Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:14])[O:8][C@@H:7]2[C@@H:9]([CH3:13])[O:10][CH:11]([OH:12])[C@@H:6]2[O:5]1.[Cl-].[Ca+2].[Cl-].C(OCC)(=O)C>C(O)C.O1CCCC1.O>[OH:12][CH2:11][C@@H:6]1[O:5][C:4]([CH3:14])([CH3:3])[O:8][C@@H:7]1[C@H:9]([OH:10])[CH3:13]
Reactant: C[C@H]1OC(O)[C@@H]2OC(C)(C)O[C@H]12
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@@H](O)[C@H]1OC(C)(C)O[C@H]1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
4.0 g of sodium tetrahydroborate was added to a solution of 12.2 g of (3aR,6R,6aR)-2,2,6-trimethyltetrahydro-2H-furo(3,4-d)(1,3)dioxol-4-ol in 10 mL of ethanol and 120 mL of tetrahydrofuran in a nitrogen atmosphere at a temperature of 5° C. to 10° C., and thereafter, a solution of 10.3 g of calcium chloride in 50 mL of ethanol was added dropwise to the mixture. The obtained mixture was stirred at room temperature for 4 hours. Thereafter, 200 mL of ethyl acetate and 300 mL of water were added to the reaction mixture. The organic layer was fractionated, and the water layer was then extracted with 200 mL of ethyl acetate six times. The organic layer was combined with the extract, and the obtained mixture was washed with a saturated sodium chloride aqueous solution and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate/hexane=1/4 to 1/1), so as to obtain 7.4 g of (1R)-1-((4R,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane-4-yl)ethan-1-ol in the form of a colorless oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[NH:13][C:14]([C:16]([O:18]CC)=[O:17])=[CH:15][C:11]=3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:12]3[NH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:11]=3[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc2c([nH]1)C(c1ccc(Cl)cc1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)C(c1ccc(Cl)cc1)CC2
Yield: 54.3 %

Procedure:
The title compound was synthesized from ethyl 6-(4-chlorophenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.0907 g, 0.34 mmol, 1 equiv) and sodium hydroxide (0.86 mL, 8.6 mmol, 10 M, 25 equiv), according to General Procedure 7. A 2-3:1 mixture of methanol (MeOH) and THF (3-4 mL) was used. The resulting product was purified by preparative HPLC using the Chromeleon purification system. A 0.1% formic acid/1% acetonitrile mixture in water (aqueous phase) and methanol (no modifier added—organic phase) using a 50 mm Dynamax HPLC C-18 column at 28 mL/min (initial gradient of 50% methanol and increasing to 100% over 7 minutes) afforded the title compound (48.3 mg, 59%) with purity by HPLC of 94.1% (UV). LCMS m/e 260.2 (M−H). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.16-2.30 (m, J=13.14, 8.19, 5.37, 5.37 Hz, 1H), 2.56-2.67 (m, 1H), 2.68-2.79 (m, 1H), 2.86-3.01 (m, 1H), 4.26 (dd, J=8.48, 5.28 Hz, 1H), 6.65 (s, 1H), 7.05-7.13 (m, 2H), 7.22-7.31 (m, 2H).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([NH2:63])[CH:58]=2)=[CH:53][C:52]=1[CH3:64]>CN(C=O)C>[CH3:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([NH:63][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:58]=2)=[CH:53][C:52]=1[CH3:64]
Reactant: COc1ccc(-c2cccc(N)c2)cc1C
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cc1C
Temperature: 25 °C
Yield: 60.5 %

Procedure:
DIEA (0.014 mL, 0.077 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.015 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-Methoxy-3′-methyl-biphenyl-3-ylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.017 g of product in 61% yield: LCMS (ESI) m/z 402 (MH+).
Reaction SMILES: [CH:1](=[N:3][OH:4])[CH3:2].[CH3:5][CH:6]([OH:9])[C:7]#[CH:8].CCN(CC)CC.[O-]Cl.[Na+]>C(Cl)Cl>[CH3:2][C:1]1[CH:8]=[C:7]([CH:6]([OH:9])[CH3:5])[O:4][N:3]=1
Reactant: C#CC(C)O
Reactant: CC=NO
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(C)O)on1
Reaction time: 18 h
Yield: 20.4 %

Procedure:
To a stirring solution of 5.2 mL (84.9 mmol) of acetaldehyde oxime, 6.7 mL (85.5 mmol) of 3-butyn-2-ol, and 1.2 mL (8.6 mmol) of Et3N in 20 mL of CH2Cl2 at 0° C. was added 275 mL of NaOCl over a period of 2 h 45 min. The ice bath was removed and stirring was continued at r.t. for 18 h. Chloroform was added, and the layers were separated. The organic layer was extracted with CHCl3 (2×) and with the extract of a mixture of (80 mL CHCl3: 10 mL H2O: 10 mL MeOH) (2×). The combined extracts were dried over Na2SO4, filtered and concentrated. Purification by flash silica gel chromatography (2% MeOH/CHCl3) provided 2.2 g of 1-(3-methylisoxazol-5-yl)ethanol as an orange-yellow oil in 20% yield.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])([OH:3])=[O:2].[Br:15]Br.O.Cl>[N+]([O-])(O)=O>[Br:15][C:12]1[CH:13]=[CH:14][C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9]
Reactant: BrBr
Reactant: O=C(O)CCc1ccccc1C(=O)O
Agent: Cl
Solvent: O=[N+]([O-])O
Solvent: O
Product: O=C(O)CCc1ccc(Br)cc1C(=O)O
Temperature: 90 °C

Procedure:
A solution of 2-(2-carboxyethyl)benzoic acid (5 g, 25.8 mmol) in 71% nitric acid (20 mL) in an amber vial was treated with bromine (1.3 mL, 25.8 mmol). The vial was capped and heated to about 90° C. for about 20 hours. The reaction was cooled, poured into water and 1M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol (20:1) as eluent to provide the desired product. MS (ESI): m/z 271, 273 (M−H)−.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:19])([O:17][CH3:18])[CH3:16])[C:9]=1[NH2:10].[Cl:20][CH2:21][C:22](Cl)=[O:23].O>C(Cl)Cl>[CH3:7][C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:19])([O:17][CH3:18])[CH3:16])[C:9]=1[NH:10][C:22](=[O:23])[CH2:21][Cl:20]
Reactant: O=C(Cl)CCl
Reactant: COC(C)(C)c1cccc(C)c1N
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(C)(C)c1cccc(C)c1NC(=O)CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
216.46 g (2.74 mols) of pyridine was slowly added to a solution containing 467.5 g (2.61 mols) of 2-methyl-6-(1-methyl-1-methoxyethyl)-aniline in 2.74 liters of methylene chloride at room temperature (about 18°-25° C.). 309.62 g (2.74 mols) of chloroacetyl chloride was added dropwise over a 20-minute period. The temperature of the mixture was maintained at about, or less than, 25° C. during this addition. The mixture was then stirred at about 18° C. for about 1 hour and then mixed with two liters of water. The methylene chloride phase was then separated treated with aqueous 5 wt. % hydrochloric acid until slightly acidic and then washed with water and dried over magnesium sulfate. The mixture was then evaporated to dryness affording a brownish solid which was then washed with a 10% isopropanol:90% hexane mixture affording 484 g of the title compound.
Reaction SMILES: C(OC([NH:11][C:12]1([PH:20]([NH:22][C:23](=[O:32])[CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:21])[CH2:17][CH2:16][CH2:15][N:14]([NH2:18])[C:13]1=[O:19])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C:12]1([PH:20]([NH:22][C:23](=[O:32])[CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:21])[CH2:17][CH2:16][CH2:15][N:14]([NH2:18])[C:13]1=[O:19]
Reactant: NN1CCCC(NC(=O)OCc2ccccc2)([PH](=O)NC(=O)COc2ccccc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: NN1CCCC(N)([PH](=O)NC(=O)COc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Palladium black (40.0 mg) was added to a solution of (3S, P (SR))-3-benzyloxycarbonylamino-1-amino(phenoxyacetylamino)phosphinyl-2-piperidone (200.9 mg, 0.4363 mmol) in ethanol (6 mL), and the resulting mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:17]=[C:11]2[C:12](=[O:16])[NH:13][CH2:14][CH2:15][N:10]2[N:9]=1)=[O:7])[CH3:4].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.O>[CH2:3]([O:5][C:6]([C:8]1[CH:17]=[C:11]2[C:12](=[O:16])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:15][N:10]2[N:9]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cc2n(n1)CCNC2=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2n(n1)CCN(Cc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
A 60% dispersion of sodium hydride in mineral oils (0.16 g, 4.0 mmol) was added to a stirred solution of 4,5,6,7-tetrahydro-4-oxo-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (0.7 g, 3.35 mmol) in DMF (14 mL) at 0° C. The mixture was stirred at room temperature for 1 hour and then benzyl bromide (0.48 mL, 4.0 mmol) was added. The mixture was stirred at room temperature for 16 hours, diluted with H2O and extracted with DCM. The organic layer was separated, washed with brine, dried (NaSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo to yield 4,5,6,7-tetrahydro-4-oxo-5-(phenylmethyl)-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (0.83 g, 83% yield) as a white oil. C16H17N3O3 LCMS: Rt 1.79, m/z 300 [M+H]+ (see LCMS Method 1).
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1Br
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1cccc(C(=O)Cl)c1Br
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A suspension of 2-bromo-3-methylbenzoic acid (2.07 g, 9.63 mmol) in DCM (48.1 mL) was cooled to 0° C. Oxalyl chloride (0.9 mL, 10.14 mmol) was added dropwise via syringe. After addition, the cooling bath was removed and the reaction mixture stirred overnight. The mixture was concentrated in vacuo to remove solvent and excess reagent, affording 2-bromo-3-methylbenzoyl chloride as a cloudy white oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:11]=[C:10]([C:21]([OH:23])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:26][C:27]1[N:32]=[CH:31][C:30]([C@H:33]([NH2:35])[CH3:34])=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:11]=[C:10]([C:21]([NH:35][C@@H:33]([C:30]3[CH:31]=[N:32][C:27]([CH3:26])=[CH:28][CH:29]=3)[CH3:34])=[O:23])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cc(Oc3ncccn3)cc(C(=O)O)c2)cc1
Reactant: Cc1ccc([C@@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(Oc3ncccn3)cc(C(=O)N[C@H](C)c3ccc(C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(pyrimidin-2-yloxy)biphenyl-3-carboxylic acid (20 mg, 0.065 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (30 mg, 0.143 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (60 mg, 0.16 mmol), and N,N-diisopropylethylamine (200 μL, 1.15 mmol). The reaction mixture was stirred at room temperature for 16 hours. LC-MS indicated the reaction was complete. The reaction mixture was purified by preparative HPLC (100×21.2 mm C18 column, CH3CN/water[10 mM Et2NH]) to afford a light color solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[C:14]([C:17]1[C:18]([OH:27])=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22][CH3:23])=[O:21])(=[O:16])[CH3:15].C1CCN2C(=NCCC2)CC1.O>N1C=CC=CC=1>[OH:27][C:18]1[C:17]([C:14](=[O:16])[CH2:15][C:9](=[O:10])[C:8]2[C:3]([C:2]([F:13])([F:12])[F:1])=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:26][CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1cccc(C(C)=O)c1O
Reactant: O=C(Cl)c1cccnc1C(F)(F)F
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: COC(=O)c1cccc(C(=O)CC(=O)c2cccnc2C(F)(F)F)c1O
Temperature: 80 °C
Yield: 111.9 %

Procedure:
2-(trifluoromethyl)pyridine-3-carbonyl chloride 25 (300 mg, 1.46 mmol) was added to a mixture of methyl 3-acetyl-2-hydroxybenzoate 38 (183 mg, 1.46 mmol) and DBU (446 mg, 2.92 mmol) in pyridine at 0° C. The reaction mixture was heated at 80° C. for 12 h. The resulting mixture was poured into H2O and extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated to give 39 (600 mg) which was used with no further purification.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C[Al](C)C.C([O:11][C:12]([C:14]1[N:19]2[N:20]=[C:21]([NH:23][C:24]([NH:26][CH2:27][CH3:28])=[O:25])[N:22]=[C:18]2[CH:17]=[C:16]([Br:29])[CH:15]=1)=O)C>O1CCCC1.CCCCCCC.ClCCl>[CH:1]1([NH:4][C:12]([C:14]2[N:19]3[N:20]=[C:21]([NH:23][C:24]([NH:26][CH2:27][CH3:28])=[O:25])[N:22]=[C:18]3[CH:17]=[C:16]([Br:29])[CH:15]=2)=[O:11])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CCNC(=O)Nc1nc2cc(Br)cc(C(=O)OCC)n2n1
Agent: C[Al](C)C
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCCCCCC
Product: CCNC(=O)Nc1nc2cc(Br)cc(C(=O)NC3CC3)n2n1

Procedure:
Cyclopropylamine (0.136 g, 2.38 mmol) was suspended in tetrahydrofuran (2.00 mL) and cooled in an ice bath. This solution was charged with 2 molar trimethylaluminum in heptane (0.300 mL). After 20 minutes the solution was charged with 7-bromo-2-(3-ethyl-ureido)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester produced as in Example 6, (0.248 g, 0.696 mmol) and shaken. After 24 hours the reaction was dissolved in dichloromethane and washed with saturated aqueous ammonium chloride. The organic layers were dried over magnesium sulfate and concentrated to afford 7-bromo-2-(3-ethyl-ureido)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid cyclopropylamide MS (ACPI+): m/z 368.2 (M+H).
Reaction SMILES: COC1C=CC(C[N:10]2[CH:15]=[C:14]([O:16]CC3C=CC=CC=3)[C:13](=[O:24])[CH:12]=[C:11]2[C:25]([NH:27][CH2:28][CH2:29][NH:30]CC2C=CC=CC=2)=[O:26])=CC=1.[C:38]1([CH3:48])[CH:43]=[CH:42][C:41]([S:44]([OH:47])(=[O:46])=[O:45])=[CH:40][CH:39]=1.[H][H]>CO.[Pd]>[C:38]1([CH3:48])[CH:39]=[CH:40][C:41]([S:44]([OH:47])(=[O:45])=[O:46])=[CH:42][CH:43]=1.[NH2:30][CH2:29][CH2:28][NH:27][C:25]([C:11]1[NH:10][CH:15]=[C:14]([OH:16])[C:13](=[O:24])[CH:12]=1)=[O:26]
Reactant: [H][H]
Reactant: COc1ccc(Cn2cc(OCc3ccccc3)c(=O)cc2C(=O)NCCNCc2ccccc2)cc1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: NCCNC(=O)c1cc(=O)c(O)c[nH]1

Procedure:
1,4-Dihydro-1-[(4-methoxyphenyl)methyl]-4-oxo-5-(phenylmethoxy)-N-[2-[(phenylmethyl)amino]ethyl]-2-pyridinecarboxamide (9.95 g) and 7.7 g of p-toluenesulfonic acid in 100 ml of methanol were treated with 3 g of palladium on charcoal (10%) and hydrogen was bubbled through the reaction mixture at 45°-50° C. over six hours. A stream of argon was then bubbled through the reaction mixture for 10 minutes. Filtration and evaporation of the filtrate yielded beige crystals of the title compound which were washed first with 20 ml of cold methanol and then 50 ml of ether. Yield: 10.5 g, melting point 271° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH:5]=[C:6]([CH3:11])[C:7]=1[C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.[CH3:27]O>>[CH3:27][O:9][C:8]([C:7]1[C:6]([CH3:11])=[CH:5][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)=[CH:3][C:2]=1[OH:1])=[O:10]
Reactant: CO
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)cc(O)c1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)cc1O
Temperature: 25 °C
Yield: 45 %

Procedure:
A solution of 2.20 g (7.40 mmol) of 3-hydroxy-5-methyl-3′-trifluoromethyl-biphenyl-4-carboxylic acid in 70 ml of MeOH was treated at RT with 0.84 ml=1.53 g (14.9 mmol) of sulfuric acid (95%) and 0.5 g of molecular sieves (0.4 nm) and the reaction mixture was heated at reflux for 72 hours. It was then cooled down to RT, filtered and the residue was washed with MeOH. The filtrate was evaporated and this residue was dissolved in CH2Cl2 and poured into crashed ice and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (heptane/EtOAc 4:1) to give 1.04 g (45%) of the title compound as colorless solid. MS: 310.0 (M+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH:11][C:12]([NH:14][CH2:15][CH:16]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[C:17]([O:19]CC)=[O:18])=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[OH-].[Li+]>C1COCC1>[CH:1]1[C:10]2[C:5](=[C:6]([NH:11][C:12]([NH:14][CH2:15][CH:16]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=3)[C:17]([OH:19])=[O:18])=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CCOC(=O)C(CNC(=O)Nc1cccc2cnccc12)Cc1ccc(C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(NCC(Cc1ccc(C(F)(F)F)cc1)C(=O)O)Nc1cccc2cnccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 40.3 %

Procedure:
Ethyl 3-{[(isoquinolin-5-ylamino)carbonyl]amino}-2-[4-(trifluoromethyl)benzyl]propanoate (Example 129, 23 mg, 0.05 mmol) in aqueous THF (1:1, 2 ml) was treated with lithium hydroxide (5 mg, 0.1 mmol) and stirred at room temperature for 20 h. The mixture was evaporated then partitioned between 7% aqueous citric acid and dichloromethane (2:1, 6 ml). A precipitate formed which was collected by filtration and dried azeotropically by adding toluene and evaporating to give the desired compound (8.4 mg). m/z (ES+) 418 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1.[H][H]>C(O)C.[NH4+].[OH-].[Rh]>[NH2:12][CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[N:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: [H][H]
Reactant: N#CCc1c[nH]c2ccncc12
Agent: [Rh]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: NCCc1c[nH]c2ccncc12
Reaction time: 24 h

Procedure:
A mixture of (1H-pyrrolo[3,2-c]pyridin-3-yl)-acetonitrile (0.260 g, 1.66 mmol) and 5% rhodium on alumina (0.26 g) in ethanol (10 mL) and concentrated NH4OH (5 mL) is placed under 55 psi hydrogen pressure on a Parr shaker. After 24 h at ambient temperature, the reaction mixture is filtered through Celite and concentrated in vacuo to afford the title amine, identified by NMR and mass spectral analyses.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([C:5]1[N:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].N1C=C(C(OC)=O)C=C[C:16]=1C(OC)=O.[Cl-].[Mg+2].[Cl-].CNC.Cl>C1COCC1.O>[CH3:1][N:2]([CH3:14])[C:3]([C:5]1[N:10]=[CH:9][C:8]([C:11]([O:13][CH3:16])=[O:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)OC)nc1
Reactant: CN(C)C(=O)c1ccc(C(=O)O)cn1
Agent: CNC
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C(=O)N(C)C)nc1
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Preparation of 6-[(dimethylamino)carbonyl]-3-pyridine carboxylic acid. To a 2° C. slurry of dimethyl 2,5-pyridinedicarboxylate (50 g, 0.256 mol) in THF (700 mL) was added magnesium chloride (26.8 g, 0.282 mol). After stirring for 15 min, dimethylamine (2 M in THF, 256 mL, 0.512 mol) was added dropwise over 40 min. The mixture was stirred for 30 min at 2° C. and then at room temperature for 1 h. To the mixture was added water (100 mL) and 1 N HCl (300 mL). The mixture was extracted with ethyl acetate (4×400 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to provide 53 g (100%) of methyl 6-[(dimethylamino)carbonyl]-3-pyridine carboxylate a pale yellow solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][C:12]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[I:34]N1C(=O)CCC1=O.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(#N)C>[CH2:1]([NH:3][C:4]([C:6]1[C:10]([I:34])=[C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][C:12]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCNC(=O)c1cc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Product: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1I
Temperature: 100 °C
Yield: 77 %

Procedure:
5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-isoxazole-3-carboxylic acid ethylamide (0.90 g, 1.94 mmol), N-Iodosuccinimide (0.44 g, 1 equiv.) and Ammonium cerium (IV) nitrate (0.53 g, 0.5 equiv) were suspended in Acetonitrile (55 ml) before heating to reflux (oil bath 100° C.) where upon the mixture became homogeneous. After 18 hrs the solution was cooled and the solvent removed in vaccuo to give a thick orange oil. This was partitioned between DCM (25 ml) and water (10 ml), the organic layer was kept and washed with brine (2×25 ml) before drying over Na2SO4. The DCM was removed in vaccuo to provide 0.88 g (77% yield) of the product as a orange/tan coloured powder.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7](=[O:15])[C:8]3[CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[C:13]=3[C:4]=2[CH:3]=1.CS(O[CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)(=O)=O>C(#N)C.CN(C)C=O>[CH3:14][N:12]1[C:13]2[C:4]3[CH:3]=[C:2]([O:1][CH:23]4[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]4)[CH:17]=[CH:16][C:5]=3[NH:6][C:7](=[O:15])[C:8]=2[CH2:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: CN1CCCc2c1c1cc(O)ccc1[nH]c2=O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CN1CCCc2c1c1cc(OC3CCN(C(=O)OC(C)(C)C)CC3)ccc1[nH]c2=O
Reaction time: 96 h
Yield: 65.1 %

Procedure:
9-Hydroxy-1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-5(6H)-one (60 mg, 0.26 mmol) prepared at Example 10 was dissolved in acetonitrile (8 ml)/N,N-dimethylformamide (4 ml), added with t-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (220 mg, 0.78 mmol) at room temperature. The resulting mixture was stirred for four days at 90˜100° C. and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure. The residue was then purified with flash column chromatography (chloroform:methanol=20:1) to obtain the title compound (70 mg, yield: 65%, brown oil).