Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[O:20][CH3:21])=[CH:9][CH:8]=1)=[O:6])[CH3:3].CN1CCOCC1.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>C1COCC1>[CH2:2]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([NH:19][C:32]([CH:29]3[CH2:31][CH2:30]3)=[O:33])[CH:16]=[CH:15][C:14]=2[O:20][CH3:21])=[CH:9][CH:8]=1)=[O:6])[CH3:3]
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=O)c1ccc(-c2cc(N)ccc2OC)cc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)C3CC3)ccc2OC)cc1
Reaction time: 18 h
Yield: 93.5 %

Procedure:
A mixture of 5′-amino-2′methoxy-biphenyl-4-carboxylic acid ethyl ester hydrochloride (100 mg), N-methylmorpholine (0.1 ml) and cyclopropanecarbonyl chloride (29 mg) in dry THF (3 ml) was stirred at 20 C for 18 h. The mixture was then evaporated and the residue partitioned between sodium bicarbonate solution and ethyl acetate. The dried extracts were then evaporated giving the title compound as a dark oil (88 mg)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])=[CH:4][N:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17].C(N(CC)CC)C>C1COCC1.[Cu](I)I>[CH2:10]([O:9][CH:8]([O:12][CH2:13][CH3:14])[C:5]1[CH:6]=[CH:7][C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[N:3][CH:4]=1)[CH3:11]
Reactant: CCOC(OCC)c1ccc(Br)nc1
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(OCC)c1ccc(C#C[Si](C)(C)C)nc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 100.4 %

Procedure:
In THF (10 mL) was dissolved 2-bromo-5-(diethoxymethyl)pyridine (1.00 g, 3.84 mmol) obtained in Step 1. To the solution were added trimethylsilyl acetylene (1.09 mL, 7.69 mmol), copper iodide (I) (37.0 mg, 0.192 mmol), (bistriphenylphosphine) palladium (II) chloride (135 mg, 0.192 mmol), and triethylamine (1.07 mL, 7.69 mmol), and the mixture was stirred at 70° C. for 6 hours. The solvent in the reaction mixture was evaporated under reduced pressure, and water and ethyl acetate were added. The mixture was filtered through Celite and the filtrate was extracted with ethyl acetate. Washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to give 5-(diethoxymethyl)-2-((trimethylsilyl)ethynyl)pyridine (1.07 g). In methanol (10 mL) was dissolved 5-(diethoxymethyl)-2-((trimethylsilyl)ethynyl)pyridine obtained. Potassium carbonate (1.06 g, 7.69 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The solvent in the reaction mixture was evaporated under reduced pressure, and water was added. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give 5-(diethoxymethyl)-2-ethynylpyridine (703 mg, 89% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([S:14][CH3:15])=[C:4]([Cl:16])[N:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[Cl:16][C:4]1[C:5]([S:14][CH3:15])=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=[C:2]([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[N:3]=1
Reactant: CSc1c(Cl)nc(Cl)nc1N1CCOCC1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CSc1c(Cl)nc(-c2ccc(N)cc2)nc1N1CCOCC1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
A mixture of 4-(2,6-dichloro-5-methylsulfanyl-pyrimidin-4-yl)-morpholine (200 mg, 0.71 mmol.), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-aniline) (172.0 mg, 0.781 mmol.), (PPh3)4Pd (437 mg, 0.07 mmol.), 2M Na2CO3 (1.0 ml, 2.13 mmol, 3.0 eq.) and dioxane (15.0 ml) was added to the reaction vessel which was flushed with argon. The reaction mixture was stirred at 90° C. for 12 hrs and then dried so that the solvent was evaporated. The reaction mixture was partitioned between EA and water. The organic layers were collected, washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (Hexane/EtOAc 3:2) to give a pale yellow solid of 102 mg (42.3%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14](=S)[CH2:15][C:16](=O)[CH3:17])=[O:4].[F:20][C:21]([F:26])([F:25])[CH2:22][NH:23][NH2:24]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14]1[N:23]([CH2:22][C:21]([F:26])([F:25])[F:20])[N:24]=[C:16]([CH3:17])[CH:15]=1)=[O:4]
Reactant: NNCC(F)(F)F
Reactant: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1C(=S)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1c1cc(C)nn1CC(F)(F)F

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-methanesulfonyl-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 448c) was reacted with 2,2,2-trifluoroethylhydrazine (CAS Reg. No. 5042-30-8) to give the title compound. MS (ESI): m/z=370.4 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-]>Cl>[CH3:13][C:7]1[CH:8]=[C:9]([C:1]([CH3:2])=[O:3])[C:10]([F:12])=[CH:11][C:6]=1[Cl:5]
Reactant: Cc1ccc(F)cc1Cl
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1cc(C)c(Cl)cc1F
Temperature: 120 °C
Reaction time: 2 h

Procedure:
At 60° C., 157 g of acetyl chloride were added dropwise to a mixture of 250 g of 2-chloro-4-fluorotoluene and 267 g of aluminum chloride. The reaction mixture was stirred at 120° C. for 2 hours and then, while still at 100° C., poured onto 2 l of an ice/water mixture. 180 ml of concentrated hydrochloric acid were subsequently stirred into the resulting mixture. The product was then extracted using three times 200 ml of dichloromethane. The organic phase was then washed with 200 ml of water, dried over sodium sulfate and finally concentrated. Yield: 290 g; oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])=[C:4]([O:17][CH3:18])[C:3]=1[F:19].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:30](O)[CH3:31]>>[CH2:30]([O:12][C:11](=[O:13])[C:10](=[O:14])[CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:19])[C:4]=1[O:17][CH3:18])([CH3:16])[CH3:15])[CH3:31]
Reactant: CCO
Reactant: COc1c(C(C)(C)CC(=O)C(=O)O)ccc(Cl)c1F
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C(=O)CC(C)(C)c1ccc(Cl)c(F)c1OC

Procedure:
5.44 g (18.84 mmol) of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid is dissolved in 117 ml of ethanol, mixed with 2.1 ml of concentrated sulfuric acid and refluxed for six hours. The reaction mixture is added to 250 ml of saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic extracts are washed with saturated sodium bicarbonate solution and with brine. After drying and after the desiccant is filtered off and the solvent is spun in, 5.19 g (87%) of the desired compound is obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH3:36])[CH2:19][C:20]([C:22]3[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH3:29])[CH:23]=3)=O)=[C:14]([F:37])[CH:13]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[NH2:39][OH:40].C([O-])(O)=O.[Na+]>>[F:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH3:36])[CH2:19]/[C:20](=[N:39]\[OH:40])/[C:22]3[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH3:29])[CH:23]=3)=[C:14]([F:37])[CH:13]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Oc2ccc(C(=O)O)c(F)c2)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Oc2ccc(C(=O)O)c(F)c2)cc1F

Procedure:
In analogy to example 151, step 3, 2-fluoro-4-{3-fluoro-4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-phenoxy}-benzoic acid was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=519.2 [M+H]+.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.C([O:45][C:46](=[O:50])[C@H:47]([CH3:49])[NH2:48])C>CCOCC>[C:30]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:48][C@H:47]([C:46]([OH:50])=[O:45])[CH3:49])=[O:11])=[CH:13][CH:14]=1)([O:32][CH3:33])=[O:31]
Reactant: CCOC(=O)[C@H](C)N
Reactant: COC(=O)CCCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)Cl)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)N[C@@H](C)C(=O)O)cc1

Procedure:
A solution of 4.75 g. of N-trifluoroacetyl-4-(15-carbomethoxypentadecylamino)benzoyl chloride and 1.2 g. of triethylamine in 20 ml. of warm ether is treated with 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the product as a white, crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].C([Li])(C)(C)C.[C:21](=[O:23])=[O:22]>O1CCCC1.CCCCC>[C:11]([O:10][C:9]([NH:8][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:21]([OH:23])=[O:22])=[O:15])([CH3:12])([CH3:14])[CH3:13]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)Nc1ccccc1F
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)OC(=O)Nc1c(F)cccc1C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 2-fluorophenylcarbamate (44.0 g, 208 mmol) in tetrahydrofuran (660 mL) at −78° C. was added tert-butyllithium in pentane (1.7 M, 306 mL, 2.5 equivx) dropwise. After addition was complete, the reaction was stirred at −78° C. for 30 min. The solution was allowed to gradually reach −20° C. before being recooled to −78° C. and transferred via canula to a slurry of carbon dioxide (excess) and tetrahydrofuran (500 mL). The solution was allowed to slowly warm to room temperature. The reaction mixture was concentrated to remove most of the tetrahydrofuran, and poured into a sep funnel containing water and diethyl ether. The layers were separated, and the aqueous extracted with diethyl ether twice more. The ethereals were discarded. The aqueous was acidified with 5% citric acid, extracted with diethyl ether (3×). The ethereal was dried over magnesium sulfate, and concentrated to give a light yellow solid which was recrystallized from hot toluene to give 37.1 g (70%) as a faint yellow solid.
Reaction SMILES: C1(C(=[N:14][C:15]([CH3:27])([CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])C2C=CC=CC=2)C=CC=CC=1.Cl>CO.C1COCC1>[NH2:14][C:15]([CH3:27])([CH2:20][C:21]1[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C(C)(Cc1ccncc1)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C(C)(N)Cc1ccncc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.5 %

Procedure:
To a suspension of methyl 2-[(diphenylmethylene)amino]-2-methyl-3-pyridin-4-ylpropanoate from Step B (5.28 g, 14.73 mmol) in 75 ml of 1:1 MeOH/THF was added 6N HCl (3.68 ml, 22.10 mmol). The reaction was concentrated in vacuo after stirring for 1.5 h at rt. Purification using ion exchange chromatography (SCX cartridge) afforded methyl 2-amino-2-methyl-3-pyridin-4-ylpropanoate as a yellow oil (2.76 g, 97%). LCMS [M+H]=195.3. 1H NMR (d4-MeOH) δ 8.43 (dd, J=4.6, 1.6 Hz, 2H), 7.24 (dd, J=4.6, 1.5 Hz, 2H), 3.70 (s, 3H), 3.09 (A of AB, d, J=12.9 Hz, 1H), 2.90 (B of AB, d, J=13.0 Hz, 1H), 1.39 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(O)c1ccc(NCc2ccc(Cl)cc2)cc1
Yield: 66.2 %

Procedure:
4-Aminobenzoic acid (13.7 g., 0.1 mole) and 4-chlorobenzaldehyde (14.05 g., 0.1 mole) were mixed in dry benzene (200 ml.), 4-toluenesulphonic acid (50 mg.) was added and the mixture was boiled under reflux in an apparatus incorporating a water-trap until the theoretical amount of water (1.8 ml) had been collected. The reaction mixture was cooled in iced water, the product filtered, dried and hydrogenated at NTP in ethanol (500 ml) in the presence of platinum oxide, (Adams catalyst), (100 mg). The catalyst was filtered off and the solution added to iced water. The product was filtered, dried and crystallised from 20% aqueous ethanol to give 4[(4-chlorobenzyl)-amino]-benzoic acid (17.32 g., 78%) which melted at 206°-8° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]=[C:12]=[S:13].[NH2:14][CH:15]([C:21]#[N:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CCO>[NH2:22][C:21]1[S:13][C:12]([NH:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[N:14][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: S=C=Nc1ccc2ccccc2c1
Reactant: CCOC(=O)C(N)C#N
Solvent: CCO
Product: CCOC(=O)c1nc(Nc2ccc3ccccc3c2)sc1N
Temperature: 80 °C
Yield: 66.8 %

Procedure:
A mixture of 2-naphthalenyl isothiocyanate (0.5 g, 2.7 mmol) and ethyl 2-amino-2-cyanoacetate (0.38 g, 2.97 mmol) in EtOH (16 mL) was heated at 80° C. for 3 h. The reaction mixture was cooled to rt, and the solvent was concentrated in vacuo. The resulting solids were collected and washed with n-Hexane-EtOAc (1:1) to give 565 mg (67% yield) of the titled compound.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[CH2:28]([O:30][C:31](=[O:34])[NH:32][CH3:33])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:34])[NH:32][CH2:33][C:24]1[CH:25]=[CH:26][C:21]([C:19]([N:16]2[CH2:17][CH2:18][N:13]([C:5]3[C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:8]([CH:10]4[CH2:11][CH2:12]4)=[CH:7][N:6]=3)[CH2:14][CH2:15]2)=[O:20])=[CH:22][CH:23]=1)[CH3:29]
Reactant: CCOC(=O)NC
Reactant: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: CCOC(=O)NCc1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)cc1

Procedure:
Using [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (473 mg) described in Preparation Example 186 and methylcarbamic acid ethyl ester (152 μL) and by the reaction and treatment in the same manner as in Example 262, the title compound (203 mg) was obtained.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:8]=2)[N:3]1[CH2:16][C:17]([OH:19])=O.[Br:20][C:21]1[C:22]([C:27]2[NH:31][N:30]=[CH:29][N:28]=2)=[C:23]([NH2:26])[S:24][CH:25]=1>>[Br:20][C:21]1[C:22]([C:27]2[NH:31][N:30]=[CH:29][N:28]=2)=[C:23]([NH:26][C:17](=[O:19])[CH2:16][N:3]2[C:4]3[C:9](=[N:8][C:7]([C:12]([F:13])([F:14])[F:15])=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[S:24][CH:25]=1
Reactant: O=C(O)Cn1c(=O)ccc2nc(C(F)(F)F)ccc21
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Product: O=C(Cn1c(=O)ccc2nc(C(F)(F)F)ccc21)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(2-oxo-6-(trifluoromethyl)-1,5-naphthyridin-1(2H)-yl)acetic acid (66 mg, 0.245 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (30 mg, 0.122 mmol) according to protocol A. Retention time (min)=5.195, method [7], MS(ESI) 499.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 8.26-8.21 (m, 3H), 7.96 (d, J=8.9 Hz, 1H), 7.17-7.13 (m, 2H), 5.37 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH2:19][C@H:18](OS(C)(=O)=O)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C@@H:20]2[CH2:19][CH2:18][CH2:17][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:21]2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](OS(C)(=O)=O)C1
Reactant: Brc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2cc(Br)cn2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromopyrazole (4.68 g, 31.83 mmol) in DMF (300 mL) at 0° C. was added sodium hydride (60% on mineral oil, 1.27 g, 31.83 mmol). The solution was allowed to stir at 0° C. for one hour, at which point a solution of (S)-3-Methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (Compound 1007, which was prepared from (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate, 9.78 g, 31.83 mmol) in DMF (50 mL) was added dropwise. The reaction mixture was allowed to stir at room temperature for 1 hour before refluxing overnight. Disappearance of both starting materials was tracked by TLC (1:1 Hexanes/Ethyl Acetate). The reaction was cooled to room temperature and quenched by addition of aqueous NaCl (300 mL), extracted with ethyl acetate (3×200 mL), washed with 1% aqueous LiCl (200 mL×3), dried and concentrated in vacuo. The resulting crude bromide (Compound 1008) was purified by silica gel chromatography (0-25% Ethyl Acetate in Hexanes) to give (R)-tert-butyl 3-(4-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate as a colourless waxy solid (4.54 g, 43% yield); 1H NMR (300.0 MHz, CDCl3): δ 7.42 (s, 1H), 7.40 (s, 1H), 4.13-4.05 (m, 2H), 3.82 (d, J=13.2 Hz, 1H), 3.20 (dd, J=10.3, 14.0 Hz, 1H), 2.94-2.85 (m, 1H), 2.08-1.97 (m, 2H), 1.74-1.45 (m, 2H) and 1.39 (s, 9H) ppm.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7]4=[C:8]([C:17](=[O:20])[NH:18][N:19]=[C:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3.[CH2:21]([O:28][P:29]([CH2:39][CH2:40]C(O)=O)([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:32]([O:31][P:29]([CH2:39][CH2:40][O:1][CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7]4=[C:8]([C:17](=[O:20])[NH:18][N:19]=[C:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3)(=[O:30])[O:28][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(O)CCP(=O)(OCc1ccccc1)OCc1ccccc1
Reactant: O=c1[nH]nc2c3c(cccc13)Oc1ccc(CO)cc1-2
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=c1[nH]nc2c3c(cccc13)Oc1ccc(COCCP(=O)(OCc3ccccc3)OCc3ccccc3)cc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a solution of compound 57 (0.5 mmol) in anhydrous DMF was added 3-bis(benzyloxy)phosphorylpropanoic acid (0.75 mmol) and EDC (0.75 mmol) and DMAP (catalytic amount). The reaction mixture was stirred at room temperature overnight. Solvent was removed in vacuo. To the residue, 100 mL ethyl acetate was added. The organic layer was washed with water, and dried with MgSO4. Solvent was removed to afford a colorless oil, which was recrystallized in EtOAc/Hexanes to afford a white solid 58 in 40% yield. MS (ES−): 581; Mp: 173-175° C. 1H-NMR (CDCl3, 400 MHz): 10.01 (s, 1H), 8.11 (d, J=2.0 Hz, 1H), 8.07 (d, J=7.5 Hz, 1H), 7.82 (t, J=8.5 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.40 (dd, J=8.5 and 2.0 Hz, 1H), 7.35-7.22 (m, 11H), 5.09 (s, 2H), 4.98 (m, 4H), 2.62 (m, 2H), 2.12 (m, 2H); Anal: Calcd for C32H27N2O7P: C, 65.98; H, 4.67; N, 4.81. Found: C, 65.69; H, 4.82; N, 5.09.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[C:6]([CH:34]=[CH:35][CH:36]=1)[C:7]([C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[C:11]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[N:10]=1)=[O:8].C(O)(C(F)(F)F)=O>ClCCl>[CH:3]([C:4]1[CH:5]=[C:6]([CH:34]=[CH:35][CH:36]=1)[C:7]([C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[C:11]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]3)=[CH:25][CH:26]=2)[N:10]=1)=[O:8])=[O:2]
Reactant: CCOC(=O)c1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1C(=O)c1cccc(C(OC)OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1C(=O)c1cccc(C=O)c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A solution of Example 215B (200 mg, 0.54 mmol) in dichloromethane (20 ml) was added TFA (5 mL). The mixture was stirred at 40° C. overnight. The reaction mixture was concentrated and the crude product was used in the next step without further purification. MS (DCI/NH3) m/z 474 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6](O)=O)[CH:3]=[N:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:21][C:22]1[C:30]([NH2:31])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([NH2:26])=[O:25]>CN(C)C=O.N1C=CC=CC=1>[NH:2]1[CH:3]=[C:4]([C:6]2[NH:21][C:22]3[C:23]([C:24]([NH2:26])=[O:25])=[CH:27][CH:28]=[CH:29][C:30]=3[N:31]=2)[CH:5]=[N:1]1
Reactant: O=C(O)c1cn[nH]c1
Reactant: NC(=O)c1cccc(N)c1N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2nc(-c3cn[nH]c3)[nH]c12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
35 0.56 g (5 mmol) of 4-pyrazolecarboxylic acid was stirred with 0.81 g (5 mmol) of carbonyldiimidazole in 20 ml of dimethylformamide at room temp. for 2 hours. 1.12 g (5 mmol) of 2,3-diaminobenzamide in 10 ml of pyridine were added. The reaction mixture was stirred at 50° C. for 2 hours. The reaction mixture was then concentrated in vacuo, and the residue was stirred with water. The precipitate was filtered off and dried in vacuo at 40° C. and then stirred in 10 ml of glacial acetic acid at 100° C. The residue after concentration in vacuo was stirred with saturated sodium bicarbonate solution. After filtration, the filtrate was concentrated with toluene in vacuo several times. The residue was stirred with tetrohydrofuran. Concentration in vacuo resulted in 150 mg of yellow powder.