Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:15][C:16]1[CH:17]=[C:18]([CH:26]=[C:27]([CH3:29])[CH:28]=1)[O:19][CH:20]([CH2:24][CH3:25])[C:21](Cl)=[O:22]>C1C=CC=CC=1>[CH2:1]([NH:8][C:21](=[O:22])[CH:20]([O:19][C:18]1[CH:17]=[C:16]([CH3:15])[CH:28]=[C:27]([CH3:29])[CH:26]=1)[CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCC(Oc1cc(C)cc(C)c1)C(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCC(Oc1cc(C)cc(C)c1)C(=O)NCc1ccccc1
Reaction time: 5 h
Yield: 62.1 %

Procedure:
In 30 ml of benzene were dissolved 1.8 g (0.017 mole) of benzylamine and 1.2 g (0.015 mole) of pyridine, and thereto was added dropwise 3.0 g (0.013 mole) of 2-(3,5-dimethylphenoxy)-butyroyl chloride at room temperature with stirring. After the reaction was carried out for 5 hours, the reaction mixture was washed with water, dilute hydrochloric acid, dilute aqueous sodium hydroxide and then water successively. After the benzene layer was dried, the benzene was removed by distillation. The resultant crude crystals were recrystallized from n-hexane to give 2.4 g of N-benzyl-2-(3,5-dimethylphenoxy)-butyramide melting at 93°-94° C. as colorless needles.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][C:12]=1[C:20]([F:23])([F:22])[F:21].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=2)=[CH:13][C:12]=1[C:20]([F:21])([F:22])[F:23]
Reactant: OB(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: O=Cc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=Cc1cccc(-c2ccc(F)c(C(F)(F)F)c2)n1
Temperature: 80 °C
Yield: 90.5 %

Procedure:
To a solution of 6-bromopicolinaldehyde (1.00 g, 5.38 mmol) in dioxane (30 mL) at ambient temperature was added 4-fluoro-3-(trifluoromethyl)phenylboronic acid (1.11 g, 5.38 mmol), 2M cesium carbonate (8.0 mL, 16 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.220 g, 0.269 mmol). The mixture was degassed (3× vacuum/purge N2), then heated at 80° C. overnight. After cooling to room temperature the mixture was concentrated and the residue partitioned between water and CH2Cl2. The organic extract was concentrated and purified by chromatography (10% ethyl acetate:hexanes) to provide 1.31 g (91%) of the title compound. MS (DCI+) m/z 270 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([Cl:10])[C:3]=1[NH:11][C:12](=O)[C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH:16]=[CH:15][C:14]=1[F:26]>C1COCC1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([Cl:10])[C:3]=1[NH:11][CH2:12][C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH:16]=[CH:15][C:14]=1[F:26]
Reactant: COc1ccc(Cl)c(NC(=O)c2cc(-c3cccc(F)c3)ccc2F)c1Cl
Solvent: C1CCOC1
Product: COc1ccc(Cl)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1Cl
Temperature: 60 °C
Yield: 76.1 %

Procedure:
To a solution of N-(2,6-dichloro-3-methoxy-phenyl)-2-fluoro-5-(3-fluorophenyl)benzamide (200 mg, 0.5 mmol, 1.0 eq) in dry THF (10 mL) was added a solution of BH3 (1M in THF, 2 mL, 2 mmol, 4.0 eq) dropwise. The solution was then heated at 60° C. overnight. The reaction was quenched by addition of MeOH, then concentrated and the residue obtained was purified by column chromatography (Petroleum ether:EtOAc, 10:1) to give the title compound (150 mg, 77%).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([CH3:12])=[C:7]([CH3:13])[C:6]=2[CH:14]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33]Cl)[CH2:27][CH2:26]2)=[CH:20][CH:19]=1.C(O)(C)C.Cl>O>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]2[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][CH2:33][O:1][C:2]3[C:3]([O:15][CH3:16])=[CH:4][C:5]4[O:10][C:9](=[O:11])[C:8]([CH3:12])=[C:7]([CH3:13])[C:6]=4[CH:14]=3)[CH2:29][CH2:30]2)=[CH:22][CH:23]=1
Reactant: ClCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: COc1cc2oc(=O)c(C)c(C)c2cc1O
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: COc1cc2oc(=O)c(C)c(C)c2cc1OCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 74 %

Procedure:
Method D (5 h at 90° C.); starting materials: 6-hydroxy-7-methoxy-3,4-dimethyl-2H-1-benzopyran-2-one (example 103) and 1-[(4-chlorophenyl)methyl]-4-(3-chloropropyl)piperazine; yield: 74%; fusion point 96°-97° C. (from isopropanol and petroleum ether). Hydrochloride (x 2 HCl): method G; yield 95%; fusion point 255°-260° C. (from isopropanol and water).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][C:9]([CH3:11])=[N:10][C:6]=2[CH:5]=[C:4]([O:12]C)[CH:3]=1.Cl.N1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>>[Cl:1][C:2]1[C:7]2[NH:8][C:9]([CH3:11])=[N:10][C:6]=2[CH:5]=[C:4]([OH:12])[CH:3]=1
Reactant: COc1cc(Cl)c2[nH]c(C)nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: Cc1nc2cc(O)cc(Cl)c2[nH]1

Procedure:
Under a nitrogen atmosphere 0.95 g (4.83 mmol) 7-chloro-5-methoxy-2-methyl-1H-benzo[d]imidazole and 7.0 g (0.06 mol) pyridine hydrochloride were stirred for 15 h at a bath temperature of 180° C. The reaction mixture was poured onto water while still hot and made alkaline with an aqueous K2CO3 solution. The substance was extracted with ethyl acetate and washed with water. The organic phase was separated off, dried and evaporated down i.vac.
Reaction SMILES: [OH:1][C:2]1[C:12]2=[C:13]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[CH2:10][C:11]2=[O:14])=[CH:4][CH:3]=1.[C:15](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:15][O:1][C:2]1[C:12]2=[C:13]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[CH2:10][C:11]2=[O:14])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1Cc2cccc3ccc(O)c1c23
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc2cccc3c2c1C(=O)C3
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.7 %

Procedure:
A known compound, 8-hydroxyacenaphthen-1-one (7.0 g) (J. Chem. Soc., 1954, p. 4299), was dissolved in N,N-dimethylformamide (70 ml), potassium carbonate (7.9 g) and methyl iodide (6.8 g) were added, and the mixture was stirred at room temperature for 5 hr. After completion of the reaction, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 8-methoxyacenaphthen-1-one (5.7 g). The obtained methoxy form was dissolved in methanol (25 ml), sodium borohydride (220 mg) was added, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was gradually added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 8-methoxy-1-acenaphthenol (5.6 g). The title compound (2.28 g) was obtained according to the method of Example 125 and using the obtained alcohol form.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34](=[O:35])[C:33]5[CH:37]=[CH:38][C:30]([C:29]([F:28])([F:39])[F:40])=[CH:31][CH:32]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound, off-white solid (111 mg, 88%), MS (ISP) m/z=503.3 [(M+H)+], mp 227° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 4-trifluoromethyl-benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([F:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:25](OCC)(=[O:27])[CH3:26]>>[C:25]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([F:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)(=[O:27])[CH3:26]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc(F)cc21
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2ccc(F)cc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) from 3-amino-2-benzoyl-1-(ethoxycarbonyl)-6-fluoroindole (step 2). tlc: Rf=0.2 (33% ethyl acetate in hexanes)
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:5]=[C:6]([C@H:11]2[N:16]([CH2:17][C:18]([O:20]C)=[O:19])[C:15](=[O:22])[C:14]3([CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23]3)[N:13]([CH3:29])[CH2:12]2)[CH:7]=[C:8]([F:10])[CH:9]=1>C1COCC1.O>[F:10][C:8]1[CH:7]=[C:6]([C@H:11]2[N:16]([CH2:17][C:18]([OH:20])=[O:19])[C:15](=[O:22])[C:14]3([CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23]3)[N:13]([CH3:29])[CH2:12]2)[CH:5]=[C:4]([F:3])[CH:9]=1
Reactant: COC(=O)CN1C(=O)C2(COCCOC2)N(C)C[C@H]1c1cc(F)cc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)C12COCCOC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.2 mg (0.30 mmol) lithium hydroxide were added to 75 mg (0.20 mmol) (R)-methyl 2-(3-(3,5-difluorophenyl)-1-methyl-5-oxo-8,11-dioxa-1,4-diazaspiro[5.6]dodecan-4-yl)acetate in 5 ml THF and 1 ml of water. The reaction mixture was stirred for 2 h at RT and then MeOH was distilled off. The residue was made neutral with a 0.1M hydrochloric acid solution and evaporated to dryness.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Al](C)(C)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]([CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[C:22]([C:30](OCC)=[O:31])[N:21]=[C:20]2[C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[Cl:42])=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>ClCCl.CCCCCCC>[CH:1]1([NH:7][C:30]([C:22]2[N:21]=[C:20]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=3[Cl:42])[N:19]([C:16]3[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=3)[C:23]=2[CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Cl)cc2)c1CN1CCCC1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCCC
Product: O=C(NC1CCCCC1)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Cl)cc2)c1CN1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Part C: Cyclohexylamine (0.91 ml, 8 mmol) is dissolved in dichloromethane (20 ml) and (CH3)3Al (4 ml of a 2 M solution in heptane, 8 mmol) is added. The resulting mixture is stirred for 10 minutes at room temperature and ethyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-(pyrrolidin-1-ylmethyl)-1H-imidazole-4-carboxylate (1.8 gram, 3.8 mmol) is added. The resulting mixture is stirred at room temperature for 16 hours, poured into an aqueous NaHCO3 solution, stirred for 30 minutes and filtered over hyflo. The filtrated is twice extracted with dichloromethane. The organic layers are dried over Na2SO4, filtered and concentrated in vacuo. Subsequent purification with flash chromatography (dichloromethanelmethanol=98/2 (v/v)) gives N-cyclohexyl-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-(pyrrolidin-1-ylmethyl)-1H-imidazole-4-carboxamide, compound 1 (1.06 gram, 53% yield). Melting point: 155-157° C.
Reaction SMILES: [CH3:1][O:2][C:3]1([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:8][CH2:7][CH:6]([N:28]2[CH2:27][CH2:26][N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH2:30][CH2:29]2)[CH2:5][CH2:4]1
Reactant: COC1(Cc2ccccc2C)CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC1(Cc2ccccc2C)CCC(N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reaction time: 8 h
Yield: 70.4 %

Procedure:
A solution of EXAMPLE 15C (0.42 g, 1.80 mmol) and 1-tert-butoxycarbonylpiperazine (0.391 g, 2.10 mmol) in dichloroethane (10 mL) at room temperature was treated with acetic acid (500 μL) and sodium triacetoxyborohydride (10.89 g, 4.2 mmol), stirred overnight, diluted with ethyl acetate (300 mL), washed sequentially with 1N NaOH, water, and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product (0.51 g, 70%); MS (ESI) m/e 403 (M+H)+.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=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:20]=[CH:21][C:22]([C:25](O)=[O:26])=[N:23][CH:24]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH3:36][NH2:37]>>[CH3:36][NH:37][C:25]([C:22]1[CH:21]=[CH:20][C:19]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[CH:24][N:23]=1)=[O:26]
Reactant: CN
Reactant: C[C@@H](c1ccc(-c2ccc(C(=O)O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: CNC(=O)c1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from 5-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylic acid and methylamine following a procedure analogous to that described in Example 168. Mass spectrum (ESI+): m/z=488 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:13]2[N:14]=[C:15]([C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[F:25])[CH:16]=[CH:17][C:12]2=[CH:11][N:10]=1.[OH:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[F:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[C:15]1[CH:16]=[CH:17][C:12]2[N:13]([C:9]([NH:8][C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[C:30]3[CH:29]=[CH:28][C:27](=[O:26])[NH:32][CH:31]=3)=[N:10][CH:11]=2)[N:14]=1
Reactant: Fc1cccc(F)c1-c1ccc2cnc(Nc3cnccc3Cl)n2n1
Reactant: OB(O)c1ccc(O)nc1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1ccc(-c2ccncc2Nc2ncc3ccc(-c4c(F)cccc4F)nn23)c[nH]1
Temperature: 120 °C
Yield: 2.2 %

Procedure:
A glass microwave reaction vessel was charged with N-(4-chloro-3-pyridinyl)-2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-amine (Example 27, Step 1, 40 mg, 0.11 mmol), 6-hydroxypyridin-3-ylboronic acid (19 mg, 0.13 mmol, Combi-Blocks, Inc.), Pd(PPh3)4 (13 mg, 0.01 mmol) and 2 M Na2CO3 (aq., 0.17 mL, 0.34 mmol) in dioxane (1.00 mL). The reaction was stirred and heated in a microwave at 120° C. for 20 min. H2O was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anh. Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (0-5% MeOH in CH2Cl2) to provide 3′-((2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-yl)amino)-3,4′-bipyridin-6(1 H)-one (1 mg, 2.40 μmol, 2% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 416.9 (M+1). 1H NMR (400 MHz, MeOH-d4) δ ppm 8.82 (s, 1 H), 8.30 (d, J=5.09 Hz, 1 H), 7.96 (d, J=9.39 Hz, 1 H), 7.74 (dd, J=9.59, 2.54 Hz, 1 H), 7.55-7.64 (m, 2 H), 7.37 (d, J=5.09 Hz, 1 H), 7.24 (s, 1 H), 6.69 (d, J=9.39 Hz, 1 H), 6.44 (d, J=9.39 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>ClCCl>[C:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1)(=[O:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
To a solution of (2R)-(4-amino-phenyl)-tert-butoxycarbonylamino-acetic acid (100 mg, 0.376 mmol) in dichloromethane (2 mL) was added pyridine (36 μL, 0.45 mmol) and acetic anhydride (42 μL, 0.44 mmol) and the mixture stirred at ambient temperature for 2 hours. The reaction mixture was diluted with dichloromethane, washed with 1M aqueous citric acid solution, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography over silica gel gradient eluted from 0 to 10% v/v methanol in dichloromethane to afford (2R)-(4-acetylamino-phenyl)-tert-butoxycarbonylamino-acetic acid as a yellow solid (59 mg, 51%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([NH:17][C:18]1[CH:23]=CC=CC=1)=[O:16].NC1C=[N:29][CH:28]=[C:27]([Cl:31])[N:26]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:31][C:27]1[N:26]=[C:18]([NH:17][C:15]([C:3]2[N:4]([CH3:14])[S:5](=[O:12])(=[O:13])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:16])[CH:23]=[N:29][CH:28]=1
Reactant: CN1C(C(=O)Nc2ccccc2)=C(O)c2ccccc2S1(=O)=O
Reactant: Nc1cncc(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2cncc(Cl)n2)=C(O)c2ccccc2S1(=O)=O
Yield: 22.7 %

Procedure:
1.0 g (3 mmols) of 4-hydroxy-2-methyl-N-phenyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide were refluxed with 1.3 g (10 mmols) of 2-amino-6-chloro-pyrazine and 0.1 g of p-toluenesulfonic acid in 250 ml of xylene for 72 hours. After cooling, the reaction mixture was washed with 2N hydrochloric acid and then with water, then dried and concentrated by evaporation in vacuo. The residue was purified column chromatography (Merck silicagel 60; particle size: 0.2-0.5 mm; eluant: chloroform/ethanol 90:10) and yielded 0.25 g (23% of theory) of N-(6-chloro-pyrazin-2-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][NH:18][CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[N:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:48]=[CH:47][C:34]([C:35](OC3C=CC([N+]([O-])=O)=CC=3)=[O:36])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1.[H-].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:18]([C:35](=[O:36])[C:34]3[CH:33]=[CH:32][C:31]([C:28]4[CH:27]=[CH:26][N:25]=[CH:30][CH:29]=4)=[CH:48][CH:47]=3)[CH2:17][CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: COC(=O)C1=CNCCN1S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc(-c2ccncc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C1=CN(C(=O)c2ccc(-c3ccncc3)cc2)CCN1S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reaction time: 1 h
Yield: 65.2 %

Procedure:
In N,N-dimethylformamide (1 ml), 1-[(6-chloronaphthalen-2-yl)sulfonyl]-6-methoxycarbonyl-1,2,3,4-tetrahydropyrazine (60 mg) and p-nitrophenyl 4-(pyridin-4-yl)benzoate (52 mg) were dissolved, followed by the addition of sodium hydride (60% in oil, 7.20 mg) under ice cooling. The resulting mixture was stirred for 1 hour. Water and ethyl acetate were added to the reaction mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate and the solvent was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (ethyl acetate:hexane=2:1), followed by dissolution in ethanol. To the resulting solution, 1N aqueous hydrochloric acid in ethanol was added and the resulting mixture was concentrated, whereby the title compound (58 mg, 60%) was obtained as pale yellow powder.
Reaction SMILES: [OH-:1].[K+].[O:3]=[C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]2[S:16][C:17]([C:27]#[N:28])=[C:18]([NH:19][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)[C:7]=2[CH:6]=[CH:5]1>O.CCO>[O:3]=[C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]2[S:16][C:17]([C:27]([NH2:28])=[O:1])=[C:18]([NH:19][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)[C:7]=2[CH:6]=[CH:5]1
Reactant: [OH-]
Reactant: Cc1cccc(Nc2c(C#N)sc3c2ccc(=O)n3-c2ccccc2)c1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cccc(Nc2c(C(N)=O)sc3c2ccc(=O)n3-c2ccccc2)c1
Yield: 141.3 %

Procedure:
A solution of KOH (12.69 g, 85+%) in water (230 ml) was added to a suspension of Example 23 (114 g) in EtOH (345 ml). The resulting mixture was heated at reflux for 70 minutes, by which time the reaction had gone to completion. It was cooled and water (285 ml) added. The suspension was filtered and washed with water (200 ml). The product was dried under vacuum to give the title compound as a yellow solid (120 g). δH (CDCl3) 8.90 (1H, s), 7.55-7.65 (3H, m), 7.40 (2H, m), 7.20-7.30 (2H, m), 6.90 (3H, m), 6.35 (1H, d, J 9 Hz), 5.40 (2H, br s), 3.70 (2H, q, EtOH), 2.35 (3H, s), 1.25 (3H, t, EtOH). LCMS (ES+) RT 3.1 minutes, 376 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([C:7]([O:9]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:8])[CH:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:3]1>C(OCC)(=O)C.[C].[Pd]>[C:26]([O:25][C:23]([CH:4]1[CH2:3][C:2](=[O:1])[O:6][CH:5]1[C:7]([OH:9])=[O:8])=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)C1CC(=O)OC1C(=O)OC(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1CC(=O)OC1C(=O)O
Reaction time: 15 h
Yield: 76.8 %

Procedure:
148 mg of 3-tert-butyl 2-diphenylmethyl (2RS,3RS)-5-oxotetrahydrofuran-2,3-dicarboxylate was dissolved in 4 ml of ethyl acetate, and 15 mg of a 10% palladium-carbon catalyst was added thereto, followed by catalytic reduction for 15 hours at room temperature under hydrogen atmospheric pressure. The catalyst was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was washed with benzene to obtain 66 mg of above-identified compound as white crystalline powder.
Reaction SMILES: CC([N:5]([C@H:9]([CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH2:18]Br)=[CH:13][CH:12]=1)[C:6](=[O:8])[O-:7])(C)C.[Br:33][C:34]1[C:35]([NH2:40])=[N:36][CH:37]=[CH:38][CH:39]=1.C(=O)(O)[O-].[Na+]>C(O)(C)C>[Br:33][C:34]1[C:35]2[N:36]([CH:18]=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH2:10][C@H:9]([NH:5][C:6](=[O:8])[O:7][C:11]([CH3:16])([CH3:12])[CH3:10])[CH2:21][N:22]4[C:23](=[O:32])[C:24]5[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:30]4=[O:31])=[CH:12][CH:13]=3)[N:40]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: Nc1ncccc1Br
Reactant: CC(C)(C)N(C(=O)[O-])[C@@H](Cc1ccc(C(=O)CBr)cc1)CN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cn3cccc(Br)c3n2)cc1)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 72 %

Procedure:
A solution of 1,1-dimethylethyl{(1S)-2-[4-(bromoacetyl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (6.9 mmol), 3-bromo-2-pyridinamine (8.4 mmol), and sodium bicarbonate (10.4 mmol) in isopropanol (70 mL) were stirred at 80° C. for 18 h. The reaction was then cooled to RT and a precipitate formed which was filtered, washed with cold hexanes (3×100 mL), and dried to afford the title compound as light gray solid (72%). ESMS [M+H]+: 576.2.