) and TEA (326 μL, 2.34 mmol). The reaction mixture was heated at 90° C. for 2 h, diluted with DCM and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated to afford a brown oil. The crude material was purified by flash chromatography on silica gel, eluting with 30-80% EtOAc:heptane. Fractions containing the desired product were combined and concentrated to afford a the title compound as a greasy solid (430 mg, yield: 54% (two steps)).
Reaction SMILES: [C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Li+].[Li+].[Li+]>[N+]([O-])([O-])=O.[Co+2].[N+]([O-])([O-])=O>[C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4]
Reactant: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Co+2]
Agent: O=[N+]([O-])[O-]
Agent: [Li+]
Product: O=C(O)CC(O)(CC(=O)O)C(=O)O

Procedure:
Lithium citrate and cobalt nitrate were mixed at a mol ratio of 1:3 to obtain a mixture, citric acid was added to the mixture, and the resultant was dissolved in ion-exchanged water to obtain a solution. The solution was sprayed in an air stream of 200° C. to obtain a Li—Co oxide precursor fine powder.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=O)=[CH:17][C:16]=4[CH3:24])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:25]=[O:26])=[CH:4][CH:3]=1.C(N(CC)CC)C.S(Cl)(Cl)=O>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:23]=[CH:22][C:18]([C:19]#[N:21])=[CH:17][C:16]=4[CH3:24])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:25]=[O:26])=[CH:4][CH:3]=1
Reactant: Cc1cc(C(N)=O)ccc1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(C#N)ccc1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
To a mixture of 4-(9-chloro-6-formyl-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl)-3-methylbenzamide (100 mg, 0.271 mmol) and triethylamine (0.189 mL, 1.36 mmol) in N,N-dimethylformamide (2.7 mL) was added thionyl chloride (0.0293 mL, 0.406 mmol) at room temperature, and the mixture was stirred at 40° C. for 30 min. After triethylamine (0.189 mL, 1.36 mmol) and thionyl chloride (0.0293 mL, 0.406 mmol) were added to the reaction mixture, the mixture was stirred at 40° C. for 10 min and diluted with aqueous sodium bicarbonate. The resultant mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 30-70% ethyl acetate/n-hexane gradient mixture to give the title compound as a yellow solid (66.2 mg, 0.189 mmol, 70%).