Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].C(N(CC)CC)C.[CH2:11]([N:13]1[C:25]2[CH:24]=[CH:23][C:22]([CH:26]=O)=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12]>O1CCCC1.O>[CH2:11]([N:13]1[C:25]2[CH:24]=[CH:23][C:22]([CH:26]=[N:2][NH2:3])=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12]
Reactant: NN
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCn1c2ccccc2c2cc(C=NN)ccc21
Temperature: 25 °C

Procedure:
A quantity of 98% by weight hydrazine monohydrate (50 ml, 1.4 mole, obtained from Aldrich, Milwaukee, Wis.) and 10 ml of triethylamine (obtained from Aldrich, Milwaukee, Wis.) were added to a 250 ml, 2-neck round bottom flask equipped with a mechanical stirrer and an addition funnel. The solution was stirred vigorously at room temperature for a period of 10–15 min. Then, a solution of 9-ethyl-3-carbazolecarboxaldehyde (22.3 g, 0.1 mol, obtained from Aldrich, Milwaukee, Wis.) in 30 ml of tetrahydrofuran (THF) was added slowly to the round bottom flask. After the addition of aldehyde was completed, the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with 50 ml of water. A precipitate was collected by filtration and washed repeatedly with water to give the crude 9-ethyl-3-carbazolecarboxaldehyde hydrazone, which was used in the next step immediately.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>CN(C=O)C.O>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([N:1]=[N+:2]=[N-:3])[CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(N=[N+]=[N-])C1
Temperature: 125 °C
Yield: 56.8 %

Procedure:
Sodium azide (6.96 g, 0.107 mol) and ammonium chloride (2.13 g, 0.0399 mol) were added to a solution of 1-(tert-butoxy carbonyl)3-[(methylsulphonyl)oxy]piperidine (10 g, 0.0358 mol) in DMF (75 ml) and water (12.5 ml). The mixture was heated overnight at 125° C. under stirring, cooled and diluted with water and extracted with chloroform. The organic layer was washed with water, dried over Na2SO4 and concentrated to give 4.6 g of thin reddish brown oil. 1H NMR (CDCl3) δ: 2.80-4.30 (m, 5H), 1.60-2.20 (m, 4H), 1.50 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1([CH3:21])[CH2:20][CH2:19][CH2:18][NH:17]1)[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:41][C:42](O)=[O:43])[CH:27]=[CH:28][C:29]=1[NH:30][C:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40])=[O:32].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:41][C:42]([N:17]2[CH2:18][CH2:19][CH2:20][C:16]2([CH2:15][O:14][C:13]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH3:21])=[O:43])[CH:27]=[CH:28][C:29]=1[NH:30][C:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40])=[O:32]
Reactant: COC(=O)c1ccc(OCC2(C)CCCN2)c([N+](=O)[O-])c1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)c1ccc(OCC2(C)CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 90 %

Procedure:
A mixture of methyl 3-nitro-4-(2-methyl-2-pyrrolidinylmethoxy)benzoate (0.188 g, 0.920 mmol), 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (0.289 g, 0.920 mmol), HOBt (0.149 g, 1.10 mmol), DMAP (11.2 mg, 0.0920 mmol) and EDC (0.211 g, 1.10 mmol) in DMF (5 mL) was stirred for 14 hr at room temp. EtOAC was added to the mixture and the solution was washed successively with 0.5 N HCl, sat. NaHCO3, and brine. The organic layer was dried over Na2SO4 and evaporated in vacuo to afford 0.489 g (q.y.) methyl 4-[[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-methyl-2-pyrrolidinyl]methoxy]-3-nitrobenzoate as a yellow crystalline material. 1H-NMR (CDCl3) δ1.26 (d, J=5.9 Hz), 1.85-4.50 (m, 10H), 2.30 (s, 3H), 3.67 (s, 2H), 3.92 (s, 3H), 6.36 (s, 2H), 6.75-7.52 (m, 7H), 8.02 (d, J=7.8 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 8.47 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22](I)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2].[N:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)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>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([C:46]3[CH:47]=[CH:48][N:43]=[CH:44][CH:45]=3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(I)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: OB(O)c1ccncc1
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(-c3ccncc3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 100 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-iodopyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (250 mg) is dissolved in N,N-dimethylformamide (2 ml), then thereto are added pyridine-4-boronic acid (87 mg), tetrakis(triphenylphosphine)palladium (81 mg) and potassium carbonate (117 mg), and the mixture is stirred at 100° C. under nitrogen flow for 2 hours. After allowing to cool to room temperature, water is added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (NH-silica gel; hexane: ethyl acetate=4:1) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(pyridin-4-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (131 mg). MS (m/z): 661 [M+H]+
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([OH:19])=[C:8]2[C:13](=[N:14][CH:15]=1)[N:12]=[C:11]([C:16]([OH:18])=[O:17])[CH:10]=[CH:9]2)=[O:5])C.[OH-].[K+].Cl>O>[OH:19][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:15][N:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11]([C:16]([OH:18])=[O:17])=[N:12]2
Reactant: CCOC(=O)c1cnc2nc(C(=O)O)ccc2c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc2c(O)c(C(=O)O)cnc2n1
Reaction time: 2 h

Procedure:
To a solution of 6-(ethoxycarbonyl)-5-hydroxy-1,8-naphthyridine-2-carboxylic acid (70 g, 270 mmol) in water (700 mL) was added potassium hydroxide (100 g, 560 mmol). The reaction mixture was heated to reflux. After 2 hours, the reaction mixture was cooled and acidified with hydrochloric acid (5 M) to pH 2.5. The yellow precipitates were filtered and washed with water and pyridine to afford 5-hydroxy-1,8-naphthyridine-2,6-dicarboxylic acid.
Reaction SMILES: C(O[C:6](=[O:15])[NH:7][CH2:8][CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])(C)(C)C.FC(F)(F)C(O)=O.COC([C:27]1[C:36]([OH:37])=[C:35]2[C:30]([CH:31]=[CH:32][C:33](=[O:45])[N:34]2[CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:29][N:28]=1)=O>C(Cl)Cl.CCOC(C)=O>[CH3:14][S:11]([NH:10][CH2:9][CH2:8][NH:7][C:6]([C:27]1[C:36]([OH:37])=[C:35]2[C:30]([CH:31]=[CH:32][C:33](=[O:45])[N:34]2[CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:29][N:28]=1)=[O:15])(=[O:12])=[O:13]
Reactant: COC(=O)c1ncc2ccc(=O)n(Cc3ccccc3)c2c1O
Reactant: CC(C)(C)OC(=O)NCCNS(C)(=O)=O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)NCCNC(=O)c1ncc2ccc(=O)n(Cc3ccccc3)c2c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 8 %

Procedure:
(2-Methanesulfonylamino-ethyl)-carbamic acid tert-butyl ester (77 mg, 0.32 mmol) was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (1 mL) was added, and the mixture was stirred at r.t. for 2 h. Solvent and excess TFA were removed by evaporation, and the residue was taken up in EtOH (2 mL). NaOMe was added with vigorous stirring until pH about 8. The resulting cloudy solution was transferred to a microwave vial containing 1-benzyl-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (25 mg, 0.081 mmol), and the mixture was heated at 140° C. for 6 h in a microwave reactor. The mixture was diluted with EtOAc and washed with 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was first purified by column chromatography (0-5% MeOH/CH2Cl2), then by preparative TLC (10% MeOH/CH2Cl2) to give 2.7 mg of the title compound as an off-white solid. MS: (+) m/z 417.30 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][CH2:5][NH2:6].[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1([C:26](Cl)=[O:27])[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2>>[CH3:1][O:2][C:3]([CH2:4][CH2:5][NH:6][C:26]([C:13]1([CH2:12][CH2:11][CH2:10][CH2:9][Br:8])[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:27])=[O:7]
Reactant: COC(=O)CCN
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: COC(=O)CCNC(=O)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from beta-alanine-methyl ester and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[H-].[Na+].Br[CH:21]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C1COCC1.CCOCC>[CH:21]1([N:15]2[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:17]=[CH:16]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: BrC1CCCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Oc1ccc2ncn(C3CCCCCC3)c2n1
Temperature: 25 °C
Yield: 17.3 %

Procedure:
5-(Benzyloxy)-3H-imidazo[4,5-b]pyridine (2.00 g, 8.88 mmol) was dissolved in THF and NaH (0.18 g, 14.7 mmol) was added portionwise. The resulting mixture was heated in a sealed tube for 1 h and then cooled to room temperature. Bromocycloheptane (3.14 g, 17.8 mmol) was added and the reaction was heated to 70° C. overnight. The solution was then diluted with ether and washed with water. The aqueous layer was back extracted with additional ether and the combined organic portions were washed with brine, dried over MgSO4 and purified by preparative HPLC. The resulting 5-(benzyloxy)-3-cycloheptyl-3H-imidazo[4,5-b]pyridine was then dissolved in MeOH with catalytic amount of 5% Pd/C and excess ammonium formate. The reaction mixture was heated to 80° C. until the reaction was complete. The solvent was removed under reduced pressure and the residue purified via preparative HPLC to give the title compound (0.356 g). LCMS m/z=232.1 [M+H]+; 1H NMR (400 MHz, acetonitrile-d3) δ ppm 1.55-1.80 (m, 6H), 1.80-1.90 (m, 2H), 2.05-2.20 (m, 4H), 4.50-4.60 (m, 1H), 6.57 (d, J=8.6 Hz, 1H), 7.85 (d, J=8.6 Hz, 1H), 7.96 (s, 1H).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[Cl:27][C:28]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31]>>[Cl:27][C:28]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:29]=1[C:30]([NH:26][C@H:23]1[CH2:22][CH2:21][C@H:20]([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][CH:12]([C:11]3[C:6]4[CH2:5][CH2:4][O:3][C:7]=4[CH:8]=[CH:9][CH:10]=3)[CH2:13][CH2:14]2)[CH2:25][CH2:24]1)=[O:31]
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc(Cl)cc1Cl

Procedure:
The title compound, white solid (97 mg, 78%), MS (ISP) m/z=501.1 [(M+H)+], mp 188° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 2,4-dichloro-benzoic acid.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([N+:10]([O-:12])=[O:11])=[CH:5][N:4]=1)#[N:2].[CH3:13][Mg]Br.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1>[C:1]([C:3]1[C:8]([CH3:9])=[C:7]([CH3:13])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][N:4]=1)#[N:2]
Reactant: Cc1cc([N+](=O)[O-])cnc1C#N
Reactant: C[Mg]Br
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Product: Cc1c([N+](=O)[O-])cnc(C#N)c1C
Temperature: -70 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
2-Cyano-3-methyl-5-nitropyridine (0.33 g, 2 mmol) was dissolved in 10 mL of THF and cooled in a dry ice/acetone bath under nitrogen. Methylmagnesium bromide (1.33 mL, 4 mmol) was added via syringe over five mins. The reaction was stirred for 2 h at −70° C. DDQ (0.068 g, 3 mmol) in 7 mL of THF was added and the mixture warmed to 25° C. The solvent was removed in vacuo and the residue was purified by silica gel chomatography using CH2Cl2 as the eluent to give compound 773A (0.15 g, 42%) as a red oil.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=2)[NH:11][C:10](=[O:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:20])[CH:26]=3)[CH:16]=2)[NH:11][C:10](=[O:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C1CN(Cc2ccccc2)c2cc(Br)ccc2N1
Product: O=C1CN(Cc2ccccc2)c2cc(-c3cccc(Cl)c3)ccc2N1

Procedure:
The title compound was prepared according to the procedure for Example 5 from 4-benzyl-6-bromo-3,4-dihydroquinoxalin-2(1H)-one (1.6 g, 5 mmol), and 3-chlorophenyl boronic acid (0.8 g, 5 mmol). An off-white powder (0.9 g, 51%): m.p.182-185° C. 1H-NMR (DMSO-d6) δ 3.74 (s, 2H), 4.54 (s, 2H), 6.87 (d, J=0.7 Hz), 7.0 (m, 2H), 7.36 (m, 8H), 7.52 (t, J=1.8 Hz, 1H), 10.57 (s, 1H), MS (ESI) m/z 349 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:10]#[C:11][Si](C)(C)C)[C:6]([NH2:9])=[N:7][CH:8]=1>CN1CCCC1=O.[Cu]I>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]2[CH:10]=[CH:11][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: C[Si](C)(C)C#Cc1cc(C(F)(F)F)cnc1N
Agent: [Cu]I
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1cnc2[nH]ccc2c1
Temperature: 190 °C
Reaction time: 0.5 h
Yield: 23.7 %

Procedure:
5-Trifluoromethyl-3-trimethylsilanylethynyl-pyridin-2-ylamine (43.8 g, 170 mmol) and copper(I) iodide (6.5 g, 34 mmol) were dissolved in N-methylpyrrolidone (0.85 L). The mixture was stirred at 190° C. for 30 min. The mixture was evaporated to remove N-methylpyrrolidone in vacuo. The residue was purified by flash column chromatography (QingDao silical gel, 200-300 mesh, 40% ethyl acetate/hexanes) to afford 5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine (7.5 g, 24%) as a yellow solid: LC/MS m/e calcd for C8H5F3N2 [M+H]+ 187.14, observed 187.0.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].I[CH:12](O)[C:13]([CH3:16])([CH3:15])[CH3:14]>>[CH3:12][C:13]([CH3:16])([CH3:15])[CH2:14][S:1][C:2]1[C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1cccnc1S
Reactant: CC(C)(C)C(O)I
Product: CC(C)(C)CSc1ncccc1C(=O)O
Yield: 16 %

Procedure:
2-Mercapto-nicotinic acid (0.5 g, 3.2 mmol) and 1-iodo-2,2-dimethyl-propanol were reacted in the same manner as in Step A of Preparation Example 10 to obtain the title compound (0.12 g, 16%).
Reaction SMILES: C([O:8][C:9](=[O:38])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH3:37])=[CH:31][CH:30]=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1>CO.CCOC(C)=O>[CH3:18][C:16]([CH3:17])([CH3:19])[C@H:15]([NH:14][C:12](=[O:13])[C@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH3:37])=[CH:31][CH:30]=2)=[CH:25]1)[CH2:10][C:9]([OH:38])=[O:8])[C:20](=[O:23])[NH:21][CH3:22]
Reactant: CCCc1ccc(-c2ccn([C@H](CC(=O)OCc3ccccc3)C(=O)N[C@H](C(=O)NC)C(C)(C)C)c2)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1ccc(-c2ccn([C@H](CC(=O)O)C(=O)N[C@H](C(=O)NC)C(C)(C)C)c2)cc1
Yield: 91 %

Procedure:
According to the procedure described in Example 1(a), N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]-3(R)-[3-(4-propylphenyl)-1H-pyrrol-1-yl]succinamic acid benzyl ester in MeOH and EtOAc was hydrogenolyzed to provide 30 mg (91%) of N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]-3(R)-[3-(4-propylphenyl)-1H-pyrrol-1-yl]succinamic acid as a yellow powder, mp 104-6° C.
Reaction SMILES: [CH2:1]([C:7]1[N:8]2[C:12](=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14]=1[C:15](=O)[CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:11][CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+].O.NN>C(O)COCCO>[CH2:1]([C:7]1[N:8]2[C:12](=[C:13]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:14]=1[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:11][CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1c(C(=O)CCCC(=O)O)c(-c2ccccc2)c2n1CCC2
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCCCCCc1c(CCCCC(=O)O)c(-c2ccccc2)c2n1CCC2

Procedure:
1 mmole of 71 is reacted in 10 ml of diethyleneglycol with 50 mmoles (2.8 g) of KOH and 30 mmoles (1.5 g) of hydrazine hydrate similarly to the procedure for reducing the 4-(diphenyl-2,3-dihydro-1H-pyrrolizinyl)-4-oxobutyric acids. Product purification is by means of column chromatography (silica gel/diisopropylether). After concentrating the eluates, 72 remains as an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:14]([NH:16][C@@H:17]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:18]([OH:47])[CH2:19][C@@H:20]([NH:34][C:35]([C@@H:37]([NH:42][C:43](=[O:46])[O:44][CH3:45])[C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:24][CH:23]=2)=[O:15])[C:9]1=[O:59])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:60]1(=[O:66])[O:65][C:63](=[O:64])[CH2:62][CH2:61]1.C1(NC2CCCCC2)CCCCC1>O1CCCC1.C(OCC)C>[CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:14]([NH:16][C@H:17]([C@@H:18]([O:47][C:60](=[O:66])[CH2:61][CH2:62][C:63]([OH:65])=[O:64])[CH2:19][C@H:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:24][CH:23]=2)[NH:34][C:35](=[O:36])[C@H:37]([C:38]([CH3:41])([CH3:40])[CH3:39])[NH:42][C:43](=[O:46])[O:44][CH3:45])[CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:15])[C:9]1=[O:59])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Reactant: O=C1CCC(=O)O1
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](OC(=O)CCC(=O)O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Yield: 98.5 %

Procedure:
A solution of Example 111 (60 mg, 0.074 mmol) in tetrahydrofuran (0.25 mL) and diethyl ether (0.5 mL) was treated with succinic anhydride (8.2 mg, 0.082 mmol) and dicyclohexylamine (16.3 μL, 0.082 mmol) at 25° C. for 6 h. Over the next 2 days more succinic anhydride (16.4 mg, 0.16 mmol) was added in portions. The mixture was partitioned between dichloromethane and 10% citric acid. The organic layer was separated, washed with brine, dried over MgSO4, and the solvents were evaporated to give the title compound (66 mg, 98%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.86(s, 9H), 0.89(s, 9H), 1.25(m, 1H), 1.66(m, 1H), 2.34-2.24(m, 1H), 2.83-2.55(m, 9H), 2.98-2.89(m, 1H), 3.22-2.12(m, 1H), 3.46(s, 3H), 3.86-3.83(d, J=9.93 Hz, 1H), 4.48-1.09(m, 6H), 5.15-5.10(m, 1H), 6.61-6.58(d, J=9.56 Hz, 1H), 7.05-7.00(m, 3H), 7.13-7.11(m, 2H), 7.31-7.25(m, 4H), 7.44-7.36(m, 3H), 7.92-7.87(m, 3H), 7.96(m, 2H), 8.06-8.02(d, J=9.56 Hz, 1H), 8.68-8.66(m, 1H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]([NH2:10])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[NH:1]1[C:5]2=[N:6][C:7]([N:10]3[C:14](=[O:15])[C:13]4[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:11]3=[O:16])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1ccc2cc[nH]c2n1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1c1ccc2cc[nH]c2n1
Temperature: 120 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
1H-Pyrrolo[2,3-b]pyridin-6-ylamine (0.12 g, 0.9 mmol) was suspended in acetic acid (1.5 mL), then phthalic anhydride (133 mg, 0.9 mmol) and sodium acetate (118 mg, 1.44 mmol) were added and the mixture heated to 120° C. After 3 h, the mixture was concentrated in vacuo, the residue obtained dissolved in ethyl acetate, and then cooled to 0° C. Ice-water and sodium bicarbonate solution were added then the aqueous layer was extracted with ethyl acetate. The aqueous layer was adjusted to pH 6 with 1M HCl solution and was extracted twice more with ethyl acetate. The combined organic layers were dried over sodium sulfate then concentrated in vacuo. Purification by chromatography (silica, 20 to 70% ethyl acetate in hexanes) gave 2-(1H-pyrrolo[2,3-b]pyridin-6-yl)-isoindole-1,3-dione (179 mg, 75%) as a light brown solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.91 (br. s., 1H) 8.15 (d, J=7.9 Hz, 1H) 7.90-8.05 (m, 4H) 7.59-7.65 (m, 1H) 7.21 (d, J=7.9 Hz, 1H) 6.54-6.60 (m, 1H); LCMS (EI/CI) m/z: 264 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.[Br:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26]Br)=[N:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][O:1][C:2]2[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=3)[C:4](=[O:18])[CH:3]=2)=[N:24][CH:25]=1
Reactant: BrCc1ccc(Br)cn1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccc(Br)cn2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1.23 g (5.00 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) in 8.0 mL DMF is added 1.26 g (5.00 mmol) 5-bromo-2-bromomethyl-pyridine and 2.07 g (15.0 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT, diluted with 80 mL of water, the formed precipitate is collected and dissolved in DMF. The solution is directly transferred to a reverse HPLC for purification (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]([CH3:14])[C:11](O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].S(C)C.B.C1COCC1.O>C1COCC1.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]([CH3:14])[CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](CNC(=O)OC(C)(C)C)C(=O)O
Agent: B
Solvent: O
Solvent: CSC
Solvent: ClCCl
Product: C[C@@H](CO)CNC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
To a 0° C. mixture of (2R)-3-t-butoxycarbonylamino-2-methylpropionic acid (4.6 g, 21.0 mmol) in THF (100 mL) was added 2 M Me2S.BH3/THF (16 mL, 31.5 mmol, 1.5 equivalents). After stirring for 2 h, water was added and the mixture stirred for 18 h. The mixture was diluted with CH2Cl2 and washed with satd Na2CO3. The organic layer was dried (Na2SO4), concentrated, and chromatographed (CH2Cl2; EtOAc) to give the title compound as an oil (2.4 g, 61%).