Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[CH2:31]([O:33][C:34]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)=[O:35])[CH3:32]>>[CH2:31]([O:33][C:34]([C:36]1[CH:37]=[C:38]([C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([C:34]([O:33][CH2:31][CH3:32])=[O:35])[CH:37]=4)[CH:16]=3)([OH:14])[C:10]([F:11])([F:13])[F:12])=[C:2]([Cl:1])[CH:3]=2)[CH:39]=[CH:40][CH:41]=1)=[O:35])[CH3:32]
Reactant: CC(c1ccc(OS(=O)(=O)C(F)(F)F)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Product: CCOC(=O)c1cccc(-c2ccc(C(C)C(O)(c3ccnc(-c4cccc(C(=O)OCC)c4)c3)C(F)(F)F)c(Cl)c2)c1

Procedure:
In analogy to Example 49, trifluoromethanesulfonic acid 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenyl ester) (Example 26, step 1) was reacted with 3-ethoxycarbonylphenylboronic acid 4 h at 70° C. to give the title compound as a white solid. MS (m/e)=612.2 [M+H+].
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH:4]=[N:3]1.C1C(=O)N([Br:21])C(=O)C1>>[Br:21][C:9]1[C:10]([NH2:13])=[N:11][CH:12]=[C:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1cc(-c2ccc(N)nc2)cn1
Product: Cn1cc(-c2cnc(N)c(Br)c2)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine(380 mg, 2.18 mmol) acetonitrile(30 mL) solution at 0° C. was added NBS (388 mg, 2.18 mmol) and the reaction mixture was stirred at 0° C. for 30 min, then at room temperature for additional 40 min. The reaction mixture was then concentrated, redissolved in methanol, to it was added solid LiOH (80 mg), sonicated and concentrated, the residue was triturated with water (2×5 mL), and the supernatants were discarded. the residue was dried under high vacuum, then triturated with EtOAc (2×8 mL), and the supernatants were collected, combined, and concentrated and the light brown residue was obtained as crude 3-bromo-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine. LCMS (m/z): 253.0/255.0 (MH+), 0.38 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH3:13])[CH:12]=2)=[CH:4][CH:3]=1.[Li]C(C)(C)C.[C:19](=[O:21])=[O:20]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([C:19]([OH:21])=[O:20])=[C:11]([CH3:13])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C=O
Reactant: Cc1csc(-c2ccc(Cl)cc2)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2ccc(Cl)cc2)sc1C(=O)O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 74.9 %

Procedure:
Dissolve 2-(4-chloro-phenyl)-4-methyl-thiophene (0.53 g, 1.85 mmol) in THF (25 mL) and cool to −78° C. Add t-BuLi (1.7 M, 2.3 mL, 3.88 mmol) dropwise. Stir the solution at −78° C. for 20 min. Cannulate the solution into a flask containing powdered dry ice (10 g). Stir the reaction and allow to warm to RT. Quench the reaction with saturated NH4Cl (10 mL), dilute with water (40 mL), and extract with EtOAc (2×50 mL). Dry the combined organic layers over Na2SO4, filter, and concentrate. Purify the crude material by washing with hexane (2×20 mL) to give 0.35 g (74%) of the title compound. LC-MS/ES m/z (35Cl) 251.0 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:28][C:29]1[O:30][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])=[N:32][N:33]=1.O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:28][C:29]3[O:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:40])=[N:32][N:33]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: ClCc1nnc(-c2ccccc2Cl)o1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: O=c1n(Cc2nnc(-c3ccccc3Cl)o2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
85 mg (0.28 mmol) of the compound from Example 5A were dissolved in 5 ml of acetonitrile, and 180 mg (0.55 mmol) of cesium carbonate and 66 mg (0.29 mmol) of 2-(chloromethyl)-5-(2-chloro-phenyl)-1,3,4-oxadiazole were added. The mixture was stirred at 80° C. for 1 h. For work-up, the mixture was cooled to RT, and 10 ml of water were added. The mixture was extracted twice with in each case 15 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 66 mg (48% of theory) of the target compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[NH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([NH:21][C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:19]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2c1
Product: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Nc3ccc(C#N)cc3)c2c1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-amino-benzonitrile to give 4-[3-(5-methyl-1H-pyrazol-3-ylamino)-7-methoxy-isoquinolin-1-ylamino]-benzonitrile. LC-MS m/e 371(MH+).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:38])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[NH:30][CH:29]=4)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH2:37])[CH2:9]1>C(Cl)Cl.CC(N(C)C)=O>[CH3:38][N:7]([CH3:6])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[NH:30][CH:29]=4)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH:37][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:9]1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3c[nH]c4ccccc34)n2)c(OC)cc1N1CC[C@@H](N(C)C)C1
Temperature: -5 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
A solution of acryloyl chloride (0.604 mL, 1M in CH2Cl2, 0.60 mmol) was added dropwise to 4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-N-[4-(1H-indol-3-yl)pyrimidin-2-yl]-6-methoxybenzene-1,3-diamine (Intermediate 164, 268 mg, 0.60 mmol) in CH2Cl2 (10 mL) and 10 mL DMA, which was cooled to −5° C. The resulting mixture was stirred at −5° C. for 1 h and was then diluted with CH2Cl2 (100 mL). The resulting solution was washed with sat. NaHCO3 (25 mL), water (25 mL), and then sat. brine (4×25 mL), and was then concentrated in vacuo. Purification by FCC, eluting with 0-30% CH3OH in CH2Cl2 gave the title compound (135 mg, 45%) as a beige solid; 1H NMR (CDCl3) 1.98 (1H, s), 2.18 (1H, d), 2.94 (1H, s), 3.11 (4H, d), 3.88 (3H, s), 5.73 (1H, d), 6.40 (2H, d), 6.76 (1H, s), 7.17 (1H, d), 7.22-7.24 (1H, m), 7.41-7.46 (1H, m), 7.62 (1H, s), 8.16 (1H, s), 8.39 (1H, d), 8.45 (1H, s), 8.75 (1H, s), 8.86 (1H, s), 9.56 (1H, s); m/z: ES+ MH+ 498.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14](F)[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[CH3:19][CH:20]1[CH2:24][CH2:23][CH2:22][NH:21]1>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:21]3[CH2:22][CH2:23][CH2:24][CH:20]3[CH3:19])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: CC1CCCN1
Reactant: Fc1cccc(Nc2cc(Cl)nn3ccnc23)n1
Solvent: O
Product: CC1CCCN1c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Temperature: 205 °C
Yield: 63.9 %

Procedure:
A suspension of 6-chloro-N-(6-fluoropyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (132 mg, 0.5 mmol) and 2-methylpyrrolidine (64 mg, 0.75 mmol) in water (0.3 mL) was heated to 205° C. in a microwave oven for 30 minutes. The reaction mixture was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=200:1) to give 6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (105 mg, 63.8%) as a yellow solid. LC-MS: [M+H]+, 329.1, tR=2.019 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3S[CH2:16][CH2:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][C:12]=3[CH:22]=2)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[S:34]([O-:38])([O-])(=[O:36])=S.[Na+].[Na+]>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:34](=[O:38])(=[O:36])[CH2:16][CH2:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][C:12]=3[CH:22]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C1=Cc2cc(-c3ccc(C)cc3)ccc2SCC1
Reactant: O=S([O-])([O-])=S
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1=Cc2cc(-c3ccc(C)cc3)ccc2S(=O)(=O)CC1

Procedure:
To a solution of methyl 7-(4-methylphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate (1.5 g) in dichloromethane (25 ml) was added, under ice-cooling, 70% mCPBA (2.4 g), and the mixture was stirred at room temperature for 1 hour. To the solution was added an aqueous solution of sodium thiosulfate, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give methyl 7-(4-methylphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (1.6 g) as colorless crystals.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[C:11]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.C([O-])(O)=O.[Na+]>[Br:16][C:12]1[C:11]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][N:19]=2)=[C:10]([CH2:9][CH2:8][NH2:7])[CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCc1cccc(Br)c1Oc1ccc(C(F)(F)F)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCc1cccc(Br)c1Oc1ccc(C(F)(F)F)cn1
Reaction time: 8 h
Yield: 99.2 %

Procedure:
{2-[3-bromo-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.3 g, 2.818 mmol) was dissolved in dichloromethane (10 ml) and stirred at 0° C. for 5 min TFA (1.08 ml, 14.091 mmol, 5 eq) was added and stirring was continued overnight. Reaction mixture was diluted with 10 ml NaHCO3 (sat.) and extraction with DCM (3×20 ml) followed. Organic layers were combined and evaporated in vacuo to give 2-[3-bromo-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]-ethylamine (1.01 g, 2.796 mmol, yield=99%, purity=100%). [M+H]+=361.17
Reaction SMILES: [Mg].[F:2][C:3]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:4]=1Br.[CH2:12]([C@H:15]1[CH2:20][CH2:19][C@H:18]([CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1)[CH2:13][CH3:14].Cl>C1COCC1.O>[F:2][C:3]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:4]=1[C:24]1([OH:27])[CH2:23][CH2:22][CH:21]([C@H:18]2[CH2:19][CH2:20][C@H:15]([CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17]2)[CH2:26][CH2:25]1
Reactant: Fc1ccc(Br)c(F)c1F
Reactant: CCC[C@H]1CC[C@H](C2CCC(=O)CC2)CC1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CCC[C@H]1CC[C@H](C2CCC(O)(c3ccc(F)c(F)c3F)CC2)CC1
Reaction time: 3 h

Procedure:
Into 7.6 g of magnesium and 20 mL of THF which were stirred while water-cooling in a nitrogen atmosphere, a THF solution (200 mL) containing 60 g of 2,3,4-trifluorobromobenzene was added dropwise for 2 hours, and stirred for 3 hours. Into this, a THF solution (200 mL) containing 70 g of 4-(trans-4-propylcyclohexyl)cyclohexanone was added dropwise for 2 hours, and stirred for 2 hours. After the reaction solution was poured into 10% hydrochloric acid and stirred for a while, an organic layer was separated, and an aqueous layer was extracted with toluene. After the extract and the organic layer were mixed together, washed using water and a saturated saline solution in that order, and dried using anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure to obtain 110 g of 2,3,4-trifluoro-1-[1-hydroxy-4-(trans-4-propylcyclohexyl)cyclohexyl]benzene (unsatisfactorily dried).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.Cl[CH2:10][C:11](=O)[CH3:12].C(OCC)(=O)C>CC(O)C.CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([CH:10]=[C:11]([CH3:12])[N:8]=2)[CH:7]=1
Reactant: CC(=O)CCl
Reactant: Nc1ncc(Br)cn1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: Cc1cn2cc(Br)cnc2n1
Temperature: 10 °C
Reaction time: 16 h

Procedure:
To a solution of 5-bromopyrimidin-2-amine (170.0 g, 0.98 mol) in i-PrOH (2 L) and DMF (500 mL) was added 1-chloropropan-2-one (606 g, 6.53 mol), then the mixture was stirred at 10° C. for 16 h. TLC (petroleum ether:ethyl acetate=1:2) showed the reaction was complete. The reaction mixture was quenched by Na2CO3 and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (petroleum ether:ethyl acetate=5:1) to afford compound B-8-2 (10.0 g, 4.8%) as a yellow solid.
Reaction SMILES: [CH2:1]([S:4]([N:7]1[CH2:10][CH:9]([OH:11])[CH2:8]1)(=[O:6])=[O:5])[CH2:2][CH3:3].[CH3:12][S:13](Cl)(=[O:15])=[O:14].ClCCl>N1C=CC=CC=1>[CH2:1]([S:4]([N:7]1[CH2:8][CH:9]([O:11][S:13]([CH3:12])(=[O:15])=[O:14])[CH2:10]1)(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)N1CC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCS(=O)(=O)N1CC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.5 %

Procedure:
To a solution of 1-(propane-1-sulfonyl)-azetidin-3-ol (236 mg, 1.317 mmol) in pyridine was added drop wise methane sulfonyl chloride (205 μl, 2.63 mmol) at 0° C. The mixture was allowed to warm up to room temperature and was stirred for 3 h. Dichloromethane was added. The mixture was subsequently washed with water, saturated NaHCO3 and brine, dried (MgSO4), and filtrated. The solvent was evaporated to obtain 293 mg of crude product which was used without further purification.
Reaction SMILES: [Cl-].[NH4+].O.[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([N+:20]([O-])=O)[C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C.[Zn]>[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[NH2:20])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: COc1ccc(OCc2ccccc2)cc1N
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
1.38 kg of zinc powder and 15 g of ammonium chloride in 3.25 liters of ethanol to which have been added 600 ml of water are heated to 80° C. 2.5 mole (648 g) of 3-benzyloxy-6-methoxynitrobenzene is added little by little. Stirring is continued for 15 minutes after the end of the addition. The zinc is removed by filtering the reaction medium hot. The product crystallizes from the filtrate by cooling. After centrifuging and then washing with petrol ether, the product is dried. It melts at 81° C.
Reaction SMILES: [O:1]=[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([OH:17])=O)[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH3:6].COC(=O)[C@@H]1CCCN1.[NH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[NH2:28].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C1COCC1.C(OCC)(=O)C.O>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[NH:27][NH:28][C:15]([CH:11]1[CH2:12][CH2:13][CH2:14][N:10]1[C:2](=[O:1])[C:3](=[O:9])[C:4]([CH3:7])([CH3:8])[CH2:5][CH3:6])=[O:17]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)O
Reactant: NNc1ccccn1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: COC(=O)[C@@H]1CCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCC(C)(C)C(=O)C(=O)N1CCCC1C(=O)NNc1ccccn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidine-carboxylic acid (482 mg, 2 mmol), prepared from L-proline methyl ester according to the procedure described in WO 96/40633, 2-hydrazinopyridine (364 mg, 2 mmol), PyBrop (932 mg, 2 mmol), DMAP (4-dimethyaminopyridine, 122 mg) and DIEA (4 mL) in THF (dry, 50 mL) was stirred at room temperature for 24 h. Water and ethyl acetate were added. The organic phase was washed with ammonium chloride solution, followed by brine, and dried with MgSO4. Column chromatography (silica gel, ethyl acetate:methanol=10:0.5) gave a colorless oil; 490 mg (74%); MS (m/z) 333 (M+1); 1H NMR (d6-DMSO) δ0.85 (t, J=8 Hz, 3 H), 1.21 (s, 3 H), 1.23 (s, 3 H), 1.7 (m, 2 H), 1.90 (m, 1 H), 2.10 (m, 2 H), 2.35 (m, 1 H), 3.49 (t, J=8 Hz, 2 H), 4.62 (m, 1 H), 6.76 (m, 2 H), 7.51 (t, J=6 Hz, 1 H), 8.14 (d, J=6 Hz, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].[F:13][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15]Br.Cl>C(O)C.O>[F:13][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCCC(F)CBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCC(F)COc1ccc(C(=O)O)cc1
Reaction time: 25 h
Yield: 36.6 %

Procedure:
Into a 100 ml-round bottomed flask, 1.52 g (11 mW) of p-hydroxybenzoic acid in 20 ml of ethanol was added. Thereto, 1.45 g (26 mM) of potassium hydroxide in 5 ml of water was added, and 2.15 g (10 mM) of 2-fluorooctyl bromide in 2 ml of ethanol was added, followed by 25 hours of heat refluxing. Thereafter, a solution of 1.45 g (26 mM) of potassium hydroxide in 3 ml of water was added, followed by 5 hours of heat refluxing. After the completion of the reaction, the system was cooled with ice and neutralized with conc. HCl to precipitate a crystal. The crystal was filtered out, and washed with 50 ml of water to recover 1.00 g (yield: 37%) of p-2-fluorooctyloxybenzoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[C:11]([CH2:13][C:14]([NH:16][C:17]([NH2:19])=[O:18])=[O:15])#[N:12]>C(O)C.N1CCCCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[N:19][C:17](=[O:18])[NH:16][C:14](=[O:15])[CH2:13][C:11]#[N:12]
Reactant: N#CCC(=O)NC(N)=O
Reactant: O=Cc1ccc(O)c(O)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CCC(=O)NC(=O)N=Cc1ccc(O)c(O)c1
Yield: 60.7 %

Procedure:
To 0.69 g (5 mmol) 3,4-dihydroxybenzaldehyde and 0.6 g (5.3 mmol) cyanoacetylurea in 40 ml ethanol was added 2 drops piperidine. The reaction mixture was refluxed for 2 hours, cooled, filtered and washed with cold ethanol to yield 0.75 g (60% yield) of a yellow-orange solid, m.p. 235° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]3[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1ccc(-c2oc3ncnc(Cl)c3c2-c2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2oc3ncnc(Cl)c3c2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 78(1.0 g, 0.003 mol) in DCM (10 mL) at −78° C. was treated with boron tribromide (7.7 mL, 0.045 mol) for 20 min, then slowly warmed to rt, and stirred for another 2 h. The resulting mixture was carefully poured into ice water, extracted with EtOAc, purified by silica gel column chromatography to obtain 0.95 g. MS: 323.1 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:14][CH3:15])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[Cl:16]N1CCOCC1>>[CH2:1]([C:5]1[C:13]([Cl:16])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:14][CH3:15])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: ClN1CCOCC1
Reactant: CCCCc1ccc(C(=O)O)c(OC)c1
Product: CCCCc1cc(OC)c(C(=O)O)cc1Cl

Procedure:
4-n-Butyl-2-methoxybenzoic acid (0.5 g; 2.9 mmol) and N-chloromorpholine (356 mg; 2.9 mmol) were treated in a similar manner to that described in Preparation 24 to give the title compound as a white soid (0.4 g).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[NH2:32][CH2:33][C@H:34]([OH:36])[CH3:35].[OH-].[Na+:38]>>[CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=2)[C:8]([O-:23])=[C:7]([C:24]([NH:32][CH2:33][C@H:34]([OH:36])[CH3:35])=[O:25])[C:6]1=[O:29].[Na+:38]
Reactant: C[C@@H](O)CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H](O)CNC(=O)c1c([O-])c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2R)-1-amino-2-propanol employing methods similar to those described in Example 245 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The resulting material was treated with 1.3 equivalents of 1N NaOH solution and triturated with CH3CN to afford the product as a white solid: 1H NMR (d6-DMSO) δ 10.59 (1H, br), 8.14 (1H, s), 7.26 (3H, m), 7.10 (2H, m), 4.92 (2H, s), 4.80 (1H, br), 3.99 (2H, s), 3.67 (1H, br), 3.15 (2H, m), 3.08 (3H, s), 2.78 (3H, s), 1.04 (3H, br d, J˜5 Hz); HRMS calcd for C23H25FN4O5+H+: 457.1887. Found: 457.1882.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[OH:9].N12CCCN=C1CCCCC2.[CH3:21][CH2:22][CH:23](Br)[C:24](OCC)=[O:25]>CN1CCCC1=O>[Br:1][C:2]1[C:3]2[O:9][CH:23]([CH2:22][CH3:21])[C:24](=[O:25])[NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Br)CC
Reactant: Nc1cccc(Br)c1O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN1CCCC1=O
Product: CCC1Oc2c(Br)cccc2NC1=O
Yield: 71 %

Procedure:
Procedure & NMR Data: 1.5 g (7.9 mmol) of 2-bromo-6-aminophenol, 1.08 ml (0.9 eq, 7.11 mmol) of 1.8-diazabicyclo[5.4.0]undec-7-ene and 3.5 mL of DL-Ethyl 2-bromobutyrate (3 eq, 23.7 mmol)) in 30 mL of 1-Methyl-2-pyrrolidinone were mixed. 1.447 g of P1 were obtained, yield 71%.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH2:22][CH3:23])[C:4]([C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([C:16]2[O:17][CH:18]=[CH:19][N:20]=2)[CH:15]=1)[C:9]([O:11]C)=[O:10])=[O:5])[CH3:2].O.[OH-].[Li+]>O1CCCC1.CO.O.C(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:21][CH2:22][CH3:23])[C:4]([C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([C:16]2[O:17][CH:18]=[CH:19][N:20]=2)[CH:15]=1)[C:9]([OH:11])=[O:10])=[O:5])[CH3:2]
Reactant: CCCN(CC)C(=O)c1cc(C(=O)OC)cc(-c2ncco2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCN(CC)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To methyl 3-{[ethyl(propyl)amino]carbonyl}-5-(1,3-oxazol-2-yl)benzoate (375 mg, 1.2 mmol) in tetrahydrofuran/methanol/water (1:1:1, 9 mL) is added lithium hydroxide monohydrate (100 mg, 2.4 mmol), and the reaction is stirred at room temperature 16 h. The solution is diluted in chloroform and washed with water and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to give the title compound. ESI MS m/z 301.1 [M−H]−.