Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][C:7]2[CH:8]=[N:9][CH:10]=[C:11](B3OC(C)(C)C(C)(C)O3)[CH:12]=2)[CH2:3][CH2:2]1.Br[C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32]([NH2:34])=[O:33])[CH:31]=1)[NH:28][CH:27]=[C:26]2[CH:35]1[CH2:40][CH2:39][N:38]([S:41]([CH2:44][CH3:45])(=[O:43])=[O:42])[CH2:37][CH2:36]1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>O>[CH:1]1([CH2:4][NH:5][CH2:6][C:7]2[CH:12]=[C:11]([C:23]3[CH:24]=[C:25]4[C:29](=[C:30]([C:32]([NH2:34])=[O:33])[CH:31]=3)[NH:28][CH:27]=[C:26]4[CH:35]3[CH2:36][CH2:37][N:38]([S:41]([CH2:44][CH3:45])(=[O:42])=[O:43])[CH2:39][CH2:40]3)[CH:10]=[N:9][CH:8]=2)[CH2:2][CH2:3]1
Reactant: CC1(C)OB(c2cncc(CNCC3CC3)c2)OC1(C)C
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCC5CC5)c4)cc23)CC1
Temperature: 150 °C
Reaction time: 0.13 h

Procedure:
To a CEM microwave tube containing (cyclopropylmethyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine (21 mg, 0.0725 mmol) was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), dioxane (0.75 mL), a solution of potassium carbonate (60 mg, 0.434 mmol) in H2O (0.25 mL), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol). The reaction was heated in a CEM microwave for 30 min at 150° C. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL MeOH), eluting in sequence with H2O (3 mL), MeOH (6 mL) and a 2 M solution of NH3/MeOH (9 mL). The NH3/MeOH fraction was dried under a stream of nitrogen at 40° C. and purified on an Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2×50 mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H2O (0.1% TFA) then a linear gradient of 10% CH3CN/H2O (0.1% TFA) to 95% CH3CN/H2O (0.1% TFA) over 8 min and holding at the final concentration for 30 sec. The fractions containing product were filtered through a 2 g Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies) to remove TFA and concentrated under a stream of nitrogen at 65° C. to give impure title compound, which was repurified on the Agilent MDAP as shown above to give 25 mg of the title compound (70%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH3:13])(=[O:11])=[O:10])[CH:6]=[N:7][CH:8]=1)#[N:2].[O-:14][CH2:15][CH3:16].[Na+]>C(O)C>[CH3:13][NH:12][S:9]([C:5]1[CH:6]=[N:7][CH:8]=[C:3]([CH:4]=1)[C:1](=[NH:2])[O:14][CH2:15][CH3:16])(=[O:11])=[O:10]
Reactant: CC[O-]
Reactant: CNS(=O)(=O)c1cncc(C#N)c1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=N)c1cncc(S(=O)(=O)NC)c1
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a solution of 5-cyano-N-methylpyridine-3-sulfonamide (0.1 g, 0.5 mmol) in ethanol was added sodium ethoxide (0.03 g, 0.55 mmol). After 2 h, the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was concentrated under reduced pressure to afford ethyl 5-(N-methylsulfamoyl)nicotinimidate (120 mg) as an off-white solid. The material was used without further purification. MS (ES+APCI) 244.0; LCMS retention time: 3.047 min (Method I).
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]2[CH:11]=[C:10]([CH3:12])[C:9]([OH:13])=[C:8]([CH3:14])[CH:7]=2)[CH2:5][CH2:4]1.[Cl:15][C:16]1[N:17]=[C:18](Cl)[C:19]2[NH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>CN1C(=O)CCC1.O>[Cl:15][C:16]1[N:17]=[C:18]([O:13][C:9]2[C:8]([CH3:14])=[CH:7][C:6]([CH:3]3[CH2:5][CH2:4]3)=[CH:11][C:10]=2[CH3:12])[C:19]2[NH:24][CH:23]=[CH:22][C:20]=2[N:21]=1
Reactant: Clc1nc(Cl)c2[nH]ccc2n1
Reactant: Cc1cc(C2CC2)cc(C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(C2CC2)cc(C)c1Oc1nc(Cl)nc2cc[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.1 %

Procedure:
To a stirred suspension of NaH (25 mg, 0.64 mmol) in dry NMP (1.5 mL) was added 4-cyclopropyl-2,6-dimethylphenol (103 mg, 0.64 mmol) and the resolution mixture was stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (120 mg, 0.64 mmol) in dry NMP (1.7 mL) and heated at 90° C. for 16 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (4:1-2:1), to give the product as a light yellow solid (20.2 mg, 8%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:23][CH2:24][CH3:25])=[C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:11]=3[N:12]=2)[CH:7]=1.[CH:26]1[C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]2[C:35]([O:37][C:38](=O)[C:28]=2[CH:27]=1)=[O:36]>>[CH2:24]([NH:23][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[C:35](=[O:36])[C:29]3[C:28](=[CH:27][CH:26]=[C:31]([C:32]([OH:34])=[O:33])[CH:30]=3)[C:38]2=[O:37])=[CH:7][C:6]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][C:11]=2[N:12]=1)[CH3:25]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: CCNc1ccc(N)cc1-c1nc2cc(-c3ccccc3)ccc2o1
Product: CCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 1b), from 2-(5-amino-2-ethylaminophenyl)-5-phenylbenzoxazole (158 mg, 0.48 mmol) and 1,2,4-benzenetricarboxylic anhydride (92 mg, 0.48 mmol) the title compound was obtained (154 mg, 64%). 1H NMR (DMSO) δ 8.42(m, 2H), 8.31(s, 1H), 8.14(d, 1H), 8.07(m, 2H), 7.83(d, 1H), 7.74(m, 3H), 7.50(m, 3H), 7.39(t, 1H), 7.04(d, 1H), 3.48(q, 2H), 1.39(t, 3H). MS 504 m/z (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1.[N+:10]([O-])([OH:12])=[O:11].S(=O)(=O)(O)O>>[Br:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1
Reactant: Cc1ccc(Br)c[n+]1[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])c(Br)c[n+]1[O-]
Temperature: 90 °C
Reaction time: 20 h

Procedure:
5-Bromo-2-methylpyridine 1-oxide (5.36 g) was added to a mixture of conc. nitric acid (10.1 mL) and conc. sulfuric acid (8.94 mL), and the mixture was stirred at 90° C. for 20 hr. The reaction mixture was poured into ice water, and the resulting pale-yellow precipitate was collected by filtration. The crude crystals were washed with water to give the title compound (3.83 g) as a pale-yellow solid. The filtrate was neutralized with 8N aqueous sodium hydroxide solution at room temperature, and extracted with a mixed solvent of ethyl acetate and THF. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (360 mg) as a pale-yellow solid.
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:19])[C:7](=[O:18])[C:8]([CH3:17])([CH3:16])[CH2:9][N:10]2[CH:13]([CH3:15])[CH3:14])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:35]=[CH:34][C:24]([C:25]([NH:27][CH:28]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29]2)=[O:26])=[CH:23][C:22]=1[O:36][CH3:37].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>CC(C)CC(O)C>[CH3:37][O:36][C:22]1[CH:23]=[C:24]([CH:34]=[CH:35][C:21]=1[NH:20][C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:19])[C:7](=[O:18])[C:8]([CH3:17])([CH3:16])[CH2:9][N:10]2[CH:13]([CH3:15])[CH3:14])=[CH:4][N:3]=1)[C:25]([NH:27][C@@H:28]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29]1)=[O:26]
Reactant: COc1cc(C(=O)NC2CCN(C)C2)ccc1N
Reactant: CC(C)N1CC(C)(C)C(=O)N(C)c2cnc(Cl)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)CC(C)O
Solvent: CO
Product: COc1cc(C(=O)N[C@@H]2CCN(C)C2)ccc1Nc1ncc2c(n1)N(C(C)C)CC(C)(C)C(=O)N2C
Yield: 17.2 %

Procedure:
10-chloro-4,4,6-trimethyl-2-propan-2-yl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 178; 75 mg, 0.27 mmol), 4-amino-3-methoxy-N-(1-methylpyrrolidin-3-yl)benzamide (Intermediate 187; 67 mg, 0.27 mmol) and p-toluenesulphonic acid monohydrate (127 mg, 0.66 mmol) were heated at 140° C. in 4-methyl-2-pentanol (4 mL) for 2 hours. The reaction mixture was loaded onto an SCX-3 column pre-wet with methanol. The column was washed with methanol and eluted with 2% 7N ammonia/methanol to. Product containing fractions were evaporated and the residue dissolved in DMF and purified by base modified reverse phase HPLC to give the title compound as a white solid (23 mg, 17.5%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[O:8][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[CH2:10][C:3]=12.[CH3:18][NH2:19]>>[CH3:18][NH:19][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[O:8][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[CH2:10][C:3]=12
Reactant: Clc1ccnc2c1CC1(CN3CCC1CC3)O2
Reactant: CN
Product: CNc1ccnc2c1CC1(CN3CCC1CC3)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 151 mg (0.60 mmol) of 4′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] in 25 mL of 40% aqueous methylamine was heated to 175° C. in a steel bomb for 18 hours, then cooled to ambient temperature and concentrated in vacuo. The residue was dissolved in 10 mL of ethanol containing 0.4 mL of concentrated hydrochloric acid and the solution was allowed to stand overnight. After filtering, the solution was concentrated in vacuo and the residue crystallized from isopropanol, giving 147 mg of the title compound as a white solid: electrospray MS (m/z, relative intensity) 246 ([MH]+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: BrCCCCBr
Reactant: COc1cc(C#N)ccc1O
Product: COc1cc(C#N)ccc1OCCCCBr

Procedure:
The procedure is as for Example 53, Step A, using as substrate 4-hydroxy-3-methoxybenzonitrile and 1,4-dibromobutane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=2[CH3:17])[CH:5]=[N:6][CH:7]=1.[C:18]1([S:24]([O-:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH3:17][C:9]1[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=1[C:4]1[CH:5]=[N:6][CH:7]=[C:2]([S:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:26])=[O:25])[CH:3]=1
Reactant: O=S([O-])c1ccccc1
Reactant: CC(=O)Nc1nc(C)c(-c2cncc(Br)c2)s1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC(=O)Nc1nc(C)c(-c2cncc(S(=O)(=O)c3ccccc3)c2)s1
Temperature: 110 °C
Yield: 22.5 %

Procedure:
A mixture of N-[5-(5-bromopyridin-3-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (26 mg), sodium benzenesulfinate (17 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2.9 mg), caesium carbonate (41 mg) and toluene (3 mL) was purged with nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (1.9 mg) was added and the reaction mixture was heated to 110° C. for 16 hours under a nitrogen atmosphere. A further portion of sodium benzenesulfinate (14 mg) and DMF (1 mL) were added and the reaction mixture was transferred to a microwave vial and heated in a microwave apparatus to 145° C. for 4 hours. The resultant mixture was evaporated and the residue was partitioned between dichloromethane and water. The organic phase was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by ‘basic reversed-phase chromatography’ as described hereinbefore. There was thus obtained the title compound as a solid (7 mg); 1H NMR Spectrum: (DMSOd6) 2.24 (s, 3H), 2.42 (s, 3H), 7.72 (m, 2H), 7.81 (m, 1H), 8.17 (m, 2H), 8.37 (m, 1H), 9.01 (m, 1H), 9.12 (m, 1H), 12.32 (s, 1H); Mass Spectrum: M+H+ 374.
Reaction SMILES: Br[C:2]1[C:16]([F:17])=[CH:15][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH:18]1([NH:21][C:22]([C:24]2[CH:25]=[C:26]([F:34])[C:27]([CH3:33])=[C:28](B(O)O)[CH:29]=2)=[O:23])[CH2:20][CH2:19]1.C(=O)([O-])O.[Na+]>C(O)(C)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>[CH:18]1([NH:21][C:22](=[O:23])[C:24]2[CH:29]=[C:28]([C:2]3[C:16]([F:17])=[CH:15][C:5]4[C:6]([C:9]5[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=5)=[N:7][O:8][C:4]=4[CH:3]=3)[C:27]([CH3:33])=[C:26]([F:34])[CH:25]=2)[CH2:19][CH2:20]1
Reactant: Fc1cc2c(-c3ccncc3)noc2cc1Br
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B(O)O
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: CC(C)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1cc2onc(-c3ccncc3)c2cc1F
Yield: 60.7 %

Procedure:
The procedure for Example 1 was followed using 6-bromo-5-fluoro-3-(4-pyridinyl)-1,2-benzisoxazole (Intermediate 6, 25 mg), {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (24 mg), tetrakis(triphenylphosphine)palladium(0) (1 mg) and saturated aqueous sodium hydrogen carbonate (0.25 ml) in isopropanol (1 ml). Elution of the SPE cartridge (silica, 1 g) with cyclohexane/ethyl acetate (100:0 to 66:33) gave the title compound as a white solid (21 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N+:20]([O-])=O)=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CCO.[Pd]>[NH2:20][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cc(CNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)c1cc(CNC(=O)OC(C)(C)C)ccc1N
Yield: 81.1 %

Procedure:
A mixture of 0.273 g of methyl 5-{[(tert-butoxycarbonyl)amino]methyl}-2-nitrobenzoate, 0.166 g of ammonium formate and 0.094 g of Pd/C (10%) in 10 ml of EtOH purged beforehand with nitrogen is irradiated under a microwave field at 120° C. for 5 min. The mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, elution being carried out with an AcOEt/heptane mixture, (5/95, v/v) as far as (30/70, v/v), to give 0.2 g of the expected product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14]I)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:23][C:24]1[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=1[N:31]1[S:35](=[O:37])(=[O:36])[N:34]([CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:33](=[O:44])[CH2:32]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][C:28]2[CH:27]=[CH:26][C:25]([N:31]3[CH2:32][C:33](=[O:44])[N:34]([CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[S:35]3(=[O:37])=[O:36])=[C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:29]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CI)C1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Product: CC(C)(C)OC(=O)N1CCCC(Cc2ccc(N3CC(=O)N(CC[Si](C)(C)C)S3(=O)=O)c(OCc3ccccc3)c2)C1

Procedure:
The title compound is prepared from 3-iodomethylpiperidine-1-carboxylic acid tert-butyl ester and 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one analogous to the method used in Example 57, step B.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[C:8]([OH:10])[CH:9]=1)([O-])=O.BrC1C=CC([N+]([O-])=O)=CC=1O>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:11]([F:12])([F:13])[F:14])=[C:8]([OH:10])[CH:9]=1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)c(O)c1
Agent: [Ni]
Agent: O=[N+]([O-])c1ccc(Br)c(O)c1
Solvent: CO
Product: Nc1ccc(C(F)(F)F)c(O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 20 %

Procedure:
To a solution of 5-nitro-2-(trifluoromethyl)phenol and 2-bromo-5-nitro-phenol (10 g, 48.28 mmol) in methanol (60 mL) was added Raney Nickel (2.83 g, 318 μL, 48.28 mmol) under an atmosphere of nitrogen. The reaction mixture was then stirred for 4 h at room temperature under an atmosphere of hydrogen (1 atm). The catalyst was removed by filtration through a pad of celite and the filtrate was evaporated under vacuum. The crude product was purified by preparative HPLC to obtain 5-amino-2-(trifluoromethyl)phenol (1.7 g, 20%). 1H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 7.04 (d, J=8.8 Hz, 1H), 6.10 (s, 1H), 6.01 (d, J=8.4 Hz, 1H), 5.58 (br s, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([CH2:15][CH2:16][C@@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[C:22](=[O:34])[CH2:23][N:24]([CH:31]3[CH2:33][CH2:32]3)[CH2:25][C:26]([O:28]CC)=[O:27])[N:10]2[CH2:13][CH3:14])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[OH-].[Na+]>C(O)C>[C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([CH2:15][CH2:16][C@@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[C:22](=[O:34])[CH2:23][N:24]([CH:31]3[CH2:33][CH2:32]3)[CH2:25][C:26]([OH:28])=[O:27])[N:10]2[CH2:13][CH3:14])=[CH:6][CH:5]=1)(=[NH:2])[NH2:3]
Reactant: CCOC(=O)CN(CC(=O)N1CCC[C@H]1CCc1cc2ccc(C(=N)N)cc2n1CC)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1c(CC[C@@H]2CCCN2C(=O)CN(CC(=O)O)C2CC2)cc2ccc(C(=N)N)cc21
Reaction time: 2 h
Yield: 66.5 %

Procedure:
40 mg of ethyl 2-[[2-[(S)-2-[2-(6-amidino-1-ethylindol-2-yl)ethyl]pyrrolidinyl]-2-oxoethyl]cyclopropylamino]acetate obtained in Example 43 was dissolved in 50 ml of ethanol, and 2 ml, of 2N NaOH was added thereto. The reaction mixture was stirred for 2 hours and then evaporated under reduced pressure to remove the solvent. The residue was purified with column chromatography [eluent: ethanol] on NH—DM 1020 silica to obtain 25 mg of the title compound as a pale yellow solid.
Reaction SMILES: CCO.[OH:4][C:5]1[C:6]([C:19](=[N:38][OH:39])[CH2:20][CH2:21][C:22]2[S:23][C:24]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:25]=3[C:26]=2[CH2:27][CH2:28][CH3:29])=[CH:7][C:8]([CH3:18])=[C:9]([CH:17]=1)[O:10][CH2:11][C:12]([O:14]CC)=[O:13].O.[OH-].[Li+].Cl>O>[OH:4][C:5]1[C:6]([C:19](=[N:38][OH:39])[CH2:20][CH2:21][C:22]2[S:23][C:24]3[CH:33]=[C:32]([C:34]([F:36])([F:37])[F:35])[CH:31]=[CH:30][C:25]=3[C:26]=2[CH2:27][CH2:28][CH3:29])=[CH:7][C:8]([CH3:18])=[C:9]([CH:17]=1)[O:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCCc1c(CCC(=NO)c2cc(C)c(OCC(=O)OCC)cc2O)sc2cc(C(F)(F)F)ccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCc1c(CCC(=NO)c2cc(C)c(OCC(=O)O)cc2O)sc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Yield: 112.9 %

Procedure:
To a mixture of EtOH (0.2 mL) and H2O (0.1 mL) was suspended ethyl 5-hydroxy-4-[1-hydroxyimino-3-[3-propyl-6-(trifluoromethyl)-benzothiophen-2-yl]propyl]-2-methylphenoxyacetate (7.5 mg, 0.0143 mmol) obtained above. After the addition of lithium hydroxide monohydrate (1.8 mg, 0.0429 mmol), the mixture was heated for 1 hour under reflux, and then allowed to cool to room temperature and added ice-water. The mixture was acidified by addition of 1M HCl, and extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (8.0 mg, yield>99%) as a brown crystal.
Reaction SMILES: I[C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]([NH:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][NH:22]2)[CH2:15][CH3:16].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.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:27][C:28]1[CH:33]=[C:32]([C:2]2[C:7](=[O:8])[N:6]3[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]3=[N:4][C:3]=2[CH:14]([NH:17][C:18]2[N:26]=[CH:25][N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][NH:22]3)[CH2:15][CH3:16])[CH:31]=[CH:30][CH:29]=1
Reactant: CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)n2c(=O)c1I
Reactant: OB(O)c1cccc(F)c1
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: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)n2c(=O)c1-c1cccc(F)c1
Temperature: 100 °C

Procedure:
To a mixture of 3-iodo-6-methyl-2-[1-(9H-purin-6-ylamino)propyl]-4H-pyrido[1,2-a]pyrimidin-4-one (from example 3, step 2; 0.030 g, 0.065 mmol) and (3-fluorophenyl)boronic acid (Aldrich, 10.9 mg, 0.0780 mmol) in 1,4-dioxane (0.5 mL) was added a 1M solution of sodium carbonate (8.27 mg, 0.0780 mmol) in water (0.077 mL) and tetrakis(triphenylphosphine)palladium (0) (3.76 mg, 0.00325 mmol). The reaction mixture was heated at 100° C. overnight. After cooling to rt, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified on RP-HPLC at pH 10 conditions (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to provide the desired product. LCMS calculated for C23H21FN7O (M+H)+: m/z=430.2. Found: 430.3. 1H NMR (DMSO-d6, 300 MHz) δ 8.11 (2H, m), 7.65 (1H, m), 7.45 (2H, m), 7.24 (4H, m), 7.08 (1H, m), 6.91 (1H, m), 5.17 (1H, m), 2.87 (3H, s), 1.79 (2H, m), 0.72 ((3H, t, J=7.2 Hz) ppm. 19F NMR (DMSO-d6, 282 MHz) δ −114 ppm.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13](=[O:27])[NH:14][CH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[C:18](=[O:26])O[C:20]2=[O:25])([CH3:11])([CH3:10])[CH3:9].Cl.[C:29]([O:33][C:34](=[O:42])[C@H:35]([CH2:37][CH2:38][C:39](=[O:41])[NH2:40])[NH2:36])([CH3:32])([CH3:31])[CH3:30].O>C1(C)C=CC=CC=1.C(Cl)Cl>[C:29]([O:33][C:34](=[O:42])[C@@H:35]([N:36]1[C:18](=[O:26])[C:17]2[C:21](=[CH:22][CH:23]=[CH:24][C:16]=2[CH2:15][NH:14][C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:27])[C:20]1=[O:25])[CH2:37][CH2:38][C:39](=[O:41])[NH2:40])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(N)=O
Reactant: CC(C)(C)OC(=O)NCc1cccc2c1C(=O)OC2=O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCc1cccc2c1C(=O)N([C@@H](CCC(N)=O)C(=O)OC(C)(C)C)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
Triethylamine (1.2 g, 11.8 mmol) was added to a stirred suspension of (1,3-dioxo-1,3-dihydro-isobenzofuran-4-ylmethyl)carbamic acid t-butyl ester (2.1 g, 7.9 mmol) and L-glutamine t-butyl ester hydrochloride (2.1 g, 8.6 mmol) in toluene (90 mL). The mixture was refluxed under Dean-Stark water separator overnight. The mixture was cooled to room temperature and diluted with CH2Cl2 (60 mL). The solution was washed with H2O (2×40 mL) and brine (40 mL), and dried (MgSO4). Solvent was removed, and the residue was purified by chromatography (silica gel) to give (2S)-2-[4-(t-butoxycarbonylamino-methyl)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyric acid t-butylester (1.1 g, 29%): 1H NMR (CDCl3) δ 1.41 (s, 9H), 1.43 (s, 9H), 2.25-3.60 (m, 4H), 4.65 (d, J=6.5 Hz, 2H), 4.76-4.82 (dd, J=4.9 and 9.8 Hz, 1H), 5.47-5.61 (m, 3H), 7.67-7.79 (m, 3H); Chiral HPLC: Daicel ChiralPak AD, 46×250 mm, 20/80 IPA/hexane, 1 mL/min, 240 nm, 8.87 min (98% ee).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[NH:17]1[C:25]2[C:20](=[CH:21][C:22]([C:26](O)=O)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:26]([C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[NH:17][CH:18]=[CH:19]3)=[N:16][N:15]=1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc3[nH]ccc3c2)o1
Yield: 55 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (500 mg, 2.30 mmol) was converted using indole-5-carboxylic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 430 mg, 55%) which was obtained as a colorless liquid. MS: m/e=343.1 [M+H]+.