Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1.S(Cl)(Cl)=O>C(COC)OC.C(Cl)Cl.CC(N(C)C)=O.O>[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:31])=[CH:33][CH:34]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: COCCOC
Product: CS(=O)(=O)NC(=O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Reaction time: 2 h

Procedure:
A solution of 19.0 g. of methanesulfonamide in 150 ml. of dry dimethyacetamide is added dropwise over 15 minutes to a stirred and cooled (water bath) suspension of 5.5 g. of sodium hydride in 100 ml. of dry dimethylacetamide. The mixture is then stirred and heated at 60°-80° l C. for 2 hours. In the meantime, a mixture of 36.2 g. of 4-(16-bromohexadecylamino)benzoic acid in 1200 ml. of methylene chloride, 300 ml. of dimethoxyethane, and 40 ml. of thionyl chloride is refluxed for 1 hour and 15 minutes. The solution is evaporated to an oil which is co-evaporated twice with added dioxane to remove excess thionyl chloride. To the resulting oily residue of 4-(16-bromohexadecylamino)benzoyl chloride hydrochloride is added, in one portion, the previously prepared mixture of sodium methanesulfonamide in dimethylacetamide. The mixture becomes very hot and is cooled briefly in a water bath and then is stirred at room temperature for 30 minutes. The mixture is filtered through a bed of diatomaceous earth and the filtrate is poured into 2 l. of water. The resulting suspension is coagulated by the addition of 250 ml. of saturated sodium chloride solution and the mixture is filtered. The product is washed with water, partially air dried and then crystallized from 1.5 l. of ethanol. The product is recrystallized twice from p-dioxane and dried in the Abderhalden at 65° C. to give of the title compound as tan crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].CCN(CC)CC.CN(C=O)C.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>CCOCC>[C:19]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18]
Reactant: NCCCO
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCO
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 3-aminopropanol 8-1 (Aldrich) (15 g, 0.2 mol), NEt3 (42 mL, 0.3 mol) and DMF (400 mL) at 0° C. was added BOC2O (52 g, 0.24 mol). After stirring at 0° C. for 6 h the reaction mixture was diluted with ether and then washed with H2O (2×), sat. NaHCO3, 5% KHSO4 and brine, dried (MgSO4) and concentrated to give 8-2 as a colorless oil.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH:12]2[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]3)=[N:9][CH:10]=1)=[NH:4].CN([CH:29]=[O:30])C.ClC(OC)=O>N1C=CC=CC=1>[O:30]=[C:29]1[O:1][N:2]=[C:3]([C:5]2[CH:6]=[CH:7][C:8]([N:11]3[CH:12]4[CH2:18][CH2:17][CH:16]3[CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13]4)=[N:9][CH:10]=2)[NH:4]1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2c1ccc(C(=N)NO)cn1
Agent: COC(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC2CCC(C1)N2c1ccc(-c2noc(=O)[nH]2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1 g of the compound from step c) is placed in a round-bottomed flask under a stream of nitrogen, and 10 ml of DMF and 0.3 ml of pyridine are added. 0.23 ml of methyl chloroformate is added at 0° C., and the mixture is stirred at room temperature for 3 hours. The resulting mixture is washed with water and extracted with ethyl acetate. The organic phase is dried over Na2SO4, filtered and evaporated under vacuum. 30 ml of toluene are added and the resulting mixture is stirred at reflux for 4 hours. The solvent is evaporated off to give 0.8 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:12]CCl.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>CO>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: ClCCCl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(F)cc1
Yield: 84 %

Procedure:
A solution of 4-fluorobenzoic acid (25.0 g), 1,2-dichloroethane (120 ml), methanol (21.7 ml) and concentrated sulfuric acid (0.8 ml) was stirred for 16.5 hours with refluxing. After the reaction, the reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution, extracted with chloroform, and washed with saturated brine. The mixture was dried over magnesium sulfate, and the solvent was distilled away under reduced pressure to give 23.0 g of a colorless transparent liquid (yield 84%).
Reaction SMILES: [CH2:1]([Si:3](Cl)([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].N1C=CN=C1.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C@@H:19]1[NH:22][C:21](=[O:23])[C@@:20]1([OH:25])[CH3:24].C(OCC)(=O)C.CCCCC>CN(C=O)C>[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C@@H:19]1[NH:22][C:21](=[O:23])[C@@:20]1([O:25][Si:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:1][CH3:2])[CH3:24]
Reactant: CC[Si](Cl)(CC)CC
Reactant: C[C@]1(O)C(=O)N[C@H]1c1ccco1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCC
Product: CC[Si](CC)(CC)O[C@@]1(C)C(=O)N[C@H]1c1ccco1
Yield: 67 %

Procedure:
Triethyl silyl chloride (0.316 g, 2.1 mmol) and imidazole (0.100 g, 1.5 mmol) were added to a stirred solution of (3R,4R)-4-(furan-2-yl)-3-hydroxy-3-methyl-azetidin-2-one (0.167 g, 1.0 mmol) in DMF (6.0 ml) at 25° C. under argon atmosphere. The reaction solution was quenched after 4 h with a saturated NH4Cl aqueous solution and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. Chromatography of the residue (SiO2, ethyl acetate/n-pentane, 1:2) afforded 0.190 g (0.67 mmol 67%) of (3R,4S)-4-(furan-2-yl)-3-triethylsilyloxy-3-methyl-azetidin-2-one: [α]D20=+42.8 (c 1.04, CHCl3); IR (CDCl3, cm−1): 3600–3000, 3413, 2957, 1768, 1458, 1377, 1012; 1H NMR (CDCl3): δ=0.65 (m, 6H, 3 CH2), 0.95 (t, 9H, 3 Me), 1.19 (s, 3H, Me), 4.54 (s, 1H), 6.27 (d, 1H, 2-furyl), 6.28 (m, 1H, 2-furyl), 6.72 (b, 1H, NH), 7.40 (m, 1H, 2-furyl); 13H NMR (CDCl3): δ=5.71 (CH2), 6.73 (Me), 19.3 (Me), 61.0 (CH), 89.1(C), 108.1 (CH), 110.5 (CH), 142.7 (CH), 150.9 (C), 171.5 (C).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].[F:12][C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C.[OH-].[Na+].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(Cl)Cl>[F:12][C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(F)c(Br)n1
Reactant: OB(O)c1cccc(F)c1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(F)c(-c2cccc(F)c2F)n1
Temperature: 120 °C

Procedure:
To a solution of 6-bromo-5-fluoropicolinic acid (1.0 equiv.) in DME and 2M Na2CO3 (3:1, 0.25 M) was added 2,3-difluorophenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) in a microwave vial. The vial was heated in the microwave at 120° C. for 30 minutes. The mixture was diluted with ethyl acetate and 1N NaOH was added. The organic phase was separated and extracted three more times with 1N NaOH and once with 6N NaOH. The combined aqueous phases were filtered and acidified to pH 1 by the addition of concentrated HCl and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 6-(2,3-difluorophenyl)-5-fluoropicolinic acid in 78%. LC/MS=254.1 (M+H), Rt=0.75 min.
Reaction SMILES: [Li]C(CC)C.[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[N:13]([Si](C(C)C)(C(C)C)C(C)C)[CH:14]=[CH:15][C:8]=12.[I:26]I.[Cl-].[NH4+].S([O-])([O-])=O.[Na+].[Na+].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C.O>[Cl:6][C:7]1[C:12]([I:26])=[CH:11][N:10]=[C:9]2[NH:13][CH:14]=[CH:15][C:8]=12
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Reactant: II
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1c(I)cnc2[nH]ccc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
s-BuLi (59.3 mL, 71.2 mmol, 1.4M in cyclohexane) at −78° C. was added to 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (10.0 g, 32.4 mmol) in THF (100 mL), and the reaction was stirred at −78° C. for 30 minutes. I2 (20.5 g, 80.9 mmol) in THF (50 mL) was added, and the reaction was stirred at −78° C. for 20 minutes. A saturated ammonium chloride solution (50 mL) and a saturated sodium sulfite solution (50 mL) were added, and the mixture was extracted with hexanes (200 mL), washed with brine and dried over sodium sulfate. After removal of the solvent, the residue was dissolved in THF (50 mL), and TBAF (32.4 mL, 32.4 mmol) was added. The reaction was stirred at room temperature for 10 minutes, and then water (20 mL) and ethyl acetate (100 mL) were added. The organic layer was separated, washed with brine, and dried over sodium sulfate. After removal of the solvent, the residue was suspended in dichloromethane (“DCM”; 20 mL) and stirred for 10 minutes. The solid formed was collected by filtration to give 4-chloro-5-iodo-1H-pyrrolo[2,3-b]pyridine (6.6 g, 73% yield) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([O:22]C)=[O:21])=[CH:13][C:12]=2[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[S:17](=[O:18])(=[O:19])[CH2:16][CH2:15][C:14]([C:20]([OH:22])=[O:21])=[CH:13][C:12]=2[CH:24]=1
Reactant: COC(=O)C1=Cc2cc(OCc3cccc(OC)c3)ccc2S(=O)(=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(COc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)c1
Temperature: 60 °C
Reaction time: 14.5 h
Yield: 64.5 %

Procedure:
To methyl 7-(3-methoxybenzyloxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (436 mg) dissolved in THF-methanol (10-5 ml) was added a 2 M aqueous solution of potassium carbonate (1.2 ml), and the resulting mixture was stirred at 60° C. for 14.5 hours. The reaction mixture was treated with 1 N hydrochloric acid to bring the pH to 2. The resulting mixture was diluted with ethyl acetate and was washed respectively with water and an aqueous saturated solution of sodium chloride, and the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure to remove the solvent, the precipitated crystals were washed with hexane-ethyl acetate to obtain 7-(3-methoxybenzyloxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (271 mg) as white crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.CN(C)[CH:14]=[O:15].[BH4-].[Na+].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C([Li])CCC.CO>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([CH2:14][OH:15])[CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cccc(Br)n1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: OCc1cccc(C(F)(F)F)n1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 108.5 %

Procedure:
A solution containing 2.00 g of 2-bromo-6-trifluoromethylpyridine dissolved in 50 ml of toluene was cooled to −78° C. followed by dropping in 4.0 ml of n-butyllithium (2.77 mol/L) and stirring for 10 minutes at −78° C. 0.96 g of N,N-dimethylformamide were dropped therein followed by further stirring for 10 minutes at −78° C. following completion of the reaction. 0.67 g of sodium borohydride and 5 ml of methanol were added to the resulting reaction mixture followed by heating to room temperature and stirring for 1 hour at room temperature. Following completion of the reaction, aqueous ammonium chloride solution was added to the reaction liquid followed by extraction with ethyl acetate. The ethyl acetate layer was dried by addition of anhydrous magnesium sulfate followed by filtering and distilling off the solvent from the filtrate under reduced pressure to obtain 1.70 g of a crude product in the form of (6-trifluoromethylpyridin-2-yl) methanol.
Reaction SMILES: [Li].[NH2:2][C:3]1[N:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.[O:15]([C:22]1[S:26][C:25]([CH2:27][NH2:28])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.F[P-](F)(F)(F)(F)F.N1([P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[NH2:2][C:3]1[N:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([NH:28][CH2:27][C:25]1[S:26][C:22]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:23][CH:24]=1)=[O:7]
Reactant: NCc1ccc(Oc2ccccc2)s1
Reactant: Nc1ncc([N+](=O)[O-])cc1C(=O)O
Agent: CN(C)[P+](N(C)C)(N(C)C)n1nnc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncc([N+](=O)[O-])cc1C(=O)NCc1ccc(Oc2ccccc2)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
Then, the resulting lithium salt of 2-amino-5-nitro-nicotinic acid, C-(5-phenoxy-thiophen-2-yl)-methylamine (60 mg, 0.29 mmol), benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate (162 mg, 0.367 mmol) and triethylamine (103 μl, 0.735 mmol) were dissolved in N,N-dimethylformamide (2.0 mL), and the solution was stirred for 6 hours at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate, and the organic layer was washed with water and brine. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), and the title compound (87 mg, 0.24 mmol, 96%) was obtained as a pale yellow solid.
Reaction SMILES: [N:1](OCCCC)=O.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[CH3:18])([O-:10])=[O:9].CC(C)([O-])C.[K+].Cl>CN(C)C=O>[CH3:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[C:12]=1[C:18]#[N:1]
Reactant: CCCCON=O
Reactant: Cc1cccc([N+](=O)[O-])c1C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc([N+](=O)[O-])c1C#N
Temperature: 25 °C
Reaction time: 144 h

Procedure:
A solution of 16 g (150 mmol) of n-butyl nitrite (97%) and 7.7 g (50 mmol) of 3-nitro-o-xylene (97%) in 50 ml of dimethylformamide is cooled to from −5 to −10° C., and a solution of 11 g (100 mmol) of potassium tert-butoxide in 50 ml of dimethylformamide is added at this temperature, over a period of 1.5 hours. The reaction mixture is stirred at room temperature for another 6 days. For work-up, the mixture is poured onto ice-water and adjusted to pH 1 using hydrochloric acid, and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated. This gives 8.2 g of product. The 2-methyl-6-nitrobenzonitrile can be purified by silica gel chromatography using the mobile phase toluene.
Reaction SMILES: [Mg].Br[CH2:3][CH:4]([CH3:7])[CH2:5][CH3:6].[Br-].[CH3:9][C:10](=[CH:13][CH2:14][CH3:15])[CH:11]=[O:12].[Cl-].[NH4+]>CCOCC>[CH3:7][CH:4]([CH2:3][CH:11]([OH:12])[C:10]([CH3:9])=[CH:13][CH2:14][CH3:15])[CH2:5][CH3:6]
Reactant: CCC=C(C)C=O
Reactant: CCC(C)CBr
Agent: [Br-]
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: CCC=C(C)C(O)CC(C)CC
Temperature: 10 °C
Yield: 34.3 %

Procedure:
0.72 g (29.8 mg atoms) of magnesium in 3 ml of absolute ether are placed in an apparatus which is customary for Grignard reactions. While stirring there are subsequently added dropwise 5.0 g (33.1 mmol) of 1-bromo-2-methylbutane (90%) in 5 ml of absolute ether so that the ether boils constantly. After completing the addition of the bromide, the mixture is held at reflux temperature for a further 30 minutes, then cooled to 10° C. and a solution of 2.92 g (29.8 mmol) of 2-methyl-2-pentenal in 3 ml of absolute ether is added dropwise. The exothermic reaction causes the temperature to rise to 25° C. After refluxing for a further hour, the reaction product is worked-up with crushed ice and saturated ammonium chloride solution in the customary manner. After separating the aqueous phase, the organic layer is washed with saturated sodium chloride solution, subsequently dried and freed from solvent. The crude product (4.8 g) is distilled and yields 1.74 g of pure 3,6-dimethyl-6-nonen-5-ol (boiling point about 120° C./12 mm Hg; nD20 =1.4560), which has the following spectral data:
Reaction SMILES: [F:1][C:2]([F:16])([CH:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:17]12([C:27](Cl)=[O:28])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:17]12([C:27]([O:15][CH:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])([F:16])[F:1])=[O:28])[CH2:24][CH:23]3[CH2:22][CH:21]([CH2:20][CH:19]([CH2:25]3)[CH2:18]1)[CH2:26]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CCOC(=O)C(F)(F)C(O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(F)(F)C(OC(=O)C12CC3CC(CC(C3)C1)C2)c1ccccc1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
In 60 g of methylene chloride were dissolved 9 g of ethyl 2,2-difluoro-3-hydroxy-3-phenylpropionate, prepared in Synthesis Example 1-4, and 9.5 g of 1-adamantanecarbonyl chloride. Under ice cooling, a mixture of 6 g of triethylamine, 0.5 g of 4-dimethylaminopyridine and 20 g of methylene chloride was added dropwise to the solution. The reaction solution was aged overnight, after which it was quenched with 5 wt % hydrochloric acid, washed with water, and concentrated. Methyl isobutyl ketone was added to the concentrate, which was concentrated again. There was obtained 15 g of the target compound, 2-ethoxycarbonyl-2,2-difluoro-1-phenylethyl 1-adamantanecarboxylate as colorless oily matter (yield 68%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][C:5]=1[NH:12][C:13](=[O:15])[CH3:14].CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:6][C:5]=1[NH:12][C:13](=[O:15])[CH3:14]
Reactant: COC(=O)c1ccc(CO)cc1NC(C)=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(COS(C)(=O)=O)cc1NC(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-acetylamino-4-hydroxymethyl-benzoic acid methyl ester (4 g, 17.9 mmol) and Et3N (7.5 mL, 3.0 equiv) in DCM (100 mL) at 0° C. was added MsCl (2.1 mL, 1.5 equiv) dropwise. At the end of the addition, the mixture was stirred 1 h at 0° C. The organic phase was washed with a saturated solution of NaHCO3 and then dried (Na2SO4). The solution was concentrated in vacuo to afford the title compound as a brown paste (5.4 g, 100%) (ES-MS: m/z 302.2 [M+H]+, rt 4.58 min).
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[CH:9][C:5]([C:6]([NH2:8])=O)=[C:4]([NH:20][S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])[CH:3]=1.O1CCOCC1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O>[Br:1][C:2]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[CH:9][C:5]([C:6]#[N:8])=[C:4]([NH:20][S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])[CH:3]=1
Reactant: CCS(=O)(=O)Nc1cc(Br)c(Oc2ccc(F)cc2F)cc1C(N)=O
Solvent: c1ccncc1
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)Nc1cc(Br)c(Oc2ccc(F)cc2F)cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
To a suspension of Example 324e (230 mg, 0.53 mmol) and dioxane (1.5 mL) was added pyridine (0.14 mL, 1.7 mmol) followed by 2,2,2-trifluoroacetic anhydride (0.14 mL, 0.99 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. Water was added and the solution was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 5-40% ethyl acetate/heptane gradient) to afford the title compound (135 mg, 61% yield).
Reaction SMILES: Cl[C:2]1[C:3]([N:8]2[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:20]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:20][C:2]1[C:3]([N:8]2[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nn(-c2ncccc2Cl)cc1C=O
Reactant: CB1OB(C)OB(C)O1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1nn(-c2ncccc2C)cc1C=O
Temperature: 110 °C
Reaction time: 16 h
Yield: 13.2 %

Procedure:
A mixture of ethyl 1-(3-chloro-2-pyridyl)-4-formyl-pyrazole-3-carboxylate (1.0 g, 3.5 mmol), trimethylboroxine (0.44 g, 3.50 mmol) and potassium carbonate (1.4 g, 10.1 mmol) in dioxane (18 mL) and water (2 mL) is degassed with nitrogen gas for 10 min and then palladium triphenylphosphine (0.40 g, 0.3 mmol) is added and stirred at 110° C. for 16 h. After completion, the reaction mixture is partitioned between dichloromethane (50 mL) and water (25 mL). The aqueous layer is extracted with dichloromethane (2×25 mL) and the combined organic extracts are dried over sodium sulfate and concentrated in vacuo. The crude mixture is purified by column chromatography over silica gel eluting with hexane/ethyl acetate (70:30) to yield 0.12 g (13%) of the title compound. MS (m/z): 260 (M+1).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[CH3:5][O:6][C:7](=[O:27])[C:8]1[CH:13]=[C:12]([C:14](=[O:16])[CH3:15])[C:11](F)=[C:10]([F:18])[C:9]=1[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26].CC(C)=O>CCOC(C)=O.O>[CH3:5][O:6][C:7]([C:8]1[C:9]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])=[C:10]([F:18])[C:11]2=[N:1][O:16][C:14]([CH3:15])=[C:12]2[CH:13]=1)=[O:27]
Reactant: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc2c(C)onc2c(F)c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
Sodium azide (128 mg, 1.95 mmol) was added to a mixture of 5-acetyl-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (6) (601 mg, 1.59 mmol) in 3:1 acetone:water (16 ml) and heated to reflux. After 16 hours, the reaction mixture was cooled to room temperature, and diluted with EtOAc and water. The organic layer was washed with water, dried (MgSO4) and concentrated. The resulting residue was diluted with water (8 mL) and heated to reflux. After 5 hours, the mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water, dried (MgSO4) and concentrated. Purification by flash column chromatography using the Biotage system (20% EtOAc in hexanes) provided the desired product (55) (410 mg, 77%).