Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]3[N:13]([C:18]4[CH:23]=[CH:22][C:21](B5OC(C)(C)C(C)(C)O5)=[CH:20][CH:19]=4)[C:14](=[O:17])[NH:15][N:16]=3)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.Br[C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[CH2:39][CH2:38][CH2:37]2.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]3[N:13]([C:18]4[CH:23]=[CH:22][C:21]([C:34]5[CH:35]=[C:36]6[C:40](=[CH:41][CH:42]=5)[CH2:39][CH2:38][CH2:37]6)=[CH:20][CH:19]=4)[C:14](=[O:17])[NH:15][N:16]=3)[CH2:7]2)=[O:5])[CH2:2][CH2:3]1
Reactant: Brc1ccc2c(c1)CCC2
Reactant: CC1(C)OB(c2ccc(-n3c(C[C@@H]4CCN(C(=O)C5CC5)C4)n[nH]c3=O)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4c(c3)CCC4)cc2)C1
Temperature: 25 °C
Yield: 39 %

Procedure:
A solution of 5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (0.252 mmol) in dioxane (1.5 mL) was treated with 5-bromo-2,3-dihydro-1H-indene (0.252 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (10 mg), and 2M aq potassium carbonate (0.756 mmol). The reaction mixture was purged with nitrogen, sealed, and irradiated in a microwave (Biotage Initiator) at 150° C. for 15 min. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). The aqueous layer was acidified to pH ˜4 using 1N aq HCl and was extracted with dichloromethane. The resulting organic phase was treated with Si-Thiol (Silicycle, 20 mg), dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC (35-65% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions from the HPLC were combined, adjusted to pH˜5 with the addition of saturated aq sodium bicarbonate, and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound as an amorphous off-white solid (39%). MS(ES)+ m/e 429.1 [M+H]+.
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]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22](O)=[O:23])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[NH:49]1[CH2:59][CH2:58][CH2:57][CH2:56][CH:50]1[C:51]([O:53]CC)=[O:52]>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([N:49]3[CH2:59][CH2:58][CH2:57][CH2:56][CH:50]3[C:51]([OH:53])=[O:52])=[O:23])[C:17]1=[O:26])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: CCOC(=O)C1CCCCN1
Reactant: C[C@@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](C(=O)N1CCCCC1C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.9 %

Procedure:
To a solution of (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid (0.025 g) in DCM (10 ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.036 g), HOBT (0.026 g) and triethylamine (0.026 ml) and the mixture was stirred at room temperature for 30 min. Ethyl pipecolinate (0.030 g) was added and the resultant mixture stirred at room temperature for 16 h. The mixture was partitioned between DCM and water. The aqueous layer was re-extracted with DCM and the combined, dried (over magnesium sulphate) organic extracts were concentrated under reduced pressure. The residue was then dissolved in a mixture of THF (1 ml) and water (1 ml), treated with lithium hydroxide (0.005 g) and stirred at room temperature for 18 h. The reaction mixture was acidified to pH5 using hydrochloric acid (2N) and concentrated under reduced pressure. The residue was purified using SPE (aminopropyl stationary phase, washed with methanol and eluted with 10% hydrochloric acid in methanol) to give the title compound (0.007 g) as white solid.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]=1[C:30](O)=[O:31]>>[CH3:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]=1[C:30]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:3][CH:4]2[CH2:8]1)=[O:31]
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Reactant: Cc1ccc2ccccc2c1C(=O)O
Product: Cc1ccc2ccccc2c1C(=O)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 2-methyl-naphthalene-1-carboxylic acid. MS (ESI) mass calcd. for C25H22N4OS, 426.54; m/z found, 427.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[CH:9]=2)=[CH:4][CH:3]=1.[CH2:14]([O:16][C:17]([C:19]1([C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)[CH2:21][CH2:20]1)=[O:18])[CH3:15]>>[CH2:14]([O:16][C:17]([C:19]1([C:22]2[CH:27]=[CH:26][C:25]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[CH:9]=4)=[CH:4][CH:3]=3)=[CH:24][CH:23]=2)[CH2:20][CH2:21]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1cc(-c2ccc(Br)cc2)on1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4cc(C)no4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 5-(4-bromo-phenyl)-3-methyl-isoxazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([PH:12](=O)[C:13]2[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([N:22]([CH3:24])[CH3:23])=[C:15]([CH:25]([CH3:27])[CH3:26])[CH:14]=2)=[CH:5][C:4]=1[CH:29]([CH3:31])[CH3:30].[BH3:33].O1CCCC1>C1(C)C=CC=CC=1>[CH3:32][N:2]([CH3:1])[C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([PH:12][C:13]2[CH:18]=[C:17]([CH:19]([CH3:20])[CH3:21])[C:16]([N:22]([CH3:24])[CH3:23])=[C:15]([CH:25]([CH3:27])[CH3:26])[CH:14]=2)=[CH:5][C:4]=1[CH:29]([CH3:31])[CH3:30].[BH3:33]
Reactant: CC(C)c1cc([PH](=O)c2cc(C(C)C)c(N(C)C)c(C(C)C)c2)cc(C(C)C)c1N(C)C
Agent: B
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)c1cc(Pc2cc(C(C)C)c(N(C)C)c(C(C)C)c2)cc(C(C)C)c1N(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
Under an argon atmosphere, to a solution of bis(4-dimethylamino-3,5-diisopropylphenyl)phosphine oxide (8.08 g, 18 mmoL) synthesized in Example 7 in toluene (48 mL) was added borane-tetrahydrofuran solution (60 mL, 3.3 equivalents) at 25° C. to 30° C. over 2 hr. Then, silica gel (7.0 g, 6.3 equivalents) was added to the mixture, and the mixture was stirred at room temperature for 1 hr. Then, silica gel was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from n-hexane to give the title compound (5.5 g, white crystals). yield 67%.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([NH2:16])=O)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]#[N:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C#N)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
A solution containing 6.2 g (0.02 mole) of 2-[4-(4-trifluoromethylphenoxy)phenoxy] propanamide and 10.0 ml of phosphorus oxychloride in 50 ml of toluene is stirred at 50° until reaction is complete, as indictated by vpc techniques. The reaction mixture is cooled and poured into crushed ice, whereupon the toluene layer is washed with water, dried, and concentrated in vacuo. Purification is effected by elution through a pad of silica gel (50% toluene/hexane) to afford a colorless solid, mp 53°-56°.
Reaction SMILES: [CH3:1][OH:2].[Na].[NH2:4][C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([CH2:12][CH2:13][CH3:14])[N:6]=1.O>C(Cl)(Cl)Cl>[NH2:4][C:5]1[CH:10]=[C:9]([O:2][CH3:1])[N:8]=[C:7]([CH2:12][CH2:13][CH3:14])[N:6]=1
Reactant: CCCc1nc(N)cc(Cl)n1
Reactant: CO
Agent: [Na]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCc1nc(N)cc(OC)n1

Procedure:
To a mixture of 25 ml of methanol and 1.1 g (0.048 mole) of sodium was added 5.1 g (0.030 mole) of 4-amino-6-chloro-2-(n-propyl)pyrimidine, and the resulting mixture was heated at reflux for four days. The mixture was allowed to cool to about 20° C., at which time water and chloroform were added thereto. The layers were separated, and the aqueous layer was extracted with additional chloroform. The organic layers were combined, dried over magnesium sulfate, and evaporated to provide a residue. The residue was recrystallized from cyclohexane with treatment with decolorizing charcoal to provide white solid 4-amino-6-methoxy-2-(n-propyl)pyrimidine, m.p. 97°-99° C. The structural assignment was supported by nuclear magnetic resonance and infrared spectral analyses.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17](B3OC(C)(C)C(C)(C)O3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].Br[C:35]1[CH:36]=[C:37]([C:41]2[CH:46]=[C:45]([NH:47][CH3:48])[N:44]=[C:43]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=3)[CH:42]=2)[CH:38]=[N:39][CH:40]=1>COCCOC.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([C:35]3[CH:36]=[C:37]([C:41]4[CH:46]=[C:45]([NH:47][CH3:48])[N:44]=[C:43]([C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=5)[CH:42]=4)[CH:38]=[N:39][CH:40]=3)[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNc1cc(-c2cncc(Br)c2)cc(-c2ccccn2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: CNc1cc(-c2cncc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)cc(-c2ccccn2)n1

Procedure:
To a solution of 4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Intermediate B20) (1.5 eq, 1.095 mmol, 0.413 g) and 2M Na2CO3 (2.0 eq, 1.460 mmol, 0.730 ml) in DME (5 ml) is added (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (Example 2.1, step1) (1 eq, 0.730 mmol, 0.249 g) followed by [1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium (II), complex with DCM (0.1 eq, 0.073 mmol, 0.059 g). The reaction mixture is heated using microwave radiation at 90° C. for 3 hours. The reaction mixture is dissolved in DCM and washed with water. The organic layer is washed with brine, dried over drying agent MgSO4, filtered and the organic solvent is reduced in vacuo. The crude residue is purified by flash chromatography (0-100% EtOAc in iso-hexane and up to 10% MeOH in EtOAc), to afford title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][N:18]=1)[C:12](OC)=[O:13].O.[OH-].[Na+]>C(OCC)C.C1COCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:12][OH:13])[CH:16]=[CH:17][N:18]=1
Reactant: COC(=O)c1ccnc(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(CO)ccn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94.5 %

Procedure:
To a suspension of lithium aluminum hydride (2.92 g) in diethyl ether (200 ml) and THF (50 mL) was added dropwise a solution of methyl 2-methoxyisonicotinate (8.57 g) in diethyl ether (50 mL) at 0° C., and the reaction mixture was stirred at 0° C. for 20 min. Water (3.0 mL), 4N aqueous sodium hydroxide solution (3.0 mL) and water (9.0 mL) were successively added to the reaction mixture at 0° C., and the mixture was stirred at room temperature for 15 min. The resulting white precipitate was filtered off, and the solvent in the filtrate was evaporated under reduced pressure to give a crude product of the title compound (6.74 g) as a pale-yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:4]=1[CH:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20]>O1CCOCC1.CCOC(C)=O>[Cl:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:4]=1[CH:19]([NH2:21])[CH3:20]
Reactant: CC(NC(=O)OC(C)(C)C)c1c(Cl)c2ccccc2n1-c1cccc(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(N)c1c(Cl)c2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 118.6 %

Procedure:
Hydrogen chloride (4.0 M) in 1,4-dioxane (0.5 mL, 20 mmol) was added to a solution of tert-butyl {1-[3-chloro-1-(3-fluorophenyl)-1H-indol-2-yl]ethyl}carbamate (36 mg, 0.092 mmol) in 1,4-dioxane (1.0 mL) and the reaction was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with saturated NaHCO3 solution and water. The combined extracts were dried over MgSO4 and concentrated to give the desired product (31.5 mg). LCMS calculated for C16H12ClFN(M-NH2)+: m/z=272.1. Found: 272.0.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]#[N:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(OC(=O)[N:24]([CH2:28][CH2:29]Cl)[CH2:25][CH2:26]Cl)(C)(C)C.[H-].[Na+].C(OCC)C>CN(C)C=O.O>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([C:13]2([C:14]#[N:15])[CH2:29][CH2:28][NH:24][CH2:25][CH2:26]2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: N#CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: N#CC1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCNCC1
Temperature: 70 °C

Procedure:
To a solution of (3,5-bis-trifluoromethylphenyl)-acetonitrile (25 mmol; 6.33 g) and bis-(2-chloroethyl)-carbamic acid tert-butyl ester (28 mmol; 6.73 g) in N,N-dimethylformamide (50 mL) under Argon was added sodium hydride (75 mmol; 1.90 g) in small portions over a 30 min period. When the addition was complete, the resulting mixture was heated at 70° C. for 1 hour, then stirred for 2½ days at room temperature. Diethyl ether (250 mL) was added, followed by water (20 mL). The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered, and evaporated. The resulting residue was dissolved in a 4N hydrochloric acid solution (20 mL) and the mixture was stirred for 1 hour at room temperature. The resulting mixture was evaporated and triturated with diethyl ether (50 mL). The solid was separated via centrifugation and purified via reverse phase HPLC. The desired fractions were combined and lyophilized. The resulting residue was dissolved in ethyl acetate (50 mL) and washed with a 1N sodium hydroxide solution (20 mL). The organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in diethyl ether, and a 1N HCl solution in diethyl ether (10 mL) was added dropwise. A white precipitate formed that was separated via centrifugation and dried under vacuum to yield 4-(3,5-bis-trifluoromethylphenyl)-piperidine-4-carbonitrile as a hydrochloride salt. MS (ESI) m/z 323.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[O:5][C:6]([NH:8][C@H:9]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][C@H:10]1[C:21]([O:23]C(C)(C)C)=[O:22])=[O:7]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[O:5][C:6]([NH:8][C@H:9]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][C@H:10]1[C:21]([OH:23])=[O:22])=[O:7]
Reactant: CC(C)(C)OC(=O)[C@@H]1CN(c2ccccc2)C(=O)[C@@H]1NC(=O)Oc1ccc(Cl)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H]1C(=O)N(c2ccccc2)C[C@H]1C(=O)O)Oc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The tert-butyl ester of Example 13 is dissolved in trifluoroacetic acid and stirred for 16 h at room temperature after which time the reaction is concentrated in vacuo. The resulting material is purified by chromatography on silica gel eluting with EtOH/CH2Cl2 /HOAc to give the title compound.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:18][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH:18][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Reactant: CCOC(=O)C(C)(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOC(=O)C(C)(C)NCc1cccc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
To 3-(tert-butyldimethylsilyloxy)benzaldehyde (Example 12-1c) (3.00 g, 12.7 mmol) in DCE (100 mL) was added ethyl 2-amino-2-methylpropanoate hydrochloride (25 mmol, ˜2 equiv.), molecular sieves 4A (5 g), and Et3N (2 equiv.). The mixture was stirred for 6 hours at room temperature and treated with NaBH(OAc)3 (2 equiv.). After the addition was completed, the reaction mixture was stirred overnight under nitrogen. The mixture was diluted with DMC (200 mL), carefully quenched with saturated aqueous NaHCO3 solution and the layers were separated. The aqueous phase was further extracted with DCM (2×100 mL). The combined organic extract was washed with water (50 mL), brine (100 mL) and dried over Na2SO4. The solvent was removed under vacuum and the residue was purified over silica gel using hexanes/EtOAc (2/8) to give ethyl 2-(3-(tert-butyldimethylsilyloxy)benzylamino)-2-methylpropanoate (4.02 g, 90%). MS 352 (MH+)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]=1[NH:16][C:17](=[O:19])[CH3:18].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].[I-].[Na+].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:17]([NH:16][C:3]1[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:19])[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)Nc1c(N)cccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CNc1cccc(OCc2ccccc2)c1NC(C)=O
Temperature: 80 °C
Reaction time: 6 h
Yield: 72.6 %

Procedure:
To a mixture of N-[2-amino-6-(benzyloxy)phenyl]acetamide (2.95 g) and ethyl bromoacetate (2.11 g) in DMF (29.5 mL) were added sodium iodide (1.73 g) and K2CO3 (1.91 g) at ambient temperature. The mixture was stirred at 80° C. for 6 hours. After cooling, the reaction mixture was added water (50 mL). The formed precipitate was collected by filteration and washed with water and recrystallized from solvent (EtOAc and n-hexane) to give ethyl N-[2-acetamido-3-(benzyloxy)phenyl]glycinate (2.86 g) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([C:18]4(C(O)=O)[CH2:20][CH2:19]4)[CH:15]=[N:16][CH:17]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:24].C1(P([N:39]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.C1COCC1>[NH2:39][C:18]1([C:14]2[CH:13]=[C:12]([C:8]3[CH:7]=[C:6]4[C:11](=[CH:10][CH:9]=3)[N:2]([CH3:1])[C:3](=[O:24])[CH:4]=[CH:5]4)[CH:17]=[N:16][CH:15]=2)[CH2:20][CH2:19]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CN1C(=O)CCc2cc(-c3cncc(C4(C(=O)O)CC4)c3)ccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cn1c(=O)ccc2cc(-c3cncc(C4(N)CC4)c3)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
To solution of 1-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)cyclopropanecarboxylic acid (example 59 [C], 0.3 g, 0.931 mmol) in toluene (15 mL) were added TEA (0.141 g, 1.4 mmol) and diphenylphosphoryl azide (0.384 g, 1.4 mmol) and then the reaction mixture was heated to reflux for 4 h. The mixture was concentrated in vacuo, the residue was dissolved in THF (30 mL) and the solution cooled to 0° C. Then, a solution of KOtBu (0.627 g, 5.58 mmol) in THF (13 mL) was added and the mixture was stirred for 1 h at 0° C. and then over night at room temperature. The mixture was concentrated in vacuo, the residue was preadsorbed on silica gel and purified by silica gel flash chromatography eluting with a 0 to 10% MeOH-DCM gradient to give a yellow amorphous solid (0.104 g). This material was then further purified by reverse phase HPLC on a Gemini-NX column, eluting with a MeOH—H2O (0.05% TEA) gradient to give the title compound (0.02 g, 7%) as a colorless amorphous solid. MS: 292.3 (M+H+).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([O:13][CH2:14]C=C)[CH:7]=[CH:6]2.CN(C)[C:19]1[CH:24]=CC=C[CH:20]=1>>[CH3:14][O:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([CH2:24][CH:19]=[CH2:20])=[C:3]([OH:2])[CH:12]=[CH:11]2
Reactant: C=CCOc1ccc2cc(OC)ccc2c1
Reactant: CN(C)c1ccccc1
Product: C=CCc1c(O)ccc2cc(OC)ccc12
Yield: 82 %

Procedure:
6-Methoxy-2-(2-propenyloxy)naphthalene (24.9 g, 116.2 mmol) was dissolved in N,N-dimethyl aniline (100 ml) followed by heating under reflux for 15 hours. After the organic solvent was distilled off under reduced pressure, 2N aqueous hydrochloric acid was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/4), followed by recrystallization from ethyl acetate/hexane, to give 6-methoxy-1-(2-propenyl)-2-naphthol (20.3 g, Yield 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].Cl.[N:11]([O-])=O.[Na+].C([O-])(=O)C.[K+].C1OCCOCCOCCOCCOCCOC1>O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:6]2[C:5]([CH:9]=[N:11][NH:7]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)cc1N
Reactant: O=N[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: Clc1ccc2cn[nH]c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A slurry of 5-chloro-2-methylaniline (1-1, 30 g, 0.21 mol) in water (200 mL) was treated with HCl (12N, 53 mL, 0.64 mol). The resulting solution was cooled to 0° C. and reacted with aqueous solution of sodium nitrite (14.6 g, 0.21 mol). After 30 min. stirring, any insoluble particles were removed by filtration and the filtrate solution was treated at 0° C. with sodium tetrafluoroborate dissolved in water (150 mL). Precipitates so formed was collected by filtration, washed with ice-cold water, cold methanol and then with ethylether. The product (1-2) was dried in vacuo and then suspended in chloroform (500 mL) in the presence of potassium acetate (34 g, 0.35 mol) and 18-crown-6 (2.29 g, 8.67 mmol). The reaction mixture was stirred at the ambient temperature for 1.5 h, partitioned between ethyl acetate and water. The organic layer was washed with brine, separated, dried (MgSO4) and concentrated in vacuo. Trituation with dichloromethane and hexanes afforded the desired product as an orange powder (1-3); 1H NMR (400 MHz, DMSO-d6) δ 13.18 (bs, 1H), 8.11 (s, 1H), 7.79 (d, 1H, J=8.7 Hz), 7.62 (s, 1H), 7.13 (dd, 1H, J=7.9, 1.9 Hz).