Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]#[N:19])[CH:8]=1)=[O:5].Cl[C:34]1[C:39]([F:40])=[CH:38][CH:37]=[C:36]([CH2:41][O:42][CH3:43])[N:35]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[Cl:1][C:2]1[CH:23]=[CH:22][C:21]([C:34]2[C:39]([F:40])=[CH:38][CH:37]=[C:36]([CH2:41][O:42][CH3:43])[N:35]=2)=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]#[N:19])[CH:8]=1)=[O:5]
Reactant: CC1(C)OB(c2ccc(Cl)c(C(=O)Nc3cc(C#N)nn3-c3ccccc3)c2)OC1(C)C
Reactant: COCc1ccc(F)c(Cl)n1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COCc1ccc(F)c(-c2ccc(Cl)c(C(=O)Nc3cc(C#N)nn3-c3ccccc3)c2)n1
Temperature: 80 °C
Yield: 75.2 %

Procedure:
To a degassed solution of 2-chloro-N-(3-cyano-1-phenyl-1H-pyrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Preparation 7, 325 mg, 0.72 mmol), 2-chloro-3-fluoro-6-(methoxymethyl)pyridine (Preparation 52, 191 mg, 1.09 mmol) and potassium carbonate (200 mg, 1.45 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added Pd(PPh3)4 (83 mg, 0.072 mmol) and the reaction was heated to 80° C. for 18 hours. The reaction was cooled and concentrated in vacuo. The resulting residue was partitioned between EtOAc (15 mL) and water (15 mL). The aqueous layer was extracted with EtOAc (2×15 mL) and the organic extracts were combined, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 1:1 EtOAc in heptanes to afford the title compound (250 mg, 75%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:55][O:56][CH2:57][CH2:58][CH2:59][NH2:60]>CN(C=O)C>[CH3:55][O:56][CH2:57][CH2:58][CH2:59][NH:60][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: COCCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCCNC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (114 mg, 0.35 mmol), N,N-diisopropyl ethyl amine (275 μL, 1.6 mmol) and 3-methoxypropylamine (36 μL, 0.35 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by preparative HPLC on reversed phase eluting with acetonitrile/water [0.1% aq NH3 (25%)] afforded the title compound (101 mg, 82%) which was obtained as a white solid. MS: m/e=382.5 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][CH:11]([O:21][C:22](=[O:24])[CH3:23])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[H][H]>C(OCC)(=O)C.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH:11]([O:21][C:22](=[O:24])[CH3:23])[CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1
Reactant: CC(=O)OC(C#CCOC1CCCCO1)COc1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)OC(CCCOC1CCCCO1)COc1ccc(F)cc1

Procedure:
1-(2-Tetrahydropyranyloxy)-4-acetoxy-5-(4-fluorophenoxy)-2-pentyne (13.4 g.; 0.04 mole) is dissolved in ethyl acetate (100 ml.). 5% Palladium on carbon is added and the mixture is hydrogenated on the Parr apparatus at an initial pressure of 41 lbs./in2 and 25°. When 0.08 mole of hydrogen is absorbed, the catalyst is removed by filtration and the solvent is evaporated under vacuum to give the title compound as a light orange residual oil, yield 12.90 g.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH:11]([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:22]2[CH:23]=[C:24]([C:28]3[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:25]=[CH:26][CH:27]=2)O1>>[F:12][CH:11]([F:13])[C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:26]3[CH:25]=[C:24]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:23]=[CH:22][CH:27]=3)=[CH:3][N:4]=[C:5]2[N:10]=1
Reactant: CC1(C)OB(c2cccc(-c3ccccc3C#N)c2)OC1(C)C
Reactant: FC(F)c1ccn2c(Br)cnc2n1
Product: N#Cc1ccccc1-c1cccc(-c2cnc3nc(C(F)F)ccn23)c1
Yield: 58 %

Procedure:
3-Bromo-7-difluoromethylimidazo[1,2-a]pyrimidine (248 mg, 1.00 mmol) was coupled with 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3′-(7-difluoromethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile (201 mg, 58%) as a yellow powder: δH (400 MHz, CDCl3) 6.67 (1H, t, J 55) 7.29 (1H, d, J 7), 7.52 (1H, td, J 9 and 1), 7.58-7.74 (5H, m), 7.87 (2H, m), 8.01 (1H, s), 9.12 (1H, d, J 7); m/z (ES+) 347 (M++H).
Reaction SMILES: [CH:1]1[CH:5]=[C:4]([CH:6]([OH:14])[C:7]([C:9]2[O:13][CH:12]=[CH:11][CH:10]=2)=O)[O:3][CH:2]=1.[N:15]#[C:16][NH2:17].[O-]CC.[Na+].O>C(O)C>[NH2:17][C:16]1[O:14][C:6]([C:4]2[O:3][CH:2]=[CH:1][CH:5]=2)=[C:7]([C:9]2[O:13][CH:12]=[CH:11][CH:10]=2)[N:15]=1
Reactant: N#CN
Reactant: O=C(c1ccco1)C(O)c1ccco1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1nc(-c2ccco2)c(-c2ccco2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
Furoin (0.50 g, 2.60 mmol) was dissolved in ethanol (15 mL). Cyanamide (218.8 mg, 5.20 mmol) and sodium ethoxide (530.8 mg, 7.80 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (hexane:ethyl acetate=1:1→1:2) to give the title compound (175.0 mg, 31.1%) as a dark brown crystal.
Reaction SMILES: [CH3:1][C:2]1[C:6](=[O:7])[N:5]=[N:4][CH:3]=1.[H-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:14]Cl>CN(C)C=O>[CH3:1][C:2]1[C:6](=[O:7])[N:5]([CH2:14][C:13]2[CH:16]=[CH:17][C:18]([Cl:19])=[C:11]([Cl:10])[CH:12]=2)[NH:4][CH:3]=1
Reactant: CC1=CN=NC1=O
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c[nH]n(Cc2ccc(Cl)c(Cl)c2)c1=O

Procedure:
19.6 g of 4-methylpyrazol-5-one were added in portions to a suspension of 5.0 g of sodium hydride in 100 ml of absolute dimethylformamide. After the evolution of H2 had ceased, 39 g of 3,4-dichlorobenzyl chloride were added dropwise to the reaction solution.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][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][CH2:25][C:26]([NH:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH:33]([C:36]([OH:38])=[O:37])[CH2:32][CH2:31]1)=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:52]1[C:57](=[O:58])[CH2:56][CH2:55][C:53]1=[O:54])=[N+](C)C)C>C1COCC1.C(#N)C>[O:54]=[C:53]1[CH2:55][CH2:56][C:57](=[O:58])[N:52]1[O:37][C:36]([CH:33]1[CH2:34][CH2:35][CH:30]([CH2:29][NH:28][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:31][CH2:32]1)=[O:38]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NCC1CCC(C(=O)O)CC1
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NCC1CCC(C(=O)ON2C(=O)CCC2=O)CC1
Yield: 87.8 %

Procedure:
To a solution of 4-[(19-tert-butoxycarbonylnonadecanoylamino)methyl]cyclohexanecarboxylic acid (5.56 g) in THF (100 ml) was added a solution of TSTU (3.42 g) in acetonitrile (25 ml). The mixture was concentrated in vacuo after stirring over night. The solid residue was recrystallized from acetonitrite to give 4-[(19-tert-butoxycarbonylnonadecanoylamino)methyl]cyclohexanecarboxylic acid 2,5-dioxopyrrolidin-1-yl ester (5.76 g, 88%).
Reaction SMILES: [OH:1][CH:2]([CH2:12][OH:13])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH3:14][S:15][CH2:16][C:17](Cl)=O>[OH-].[Na+].CO>[CH3:14][S:15][CH2:16][CH2:17][O:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:12][OH:13])=[CH:6][CH:7]=1
Reactant: CSCC(=O)Cl
Reactant: OCC(O)COc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSCCOc1ccc(OCC(O)CO)cc1
Yield: 87.2 %

Procedure:
A 1.84 g quantity of 4-(2,3-dihydroxypropoxy)phenol was dissolved in 0.40 g of sodium hydroxide and 10 ml of 90% methanol. To the solution was added 1.11 g of 2-methylmercaptoacetyl chloride, and the mixture was refluxed for 6 hours. The reaction mixture was concentrated and the residue was extracted with chloroform. The chloroform layer was washed with water, dewatered with Glauber's salt and concentrated. The residue was recrystallized from benzene-petroleum ether, giving 2.25 g of 2-{4-(2,3-dihydroxypropoxy)phenoxy}ethyl methyl sulfide in 87.2% yield, M.P. 59° to 61° C.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)[O:12][C@H:13]([C:15](=[O:37])[NH:16][C@@H:17]2[C:23](=[O:24])[N:22]([CH2:25][CH2:26][O:27][CH3:28])[C:21]3[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=3[C:19]3[CH:33]=[CH:34][CH:35]=[CH:36][C:18]2=3)[CH3:14])=CC=1)([O-])=O.[F:39][C:40]([F:47])([C:43]([F:46])([F:45])[F:44])[CH2:41][NH2:42]>>[CH3:28][O:27][CH2:26][CH2:25][N:22]1[C:23](=[O:24])[C@@H:17]([NH:16][C:15]([C@@H:13]([O:12][C:11](=[O:10])[NH:42][CH2:41][C:40]([F:47])([F:39])[C:43]([F:46])([F:45])[F:44])[CH3:14])=[O:37])[C:18]2[CH:36]=[CH:35][CH:34]=[CH:33][C:19]=2[C:20]2[CH:32]=[CH:31][CH:30]=[CH:29][C:21]1=2
Reactant: NCC(F)(F)C(F)(F)F
Reactant: COCCN1C(=O)[C@@H](NC(=O)[C@H](C)OC(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc2-c2ccccc21
Product: COCCN1C(=O)[C@@H](NC(=O)[C@H](C)OC(=O)NCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Using carbonic acid (S)-1-[(S)-5-(2-methoxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl]-ethyl ester 4-nitro-phenyl ester and 2,2,3,3,3-pentafluoropropylamine, the title compound was prepared in the same manner as described for example 5c. White solid (49%). MS: m/e=530(M+H+).
Reaction SMILES: [I-:1].[Na+].S(O[CH2:8][CH:9]1[CH2:14][CH2:13][C:12]([CH3:21])([C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])[CH2:11][CH2:10]1)(C)(=O)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O>[I:1][CH2:8][CH:9]1[CH2:14][CH2:13][C:12]([CH3:21])([C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])[CH2:11][CH2:10]1
Reactant: [I-]
Reactant: C=CCOC(=O)C1(C)CCC(COS(C)(=O)=O)CC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Product: C=CCOC(=O)C1(C)CCC(CI)CC1
Yield: 49.6 %

Procedure:
5 g of sodium iodide was added to a solution of 2 g of allyl 4-mesyloxymethyl-1-methyl-1-cyclohexanecarboxylate (Example 45) in 50 ml of acetone. The solution was reacted for 4 hours, while it was refluxed. After reaction, 100 ml of an aqueous sodium thiosulfate solution was added to the reaction solution. The solution was extracted three times with 30 ml of ethyl acetate. The organic layer obtained was washed twice with an aqueous sodium thiosulfate solution and twice with an aqueous sodium chloride solution, and was dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo. The oily substance obtained was subjected to column chromatography using 10 g of silica gel. From the fraction eluted with hexane and ethyl acetate=2:1, the solvent was removed in vacuo, yielding 1.1 g of allyl 4-iodomethyl-1-methyl-1-cyclohexanecarboxylate as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[C:28]=2[Cl:35])[C:7]=1[N:8]([C:18]([O:20][C:21]1C=CC=C[CH:22]=1)=[O:19])C(OC1C=CC=CC=1)=O)#[N:2].[CH2:36]([O:38]CCO)[CH3:37]>>[C:1]([C:3]1[CH:4]=[N:5][N:6]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[C:28]=2[Cl:35])[C:7]=1[NH:8][C:18]([O:20][CH2:21][CH2:22][O:38][CH2:36][CH3:37])=[O:19])#[N:2]
Reactant: CCOCCO
Reactant: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1N(C(=O)Oc1ccccc1)C(=O)Oc1ccccc1
Product: CCOCCOC(=O)Nc1c(C#N)cnn1-c1ccc(Cl)c(Cl)c1Cl

Procedure:
A stirred mixture of 4-cyano-5-di(phenoxycarbonyl)amino-1-(2,3,4-trichlorophenyl)pyrazole (prepared as described in Example 27; 20 g) in 2-ethoxyethanol (400 ml) was heated at reflux for 4 hours. The reaction mixture was evaporated to dryness and the residue crystallized from ethyl acetate-n-hexane to give 4-cyano-5-[(2-ethoxy)ethoxycarbonylamino]-1-(2,3,4-trichlorophenyl)pyrazole (10 g), m.p. 122°-124° C., in the form of colourless crystals. The mother liquors were evaporated to dryness and the residue chromatographed on aluminium oxide (120 g; May & Baker grade) using dichloromethane as eluent. Evaporation of the eluate and crystallisation of the residue from ethyl acetate-n-hexane gave a further quantity of 4-cyano-[5-(2-ethoxy)ethoxycarbonylamino]-1-(2,3,4-trichlorophenyl)pyrazole (3 g).
Reaction SMILES: [O-]CC.[Na+].[Na].[CH:6](=O)[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[OH:9].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]>C(O)C.CN(C)C=O>[C:17]([C:16]1[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=1)(=[O:18])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=Cc1ccccc1O
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1cc2ccccc2o1
Temperature: 80 °C
Yield: 34.1 %

Procedure:
To a solution of sodium ethoxide prepared from 28 g sodium metal and 500 ml absolute ethanol was added 122 g (1 mole) salicylaldehyde and 200 ml dimethylformamide. The mixture was heated to 80° C. Then 200 g (1 mole) alpha-bromoacetophenone was added in small portions. The mixture was stirred at reflux for 1.5 hours after which the ethanol was distilled. The residue was cooled and partitioned between 750 ml water and 750 ml ethyl acetate. The organic layer was washed twice with 400 ml portions of 1N sodium hydroxide, water (2×300 ml), dried (Na2SO4), concentrated to one-third volume, filtered to remove precipitated product which was washed with ethyl ether to yield 75.8 g of 2-benzoylbenzo(b)furan as pink crystals, m.p. 88°-90° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:8][CH2:7][CH2:6]2.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:8][CH2:7][CH2:6]2
Reactant: [H][H]
Reactant: CCOC(=O)C=C1CCCc2cc(OC)ccc21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1CCCc2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a solution of the alkene (512) (0.792 g, 3.22 mmol) in ethanol (53 mL) was added Pd/C (100 mg, 10% Degussa type). A balloon of hydrogen gas was added and the reaction was evacuated and back-filled with hydrogen three times. The reaction was stirred under a hydrogen balloon overnight at room temperature, then filtered through a pad of celite and concentrated in vacuo to give ethyl 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)acetate (513) (0.708 g, 88.7%) as a colorless oil.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)O)[OH:2].[OH-:9].[Na+]>O>[CH:1]1[CH:3]=[C:5]([C:7]2[CH:6]=[CH:5][CH:3]=[C:1]([OH:2])[CH:8]=2)[C:6]([OH:9])=[CH:7][CH:8]=1
Reactant: Oc1ccccc1O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: Oc1cccc(-c2ccccc2O)c1

Procedure:
In this two step synthesis, the first step is the reaction of bis-2-chloroethyl ether with catechol and sodium hydroxide in water. An excess of catechol and a controlled amount of base are used to produce the diphenol (j) without employing a blocking group. The diphenol (j) precipitates from the reaction solution and is washed with water to remove contaminating catechol. The diphenol (j) is then recrystallized from methanol. Based upon the limiting reagent bis-2-chloroethyl ether (i) 40% yields (200 gs) of diphenol (j) have been obtained.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:22][C@@H:23]1[CH2:27][NH:26][C@H:25]([C:28]([NH2:30])=[O:29])[CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][C@@H:23]([F:22])[CH2:24][C@H:25]3[C:28]([NH2:30])=[O:29])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)[C@@H]1C[C@H](F)CN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with (2S,4S)-4-fluoropyrrolidine-2-carboxamide hydrochloride (426844-23-7) in the presence of TBTU and DIEA to obtain the title compound as white solid; MS (EI): m/e=399.4 [MH+].
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([OH:25])=O)=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[N:33]1[CH2:38][CH2:37][CH2:36][C@H:35]([NH:39][C:40](=[O:49])[O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([NH:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][C:32]=2[N:33]2[CH2:38][CH2:37][CH2:36][C@H:35]([NH:39][C:40](=[O:49])[O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:34]2)=[O:25])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cnccc1N1CCC[C@H](NC(=O)OCc2ccccc2)C1
Reactant: O=C(Nc1cc2ccc(Br)cc2nc1C(=O)O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc2ccc(Br)cc2nc1C(=O)Nc1cnccc1N1CCC[C@H](NC(=O)OCc2ccccc2)C1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylic acid (632.0 mg, 1.575 mmol), benzyl [(3S)-1-(3-aminopyridin-4-yl)piperidin-3-yl]carbamate (559.9 mg, 1.715 mmol) and HATU (1822 mg, 4.792 mmol), DMF (15.0 mL) was added, followed by DIPEA (1854 mg, 14.34 mmol). The reaction mixture was stirred at room temperature for 2 h, then concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL), washed with brine (2×100 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-10% MeOH in DCM) to afford the sub-title compound (912.7 mg, 82%). LCMS calc. for C36H34BrN6O5(M+H)+: m/z=709.2. found 709.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].I[CH2:23][CH2:24][CH2:25][CH2:26]I>C1COCC1>[Cl:1][C:2]1[C:3]2[C:10]3([CH2:26][CH2:25][CH2:24][CH2:23]3)[C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Reactant: ICCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2ncnc(Cl)c2C12CCCC2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
Add 4-chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.6 g; 0.0035 mol; 1.0 equiv) in anhydrous THF (20 mL) and cool the reaction to −78° C., under an inert atmosphere. Add drop-wise lithium hexamethyldisilazide (8.8 mL; 0.0088 mol; 2.5 equiv; 1M in THF). Stir at −78° C. for 30 min. Add drop-wise 1,4-diiodobutane (0.56 mL; 0.0042 mol; 1.2 equiv), allow the reaction temperature to reach 0° C. slowly, and stir for 2 h. Then allow the reaction to reach RT and stir for additional 1 h. Quench the reaction with saturated ammonium chloride solution and extract with EA. Wash the organic layer with water, brine, and dry over anhydrous sodium sulfate. Evaporate the organic layer and purify over a 10 g silica column with acetone (5%) in DCM. Pool fractions to give the title compound (0.34 g; 43.09%). H NMR (DMSO-d6): 11.68 (1H, s), 8.53 (1H, s), 2.0-2.1 (m, 2H), 1.91-1.99 (m, 6H).
Reaction SMILES: COP([CH2:7][C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH:11]=[CH2:12])(OC)=O.[CH:22]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:34])[O:32][CH3:33])=[CH:26][C:25]=1[N+:35]([O-:37])=[O:36])=O.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CCO>[C:16]([O:15][C:14]([NH:13][C@@H:9]([CH2:10][CH:11]=[CH2:12])[C:8](=[O:21])/[CH:7]=[CH:22]/[C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:34])[O:32][CH3:33])=[CH:26][C:25]=1[N+:35]([O-:37])=[O:36])=[O:20])([CH3:17])([CH3:18])[CH3:19]
Reactant: COC(=O)Nc1ccc(C=O)c([N+](=O)[O-])c1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)CP(=O)(OC)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)/C=C/c1ccc(NC(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 90 %

Procedure:
To a vigorously stirred solution of 5E (4.47 g, 13.92 mmol) and 5D (2.6 g, 11.60 mmol) in THF (anhydrous) (115 mL) and EtOH (absolute) (1.148 mL) under nitrogen was added portion wise K2CO3 (anhydrous) (2.56 g, 18.56 mmol) at 0° C. The reaction mixture was allowed to raise to rt and then the mixture was heated at 55° C. The reaction mixture was then filtered with the aid of EtOAc and the filtrate evaporated to a residue which was dissolved in a small amount of methylene chloride and purified by normal phase chromatography to give 5F (4.38 g, 90%) as yellow solid. MS (ESI) m/z: 420.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.22 (d, J=2.2 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.83-7.73 (m, 2H), 7.21 (d, J=7.7 Hz, 1H), 7.02 (d, J=15.9 Hz, 1H), 5.77 (ddt, J=17.0, 10.2, 6.7 Hz, 1H), 5.16-5.01 (m, 2H), 4.32 (td, J=8.5, 4.9 Hz, 1H), 3.71 (s, 3H), 2.34-2.23 (m, 1H), 1.36 (s, 9H) ppm.