Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:35])[CH:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][C:23]3=[N:32][C:33]#[N:34])[CH2:18][CH2:17]2)[CH3:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[BH4-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]([OH:35])[CH:14]([N:16]2[CH2:17][CH2:18][CH:19]([N:22]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][C:23]3=[N:32][C:33]#[N:34])[CH2:20][CH2:21]2)[CH3:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C(=O)C(C)N2CCC(N3Cc4ccccc4NC3=NC#N)CC2)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C(O)C(C)N2CCC(N3Cc4ccccc4NC3=NC#N)CC2)cc(OC)c1OC
Yield: 65.1 %

Procedure:
In this example, 848 mg of the product obtained in Example 7 is dissolved in 30 ml of ethanol. The solution is subjected to reaction in the same conditions as those of Example 6 by using 1 g of sodium borohydride. The reaction mixture is subjected to the same post-treatment as that of Example 6 to obtain crude crystals. The crude crystals are recrystallized from methanol to obtain 554 mg of the desired product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@:4]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[N:25]=[CH:24][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:22][C:21]=3[CH2:20]2)=[O:18])[CH2:8][C@H:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5]1.[C:33]1([Se:39]N2C(=O)C3=CC=CC=C3C2=O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.B(F)(F)F.[OH-].[Na+]>C(Cl)Cl.O>[C:33]1([Se:39][C@@H:6]2[C@H:5]3[O:1][CH2:2][CH2:3][C@@:4]3([C:17]([N:19]3[CH2:28][CH2:27][C:26]4[N:25]=[CH:24][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:22][C:21]=4[CH2:20]3)=[O:18])[CH2:8][C@@H:7]2[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C1c2ccccc2C(=O)N1[Se]c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@](CCO)(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1C[C@]2(C(=O)N3CCc4ncc(C(F)(F)F)cc4C3)CCO[C@@H]2[C@H]1[Se]c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of the product of Step D (1.51 g, 3.32 mmol, 1 eq) in DCM (40 mL) at rt under Ar was added N-(phenylseleno)phthalimide (1.60 g, 4.97 mmol, 1.5 eq) and BF3-etherate (0.042 mL, 0.33 mmol, 0.1 eq). After 2 hrs, 1 N NaOH was added and stirred 5 min., water was added, the solution extracted with DCM, the organics combined, dried over MgSO4, and concentrated. Purification by chromatography (80 g column) eluting with 50 to 100% EtOAc/heptane afforded the title compound of Step E. 1H NMR (CHLOROFORM-d) δ: 8.72 (s, 1H), 7.69 (s, 1H), 7.50-7.62 (m, 2H), 7.22-7.27 (m, 3H), 5.35 (s, 1H), 5.06 (d, J=8.1 Hz, 1H), 4.79-5.01 (m, 1H), 4.66-4.78 (m, 1H), 4.53 (br. s., 1H), 3.78-4.06 (m, 4H), 3.68-3.78 (m, 1H), 3.05-3.19 (m, 2H), 2.32 (dd, J=11.6, 5.8 Hz, 2H), 2.16 (d, J=10.9 Hz, 2H), 1.36 (s, 9H). Calculated for C28H32F3N3O4Se: 634.2 (M+23). found: 634.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1B(O)O.[CH3:14][C:15]([NH:22][S:23]([C:26]1[CH:27]=[N:28][C:29](Cl)=[CH:30][CH:31]=1)(=[O:25])=[O:24])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:21][C:15]([NH:22][S:23]([C:26]1[CH:27]=[N:28][C:29]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=2[O:9][CH3:10])=[CH:30][CH:31]=1)(=[O:25])=[O:24])([CH3:14])[CH2:16][C:17]([CH3:18])([CH3:19])[CH3:20]
Reactant: COc1cccc(OC)c1B(O)O
Reactant: CC(C)(C)CC(C)(C)NS(=O)(=O)c1ccc(Cl)nc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cccc(OC)c1-c1ccc(S(=O)(=O)NC(C)(C)CC(C)(C)C)cn1
Temperature: 90 °C

Procedure:
2,6-dimethoxyphenylboronic acid (1.0 g, 5.5 mmol), 6-Chloro-pyridine-3-sulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (555 mg, 1.8 mmol) and potassium carbonate (1.0 g, 7.3 mmol) were added to a degassed solution of tetrakis(triphenylphosphine) palladium (404 mg, 0.35 mmol) in toluol (12 ml) and ethanol (6 ml) and heated in a microwave reactor for 90 minutes at 90° C. The mixture was evaporated to dryness, suspended in 50 methanol and filtered off. The filtrate was evaporated to dryness and the residue was purified by flash chromatography (SiO2, heptane-ethyl acetate gradient) to return 639 mg of the title compound as an off-white solid, m/z=407 (ES+), 405 (ES−).
Reaction SMILES: [Li+].[OH-].C([O:5][C:6](=[O:20])[CH2:7][NH:8][C:9](=[O:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)C>C1COCC1.CO.O>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][C:9]([NH:8][CH2:7][C:6]([OH:20])=[O:5])=[O:19])=[CH:13][CH:14]=1
Reactant: CCOC(=O)CNC(=O)CCc1ccc(O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CNC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.6 %

Procedure:
LiOH (56 mg, 2.33 mmol) was added at room temperature to a stirred solution of [3-(4-hydroxy-phenyl) propionylamino]-acetic acid ethyl ester (151 mg, 0.6 mmol) in THF:MeOH:H2O (3:1:1, 5 mL). The resulting mixture was stirred at room temperature for five hours. The MeOH and THF were then evaporated and the residue was diluted with water (2 mL), acidified with 20% aqueous HCl and extracted with EtOAc. The organic layer was washed with saturated brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford 120 mg (89.55% yield) of [3-(4-hydroxy-phenyl) propionylamino]-acetic acid as a pale white solid (120 mg). LCMS purity: 90.42%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][CH:31]2[CH2:39][CH3:40])=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:39]([CH:31]1[CH2:32][C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:30]1[C:28]([C:24]1[N:25]=[CH:26][N:27]=[C:22]([N:17]2[CH2:18][CH2:19][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:15][CH2:16]2)[CH:23]=1)=[O:29])[CH3:40]
Reactant: CCC1Cc2ccccc2N1C(=O)c1cc(Cl)ncn1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC1Cc2ccccc2N1C(=O)c1cc(N2CCC(N3CCc4cc(OC)ccc4NC3=O)CC2)ncn1

Procedure:
110 mg (0.40 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 103 mg (0.36 mmol) (6-chloro-pyrimidin-4-yl)-(2-ethyl-2,3-dihydro-indol-1-yl)-methanone and 0.14 mL (0.80 mmol) DIPEA in 3.0 mL DMF were stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined, the organic solvent was evaporated down and the residue was neutralised with 1N aqueous sodium hydroxide solution. The precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][C:7]2[C:10]3[C:15]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=4)=[N:14][CH:13]=[N:12][C:11]=3[S:24][C:6]=2[CH2:5]1.[I-].[Na+].[CH3:27][O-:28].[Na+]>CN(C=O)C>[Br:23][C:19]1[CH:18]=[C:17]([NH:16][C:15]2[C:10]3[C:7]4[CH2:8][CH2:9][CH:4]([CH2:3][CH2:2][O:28][CH3:27])[CH2:5][C:6]=4[S:24][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: C[O-]
Reactant: BrCCC1CCc2c(sc3ncnc(Nc4cccc(Br)c4)c23)C1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCC1CCc2c(sc3ncnc(Nc4cccc(Br)c4)c23)C1
Temperature: 80 °C
Yield: 43.5 %

Procedure:
To a solution of DMF were added 52 mg (0.11 mmol, 1 equiv) of N-[7-(2-bromoethyl)5,6,7,8tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl]-N-(3-bromophenyl)amine, 17 mg (0.11 mmol, 1 equiv) sodium iodide, and 18 mg (0.33 mmol, 3 equiv) sodium methoxide. The solution was heated at 80° C. for 2 h and upon cooling the solution was purified by prep HPLC (10–90% ACN-H2O). The resulting pure fractions were made basic in aqueous saturated sodium bicarbonate and extracted into EtOAc (10 mL). The EtOAc layer was washed with water (1×10 mL) and dried over MgSO4. The solution was evaporated under reduced pressure yielding 20 mg (44%) of desired product, 90, as a white solid. 1H-NMR (CDCl3-d) δ 8.52 (s, 1H), 7.94 (m, 1H), 7.59 (m, 1H), 7.24 (m, 2H), 7.13 (s, 1H), 3.55 (t, 2H), 3.39 (s, 3H), 3.12 (m, 2H), 3.01 (m, 1H), 2.56 (m, 1H), 2.13 (m, 2H), 1.74 (m, 3H); TLC Rf=0.75 (9:1 CH2Cl2/MeOH); LCMS RT=3.57 min; [M+H]+=418.2.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([OH:13])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.N1C=CN=C1.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C1COCC1>[C:20]([Si:23]([CH3:25])([CH3:24])[O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([OH:13])=[O:12])[NH:8]2)=[CH:4][CH:3]=1)([CH3:22])([CH3:21])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(O)c1cc2ccc(O)cc2[nH]1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(C(=O)O)[nH]c2c1
Reaction time: 0.08 h
Yield: 90.1 %

Procedure:
6-Hydroxy-1H-indole-2-carboxylic acid (5.40 g, 30.48 mmol) is dissolved in THF (100 ml) and imidazole (10.38, 152.4 mmol) is added. The mixture is stirred for 5 minutes, TBDMS-Cl (13.78 g, 91.44 mmol) is added. The reaction is stirred at room temperature for 1 hour. The mixture is filtered into water (200 ml). The solid is washed with THF (50 ml). The filtrate is concentrated to remove THF. The product is extracted with ethyl acetate (100 ml) three times. The organic is dried (MgSO4), filtered, and concentrated to provide 6-(tert-Butyl-dimethyl-silanyloxy)-1H-indole-2-carboxylic acid (8.0 g, 90% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.73 (s, 1H) , 11.43 (s, 1H), 7.49 (d, 1H), 7.00 (s, 1H), 6.84 (s, 1H), 6.63 (m, 1H), 0.97 (s, 9H), 0.20 (s, 6H).
Reaction SMILES: [OH:1][CH:2]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].C1([O:24][C:25](=O)[NH:26][C:27]2[N:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[N:28]=2)C=CC=CC=1.C1CCN2C(=NCCC2)CC1.CCCCCl>Cl.C(Cl)Cl>[CH3:34][O:33][C:31]1[CH:30]=[C:29]([O:35][CH3:36])[N:28]=[C:27]([NH:26][C:25]([NH:12][S:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:2]([OH:1])[C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:11])=[O:24])[N:32]=1
Reactant: NS(=O)(=O)c1ccccc1C(O)c1cccs1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCCCCl
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C(O)c2cccs2)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 35.9 %

Procedure:
To 0.5 g of the product of Example 6, dissolved in 30 mL of p-doxane, was added 0.51 g of phenyl(4,6-dimethoxypyrimidin-2-yl)carbamate followed by 0.27 mL of "DBU". The reaction was stirred for 1.5 hours, diluted with 45 mL of ice-water and acidified with 10 drops of concentrated hydrochloric acid to obtain an oily precipitate. The water was decanted from the oil and the oily residue was dissolved in methylene chloride, washed with water and brine, and finally dried (MgSO4). Filtration and concentration of the filtrate, in vacuo, yielded an oil. Trituration with a 10:1 mixture of n-chlorbutane and methylene chloride provided 0.3 g of the subject compound as an off-white solid, m.p. 152°-54°.
Reaction SMILES: [OH:1][C:2]([CH3:17])([CH3:16])[CH:3]([NH:8][C:9](=[O:15])OC(C)(C)C)[C:4](=[O:7])[NH:5][CH3:6].FC(F)(F)C(O)=O.[CH:25]1([C:28]2[C:29]([O:37][C@@H:38]([CH3:43])[C:39]([F:42])([F:41])[F:40])=[CH:30][C:31](C(O)=O)=[N:32][CH:33]=2)[CH2:27][CH2:26]1>ClCCl>[CH:25]1([C:28]2[C:29]([O:37][C@@H:38]([CH3:43])[C:39]([F:42])([F:40])[F:41])=[CH:30][C:31]([C:9]([NH:8][CH:3]([C:2]([OH:1])([CH3:16])[CH3:17])[C:4]([NH:5][CH3:6])=[O:7])=[O:15])=[N:32][CH:33]=2)[CH2:27][CH2:26]1
Reactant: CNC(=O)C(NC(=O)OC(C)(C)C)C(C)(C)O
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)C(NC(=O)c1cc(O[C@@H](C)C(F)(F)F)c(C2CC2)cn1)C(C)(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl N-[2-hydroxy-2-methyl-1-(methylcarbamoyl)propyl]carbamate (example 236a, 760 mg, 1.94 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (3.00 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated down to dryness and the crude residue was dissolved in toluene. Volatiles were removed in vacuo to afford a white solid which was dried in HV overnight to yield the crude amine (680 mg) as a trifluroacetate salt which was used without any purification. The crude amine salt was used to synthesize the title compound in analogy to Example 112e, using 5-Cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (Example 68a) as starting materials and the title compound was isolated (76 mg, 59%); MS (ESI, m/z): 404.6 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:4]([NH:11][C@H](C2C=CC=CC=2)CO)[CH2:3]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].Cl>CO>[CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:4]([NH2:11])[CH2:3]1
Reactant: CC1(C)C[C@H](N[C@@H](CO)c2ccccc2)c2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Pb+4]
Solvent: CO
Product: CC1(C)C[C@H](N)c2ccccc21
Reaction time: 0.75 h
Yield: 51 %

Procedure:
A solution of (2R)-2-{[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-2-phenylethanol (1.44 g, 5.13 mmol) in MeOH (40.0 mL) was added to a stirred solution of lead tetraacetate (3.75 g, 8.03 mmol) in MeOH (60.0 mL) at 0° C. dropwise over 20 min. After stirring for 45 min, the reaction was quenched via addition of a 10% solution of Na2CO3 in H2O (76.0 mL) and the mixture was stirred for 10 min. DCM (200 mL) was then added and the layers were separated. The aqueous layer was extracted with DCM (50.0 mL). The combined organic layers were concentrated in vacuo and the residue was dissolved in EtOH (190. mL) and treated with a 10.4 M aqueous solution of HCl (5.70 mL, 59.3 mmol). The resulting mixture was then heated to reflux for 16 h. The cooled reaction was concentrated in vacuo and partitioned between H2O (150. mL) and Et2O (50.0 mL). The aqueous layer was adjusted to pH 10 via addition of Na2CO3 and extracted with Et2O (3×50.0 mL). The combined organic layers were concentrated in vacuo and silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to afford the title compound as a pale yellow oil (420. mg, 51%). 1H NMR (CD3OD, 300 MHz) δ: 7.34-7.14 (m, 4H), 4.45-4.37 (m, 1H), 2.38 (dd, J=7.1, 12.4 Hz, 1H), 1.73 (bs, 2H), 1.60 (dd, J=8.7, 12.4 Hz, 1H), 1.39 (s, 3H), 1.19 (s, 3H) ppm.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)C(C)C)(C)C.[NH2:53][C:54]1[NH:58][N:57]=[N:56][N:55]=1>CN(C)C=O>[CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:53][C:54]2[N:55]=[N:56][NH:57][N:58]=2)=[O:28])=[CH:24][N:23]=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: CC(C)CC(Nc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)O)cn1
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC(Nc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)Nc2nn[nH]n2)cn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
To a solution of 6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-ylamino)butyl) nicotinic acid (0.100 g, 0.233 mmol) in N,N-dimethylformamide (1.5 mL) was added 1,1′-carbonyldiimidazole (49.1 mg, 0.303 mmol) and N,N-diisopropylethylamine (45.2 mg, 0.350 mmol). The mixture was stirred for 30 minutes at 80° C. 5-Aminotetrazole (59.5 mg, 0.699 mmol) was then added. The resulting mixture was stirred overnight at 80° C. The reaction was concentrated and purification by preparative HPLC gave 6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-ylamino)butyl)-N-(2H-tetrazol-5-yl)nicotinamide (50.0 mg, 43%) as a light yellow solid. 1H NMR (400 MHz, CD3OD, 5): 8.90 (s, 1H), 8.05-8.15 (d, 1H), 7.52-7.69 (m, 5H), 7.35-7.38 (m, 2H), 6.61-6.69 (m, 2H), 4.69 (m, 1H), 1.76-1.88 (m, 2H), 1.60-1.70 (m, 1H), 0.98-1.03 (m, 6H). MS (M+1): 496.3.
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:5]=[C:4]([I:16])[N:3]=1.C([Li])CCC.O.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[I:16][C:4]1[CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:7]([O:8][CH3:9])=[CH:2][N:3]=1
Reactant: COCCCOc1cc(I)nc(I)c1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COCCCOc1cc(I)ncc1OC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
2 mmol of 2,6-diiodo-3-methoxy-4-(3-methoxy-propoxy)-pyridine are added to a solution of 4 mmol n-butyllithium in 1.6 ml hexane and 10 ml tetrahydrofuran at −78° C. under an argon atmosphere. The reaction mixture is stirred at −78° C. for 15 minutes. 2 mmol of water are introduced and the reaction mixture is allowed to reach room temperature. 10% Aqueous ammonium chloride solution is added to the mixture followed by extraction with tert-butyl methyl ether (3×). The combined organic layers are dried over sodium sulphate, filtered and concentrated. The title compound is obtained from the residue by means of flash chromatography (SiO2 60 F) and identified based on its Rf value.
Reaction SMILES: Cl(O)(=O)(=O)=O.[Br:6][C:7]1[C:8]2[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=2[S:10][C:11]=1[CH:12]([OH:17])[C:13]([O:15][CH3:16])=[O:14]>C(OC(C)(C)C)(=O)C>[Br:6][C:7]1[C:8]2[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=2[S:10][C:11]=1[CH:12]([O:17][C:8]([CH3:21])([CH3:9])[CH3:7])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(O)c1sc2ccccc2c1Br
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)C(OC(C)(C)C)c1sc2ccccc2c1Br
Reaction time: 1 h
Yield: 150.5 %

Procedure:
Under a nitrogen atmosphere, perchloric acid (70%, 1.9 mL) was added at −10° C. to a solution of methyl (3-bromo-benzo[b]thiophen-2-yl)-hydroxy-acetate (21c) (560 mg, 1.86 mmol) in tertbutyl acetate (15 mL). After 1 hour, the reaction was quenched with a saturated solution of sodium carbonate and extracted with dichloromethane (2×30 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 95/5) to afford the desired product (21d) as a yellow oil (500 mg, 1.40 mmol, 75%).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=1.O.[NH2:32][NH2:33]>CN(C=O)C>[C:28]([C:24]1[CH:23]=[C:22]([CH2:21][CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:33][N:32]=2)[CH:27]=[CH:26][CH:25]=1)#[N:29]
Reactant: NN
Reactant: N#Cc1cccc(CCC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)c1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(CCc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)c1
Yield: 93.2 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-3-(3-cyanophenyl)propyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (495 mg, 1.25 mmol, prepared in Synthetic Example 12) in DMF (12 ml) was added hydrazine monohydrate (80%, 148 μl, 3.69 mmol, 3.0 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-[2-(3-cyanophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (456 mg, 93%).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:7]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=O.C1C=CC2N(O)N=[N:28]C=2C=1.CN1CCOCC1.C(Cl)CCl.[OH-].[NH4+]>C1COCC1>[C:18]([O:17][C:15](=[O:16])[NH:14][CH2:13][C:5]1([C:3](=[O:2])[NH2:28])[C:7]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)C1(CNC(=O)OC(C)(C)C)CC12CCCCC2
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC1(C(N)=O)CC12CCCCC2
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino-methyl)-spiro[2.5]octane-1-carboxylic acid methyl ester (17.9 g, 63.2 mmol) in THF (700 mL) was added HOBT (9.00 g, 66.4 mmol), 4-methylmorpholine (7.3 mL, 66.4 mmol) followed by EDC (13.9 g, 72.7 mmol). The solution was stirred for 2 hours and then concentrated ammonium hydroxide (8.5 mL, 126 mmol) was added. The mixture was stirred for 18 hours and then the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and half saturated potassium hydrogen sulfate. An emulsion occurred but the layers were separable. The organic layer was washed with half saturated potassium hydrogen sulfate (2 times) and brine. The organic layer was filtered to remove the emulsified solid. The organic layer was dried over sodium sulfate and filtered. Hexane was added to the filtrate to induce crystallization. The precipitate was isolated by vacuum filtration, washed with hexane and dried in a vacuum oven to give 16.2 g (91%) of (1-carbamoyl-spiro[2.5]oct-1-ylmethyl)-carbamic acid tert-butyl ester as a white solid: 1H NMR (300 MHz, CDCl3) δ 0.65 (d, J=5.0 Hz, 1H), 1.17 (d, J=5.0 Hz, 1H), 1.43(s, 9H), 1.4-1.5 (m, 4H), 1.7-1.7 (m, 6H), 3.37 (dd, J=6.0, 14.0 Hz, 1H), 3.60 (dd, J=6.0, 14.0 Hz, 1H), 5.0 (s, 1H), 5.38 (s, 1H), 6.1 (s, 1H); MS (APCI) m/z 283 [M+H]+.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40](OC)=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].[OH-].[Na+].Cl.OC(C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)(C1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.[CH:89]1([NH2:92])[CH2:91][CH2:90]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C1COCC1.O.CO>[CH:89]1([NH:92][C:40]([C:35]2[CH:34]=[CH:33][C:32]3[C:37](=[CH:38][CH:39]=[C:30]([C:2]([OH:1])([C:6]4[N:7]=[CH:8][NH:9][CH:10]=4)[CH:3]([CH3:5])[CH3:4])[CH:31]=3)[CH:36]=2)=[O:41])[CH2:91][CH2:90]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)C(O)(c1ccc2cc(C(=O)NC3CC3)ccc2c1)c1c[nH]cn1
Reaction time: 2 h

Procedure:
To a solution of methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (16.5 g) in THF (160 mL) was added methanol (35 mL) and 4N-NaOH (35 mL) at 60° C. The mixture was stirred for 2 h, neutralized with conc.HCl. The mixture was concentrated, diluted with water and extracted with ethyl acetate. The extract was concentrated to give crude mixture of 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid. To a solution of the crude mixture was added cyclopropylamine (3.24 mL), 1-hydroxybenzotriazole (5.37 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.72 g) under ice cooling. The mixture was stirred at room temperature for 63 h, diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried and concentrated. The residue was washed with diethyl ether to give the titled compound (17.6 g) as a colorless powder.