Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[F:9][C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1>>[F:9][C:10]1[CH:11]=[C:12]([S:16]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Product: Cc1noc(NS(=O)(=O)c2cccc(F)c2)c1Br
Yield: 88 %

Procedure:
3-Fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 3-fluorobenzenesulfonyl chloride according to the procedures described in Example 25b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a light yellow solid, m.p. 125-128° C., yield 88%.
Reaction SMILES: [CH2:1]([NH:4][CH2:5]/[CH:6]=[CH:7]/[CH:8]=[CH2:9])[CH:2]=[CH2:3].C(OC(=O)C)(=O)C>>[CH:6]12[CH2:5][NH:4][CH2:1][CH:2]1[CH2:3][CH2:9][CH:8]=[CH:7]2
Reactant: C=C/C=C/CNCC=C
Solvent: CC(=O)OC(C)=O
Product: C1=CC2CNCC2CC1

Procedure:
Introduce 24.6 g (0.2 mol) of (E)-1-(2-propenylamino)-2,4-pentadiene (title compound of Example A.2.), dropwise add 22.4 g of acetic anhydride, and stir overnight at room temperature. Concentrate and react further in the form of the crude product.
Reaction SMILES: C1(OC)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:13]([O:16][C@@H:17]1[NH:20][C:19](=[O:21])[C@H:18]1[NH2:22])(=[O:15])[CH3:14].C(N(CC)CC)C.[C:30]1([CH2:36][C:37](Cl)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(OCC)(=O)C.C(OCC)(=O)C.CO>[C:13]([O:16][C@@H:17]1[NH:20][C:19](=[O:21])[C@H:18]1[NH:22][C:37](=[O:38])[CH2:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:15])[CH3:14]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1N
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: COc1ccccc1
Solvent: CO
Product: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 0.55 g (2 moles) of (3S,4S)-4-acetoxy-3-benzyl oxycarbonylamino-azetidin-2-one in 2 ml of anisole 0.40 g (3 mmoles) of anhydrous aluminum chloride are added at 20° C., by controlling the reaction by TLC (eluent: ethyl acetate/methanol=95/5 v/v). When the reaction is over, the mixture is filtered off and the filtered solution is concentrated under vacuum to obtain a residue of 0.260 g consisting of crude (3S,4S)-4-acetoxy-3-amino-azetidin-2-one. The residue is taken up with 30 ml of ethyl acetate and to the resulting solution 0.31 g (3 moles) of triethylamine and, afterwards, 0.695 g (4.5 mmoles) of phenylacetyl chloride are added. The mixture is stirred for 6 hours at 20°÷25° C., then it is concentrated under vacuum to obtain a residue which is taken up with ethyl acetate and subjected to a purification on a silica gel column (eluent: ethyl acetate). Thus, 0.165 g of (3S,4S)-4-acetoxy-3-phenylacetamido-azetidin-2-one (II) is obtained.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=[O:3].CC1C(O)=CC=CC=1.C1C(O)=CC=CC=1C.[OH-].[Na+]>O.O1CCOCC1>[C:2]([OH:4])(=[O:3])[C:1]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH2:6]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: Cc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: Cc1cccc(O)c1
Solvent: O
Product: Nc1ccccc1C(=O)O

Procedure:
A mixture of 19.2 parts of isatoic anhydride, 13.8 parts of cresylic acid (a mixture of phenols of which the main constituent is m-cresol), 0.5 parts of sodium hydroxide and 50 parts of dioxan are heated at 45°-50° C. for 4 hours. Residual sodium hydroxide is screened off and 500 parts of water are added to the filtrates. The brown oil which is formed is extracted into ether and the ether extract is washed three times with water. The ether solution is dried over magnesium sulphate and the ether is then distilled off leaving the cresylic acid ester of anthranilic acid as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:14])[C:10](OC)=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.O.[NH2:16][NH2:17]>CC(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:14])[C:10]([NH:16][NH2:17])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: NN
Reactant: COC(=O)C(O)c1cc(F)cc(F)c1
Solvent: CC(C)O
Solvent: O
Product: NNC(=O)C(O)c1cc(F)cc(F)c1

Procedure:
5.0 g of methyl 3,5-difluorophenylhydroxyacetate (C2) are dissolved in 45.0 ml of 2-propanol. 1.32 ml of hydrazine hydrate are then added dropwise, and the reaction mixture is kept under reflux for 18 hours. The solution is subsequently evaporated to dryness, and the resultant residue is purified by flash chromatography on silica gel (gradient for elution: ethyl acetate/0-20.0% by vol. of methanol), giving 3.70 g of the title compound as colourless solid having a melting point of 119.3° C. (MS: 202.8 (MH+)).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=[CH:5][N:4]=1.[OH-].[NH4+].[CH:19](O)=[O:20]>>[CH:19]([NH:1][CH2:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:20]
Reactant: O=CO
Reactant: COC(=O)CCCCc1cccnc1CN
Agent: [NH4+]
Agent: [OH-]
Product: COC(=O)CCCCc1cccnc1CNC=O

Procedure:
A solution of 0.1 g of 2-aminomethyl-3-(4-methoxycarbonylbutyl)pyridine in 0.6 ml of formic acid is heated at 90° for 18 hours. The mixture is cooled to 0°, made basic with saturated ammonium hydroxide solution and extracted with methylene chloride (4×10 ml). Drying, filtration and evaporation of the extracts yields 2-(N-formylaminomethyl)-3-(4-methoxycarbonylbutyl)pyridine, melting at 43°-45° C. which is redissolved in 1 ml of toluene and heated at 90° for 17 hours with 75 mg of phosphorus oxychloride. Evaporation of excess phosphorus oxychloride with toluene, basification at 0° with saturated ammonium hydroxide solution, extraction with methylene chloride (4×15 ml) and drying over sodium sulfate yields an oil, which is chromatographed (silica gel, ethyl acetate) to yield as an oil, 8-(4-methoxycarbonylbutyl)imidazo[1,5-a]pyridine; Rf 0.29;NMR (CDCl3) 3.70 (s, 3H), 6.50 (d, 2H), 7.43 (s, 1H), 7.83 (t, 1H), 8.22 (s, 1H); IR (CH2Cl2) 1725 cm-1.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)=[CH:3]1.[Cl:18][C:19]1[O:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.Cl.O1CCOCC1>CN1CCCC1=O.CCOC(C)=O>[ClH:18].[CH3:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:17]=[CH:16][C:14]([NH:15][C:19]3[O:20][C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)=[CH:13][CH:12]=2)=[CH:3]1
Reactant: Clc1nc2ccccc2o1
Reactant: Cn1cc(-c2ccc(N)cc2)c2ncccc21
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc(Nc3nc4ccccc4o3)cc2)c2ncccc21
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
A mixture of 4-(1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)aniline (70 mg) and 2-chlorobenzo[d]oxazole (57 mg) in 1-methylpyrrolidinone (2 mL) was stirred at 120° C. for 30 min. After this time, the reaction was cooled to room temperature, diluted with AcOEt (50 mL), washed with saturated NaHCO3 aqueous solution (50 mL), water (2×50 mL) then brine (50 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (CH2Cl2 to 1:19 MeOH/CH2Cl2), dissolved in 1,4-dioxane (2 ml), treated with 4 M HCl in 1,4-dioxane (0.500 mL, 2.00 mmol) and concentrated under reduced pressure. The residue obtained was triturated with boiling is CH3CN to give the title compound (60 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH:10]=[C:11]([C:13](N(OC)C)=[O:14])[N:12]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][CH:28]=1.[NH4+].[Cl-]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[CH:10]=[C:11]([C:13]([C:30]2[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=2)=[O:14])[N:12]=1
Reactant: CON(C)C(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Product: O=C(c1ccc(F)cc1)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Yield: 69.5 %

Procedure:
To a solution of 2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-methoxy-N-methyl-1H-imidazole-4-carboxamide (50.0 mg, 0.133 mmol) in 1.5 mL THE was added a 1.0 M solution of 4-fluorophenylmagnesium bromide (0.27 mL, 0.27 mmol) under argon at rt with stirring. The resultant mixture was stirred for 30 minutes and a saturated aqueous solution of NH4Cl was added. The mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated down in vacuo. The crude product was purified on HPLC to give [2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl](4-fluorophenyl)-methanone as a solid (38.0 mg, 69%): Rf=0.58 (1:1 ethyl acetate/hexanes).
Reaction SMILES: C[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.FC(F)(F)C(O)=O.B(OC)(OC)OC>S1(CCCC1)(=O)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][O:4][CH3:2])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Solvent: O=C(O)C(F)(F)F
Solvent: O=S1(=O)CCCC1
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 30 °C

Procedure:
To 10 ml of sulfolane were added 1.41 g of 7-ACA, 1.96 g of ferric chloride, 0.40 ml of trifluoroacetic acid and 1.95 ml of trimethyl borate. The mixture was heated at 30° C. for 5 hours to advance a reaction. After completion of the reaction, substantially the same procedure as in Example 1 was repeated, to thereby obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.70 g. The yield of the desired product was 55%.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH2:4]1)=O.[C:31]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH2:41][CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:35][CH:34]=1)#[N:32]>>[C:31]([C:33]1[CH:34]=[CH:35][C:36]([CH2:39][CH2:40][CH2:41][CH:42]2[CH2:47][CH2:46][N:45]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:6][N:5]([C@H:14]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:15]([OH:17])=[O:16])[CH2:4]3)[CH2:44][CH2:43]2)=[CH:37][CH:38]=1)#[N:32]
Reactant: N#Cc1ccc(CCCC2CCNCC2)cc1
Reactant: O=C[C@H]1CN([C@@H](C(=O)OCc2ccccc2)C2CCCCC2)C[C@@H]1c1ccccc1
Product: N#Cc1ccc(CCCC2CCN(C[C@H]3CN([C@@H](C(=O)O)C4CCCCC4)C[C@@H]3c3ccccc3)CC2)cc1

Procedure:
The title compound was prepared from 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, benzyl ester (from EXAMPLE 1, Step 1) and 4-(3-(4-cyanophenyl)propyl)piperidine×HCl (from EXAMPLE 116, Step A) using procedures analogous to those described in EXAMPLE 1, Steps J and K. For the title compound: HPLC (Zorbax SB-C8 4.6 mm×7.5 cm column, gradient elution using 10:90 v/v CH3CN/H2O+0.1% TFA to 100% CH3CN over 7.5 min, hold for 45 sec, 2.25 mL/min, 220 nm): Retention Time: 4.13 min; ESI-MS 528 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.Br[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O>CS(C)=O.[Cu]I>[F:25][C:22]1[CH:23]=[CH:24][C:19]([O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]3)=[N:20][CH:21]=1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(O)cc2C1
Reactant: Fc1ccc(Br)nc1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(Oc3ccc(F)cn3)cc2C1
Temperature: 190 °C
Yield: 29.3 %

Procedure:
A reaction mixture of N-[(2S)-5-hydroxy-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (100 mg, 0.39 mmol, Description 3), 2-bromo-5-fluoropyridine (69 mg, 0.39 mmol), caesium carbonate (382 mg, 1.17 mmol), copper(I) iodide (82 mg, 0.43 mmol) and N,N-dimethylglycine (49 mg, 0.47 mmol) in DMSO (1.5 ml) was heated in a microwave at 190° C. for 30 minutes. The resulting mixture was then partitioned between dichloromethane and water and the organic solution was dried (MgSO4) and evaporated under reduced pressure to yield the crude product. The crude product was purified using MDAP. The resulting solution was diluted with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic solution was dried (MgSO4) and evaporated under reduced pressure to obtain the title compound as a pale yellow solid (40 mg).
Reaction SMILES: [N-:1]=[C:2]=[O:3].[Na+].[NH2:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[S:8][C:7]=1[C:18]([NH2:20])=[O:19]>C(O)(=O)C.O>[NH2:1][C:2]([NH:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[S:8][C:7]=1[C:18]([NH2:20])=[O:19])=[O:3]
Reactant: [N-]=C=O
Reactant: NC(=O)c1sc(-c2ccc(F)cc2)cc1N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1cc(-c2ccc(F)cc2)sc1C(N)=O
Reaction time: 20 h
Yield: 13.2 %

Procedure:
Sodium isocyanate (1.08 g) was added portionwise to a stirred suspension of 3-amino-5-(4-fluorophenyl)-2-thiophenecarboxamide (3.2 g) in acetic acid (150 mL) and water (90 mL). After 20 h, the solid was filtered off and washed with water, methanol and ether. Recrystallisation from methanol/dimethylsulphoxide gave the title urea (0.5 g) as a 1:1 dimethylsulphoxide solvate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:37])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH2:25]O)=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH2:34][CH3:35])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:58].O>C(Cl)Cl>[Br:58][CH2:25][C:22]1[N:21]=[CH:20][C:19]([C:17]2[CH:16]=[C:15]([N:27]([CH2:34][CH3:35])[CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:14]([CH3:36])=[C:13]([CH:18]=2)[C:12]([NH:11][CH2:10][C:3]2[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])=[O:37])=[CH:24][CH:23]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCN(c1cc(-c2ccc(CO)nc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CCN(c1cc(-c2ccc(CBr)nc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.9 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(6-(hydroxymethyl)pyridin-3-yl)-2-methylbenzamide (0.35 g, 0.694 mmol) in DCM (5 mL), triphenyl phosphine (0.361 g, 1.38 mmol) was added and stirred it at room temperature for 10 min. Finally CBr4 (0.318 g, 1.38 mmol) was added portion wise to it and resulting solution was stirred at room temperature for 18 h. On completion, water was added to the reaction mass and extraction was carried out using DCM. Combined organic layers were dried over sodium sulphate, concentrated under reduced pressure to give crude material which then column purification gave desired compound (0.35 g, 89%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[CH:6]=[CH:5]2.[CH3:14][C:15]1[CH:16]=[N:17][NH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CN1C(=O)CCC1.[Cu]I>[CH3:13][N:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([N:17]3[CH:16]=[C:15]([CH3:14])[CH:19]=[N:18]3)[CH:3]=2)[C:8]1=[O:12]
Reactant: Cc1cn[nH]c1
Reactant: Cn1ccc2cc(Br)ccc2c1=O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cnn(-c2ccc3c(=O)n(C)ccc3c2)c1
Yield: 52.7 %

Procedure:
6-Bromo-2-methylisoquinolin-1-one (300.0 mg, 1.27 mmol), 4-methyl-1H-pyrazole (210.0 mg, 2.54 mmol), CuI (30.0 mg, 0.127 mmol) and K2CO3 (360.0 mg, 2.54 mmol) in NMP (3.0 mL) were microwaved at 195° C. for 5 h. Extractive work up with ethyl acetate followed by silica gel chromatography (PE:EA=5:1) gave the title compound of step 1 (160.0 mg, 52%) as a light yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.49 (d, J=8.8 Hz, 1H), 7.84 (s, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.74 (dd, J1=8.8 Hz, J2=2.0 Hz, 1H), 7.59 (s, 1H), 7.10 (d, J=7.6 Hz, 1H), 6.52 (d, J=7.6 Hz, 1H), 3.62 (s, 3H), 2.19 (s, 3H). LCMS: 240.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([N:15]=[C:16]([NH:18][CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1.Cl>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([N:15]=[C:16]([NH:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3c(-c4ccc(F)cc4Cl)cccn3n2)CC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Fc1ccc(-c2cccn3nc(NC4CCNCC4)nc23)c(Cl)c1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 101.5 %

Procedure:
To a solution of tert-butyl 4-(8-(2-chloro-4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)piperidine-1-carboxylate (810 mg, 1.82 mmol) in tetrahydrofuran (8 mL) and methanol (6 mL) was added hydrogen chloride solution (4.0 M in dioxane, 2.3 mL, 9.1 mmol). The reaction mixture was stirred for 1.5 hours at 60° C. and then concentrated in vacuo. The residue was diluted with ethyl acetate (40 mL) and washed with aqueous sodium carbonate (1 M, 30 mL), water (30 mL) and brine (30 mL). The aqueous layers were extracted with further ethyl acetate (40 mL). The organic layers were combined, dried over magnesium sulfate and filtered off. Concentration afforded the title compound as yellow foam (639 mg, 98%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH:41]1[CH2:44][O:43][CH2:42]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][CH2:10][N:11]([CH:41]1[CH2:44][O:43][CH2:42]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:31][CH2:32][CH2:33][CH2:34]2)[N:15]=1)=[O:13]
Reactant: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)C1COC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1COC1
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-oxetan-3-yl-amide (296) (240 mg, 0.39 mmol) in tetrahydrofuran (20 mL) was added a 1M solution of tetrabutylammoniumfluorid in tetrahydrofuran (1.2 mL, 1.16 mmol) at room temperature and stirring was continued for 60 min at room temperature. After completion of the reaction, the reaction mixture was concentrated and the residue purified by Combi-Flash column (eluted at 5% methanol in dichloromethane) to get 5-Benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-oxetan-3-yl-amide (297) as an off-white sticky solid (150 mg, 76.68%).
Reaction SMILES: CO[C:3](=[O:20])[C:4]([OH:19])=[CH:5][C:6](=[O:18])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)[CH3:8].C=O.ClC1C=C(C=CC=1Cl)CN.[Cl:33][C:34]1[CH:35]=[C:36]([CH:50]=[CH:51][C:52]=1[Cl:53])[CH2:37][N:38](C)[C:39](C1CN(C)C(=O)C=1O)=O>>[Cl:17][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[Cl:16])[CH2:9][N:7]([CH3:8])[C:6]([C:5]1[CH2:39][N:38]([CH2:37][C:36]2[CH:50]=[CH:51][C:52]([Cl:53])=[C:34]([Cl:33])[CH:35]=2)[C:3](=[O:20])[C:4]=1[OH:19])=[O:18]
Reactant: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: NCc1ccc(Cl)c(Cl)c1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(Cc2ccc(Cl)c(Cl)c2)C1

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and 3,4 dichloro-benzylamine as described in the preparation of Compound 12. The title compound was isolated as a white foam (155 mg, 66% yield). 1H NMR (500 MHz, CDCl3) δ: 10.70 (bs, 1H), 7.42 (d, 1H, J=3.05), 7.40 (d, 1H, J=3.05), 7.34 (d, 2H, J=1.83), 7.09 (dd, 2H, J=8.24, J=1.83), 4.62 (s, 2H), 4.57 (s, 2H), 4.06 (s, 2H), 3.00 (s, 3H). HRMS (M−H) calcd for C20H15N2Cl4O3: 470.9836. found: 470.9832.
Reaction SMILES: [OH-].[Na+].Cl.[NH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[OH:11].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1I.C(O)(C)C>[Cl-].[Na+].O.[Cu]I>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[OH:11]
Reactant: NC1CCCCC1O
Reactant: Clc1ccccc1I
Agent: [Cu]I
Agent: Cl
Agent: [Cl-]
Solvent: CC(C)O
Solvent: O
Product: O[C@@H]1CCCC[C@H]1Nc1ccccc1Cl
Temperature: 90 °C
Reaction time: 48 h
Yield: 91 %

Procedure:
A 15 mL screw top test tube fitted with a PTFE septum cap was purged with argon before addition of CuI (5.0 mg, 0.026 mmol, 2.6 mol %), NaOH (125 mg, 3.12 mmol) and rac-2-amino-1-cyclohexanol HCl (158 mg, 1.04 mmol). 2-Chloro-1-iodobenzene (152 μL, 1.25 mmol) and isopropyl alcohol (1.0 mL) were added, via syringe, under argon. The septum cap was replaced with a solid, Teflon-lined cap and the reaction was stirred magnetically at 90° C. for 48 h. The resulting homogeneous solution was allowed to cool before dilution with 10 mL brine. The reaction mixture was transferred to a separatory funnel and extracted with methylene chloride (3×10 mL). The organics were washed with brine, dried over MgSO4 and concentrated. The crude material was purified by silica gel chromatography using hexanes/ethyl acetate (60:40). The product was obtained as a yellow oil in 91% yield (212.7 mg).
Reaction SMILES: BrC1C2C=NC=CC=2N(CCCS(C)(=O)=O)C=1C[N:19]1[C:23]2[CH:24]=[N:25][CH:26]=[CH:27][C:22]=2[N:21]([CH:28]2[CH2:30][CH2:29]2)[C:20]1=[O:31].[Cl:32][C:33]1[N:38]=[C:37]2[CH:39]=[C:40]([CH2:47]O)[N:41]([CH2:42][CH2:43][CH2:44][CH2:45][F:46])[C:36]2=[CH:35][CH:34]=1>>[Cl:32][C:33]1[N:38]=[C:37]2[CH:39]=[C:40]([CH2:47][N:19]3[C:23]4[CH:24]=[N:25][CH:26]=[CH:27][C:22]=4[N:21]([CH:28]4[CH2:29][CH2:30]4)[C:20]3=[O:31])[N:41]([CH2:42][CH2:43][CH2:44][CH2:45][F:46])[C:36]2=[CH:35][CH:34]=1
Reactant: OCc1cc2nc(Cl)ccc2n1CCCCF
Reactant: CS(=O)(=O)CCCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)c(Br)c2cnccc21
Product: O=c1n(Cc2cc3nc(Cl)ccc3n2CCCCF)c2cnccc2n1C1CC1

Procedure:
3-((5-chloro-1-(4-fluorobutyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one P42 was synthesized following the procedure reported for the synthesis of 3-((3-bromo-1-(3-(methylsulfonyl)propyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one P17, using (5-chloro-1-(4-fluorobutyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methanol 11 instead of (3-bromo-1-(3-(methylsulfonyl)propyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)methanol 12. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88-0.96 (m, 2H) 1.03-1.12 (m, 2H) 1.47-1.72 (m, 4H) 2.98 (tt, J=6.93, 3.61 Hz, 1H) 4.18-4.53 (m, 4H) 5.34 (s, 2H) 6.69 (s, 1H) 7.18 (d, J=8.53 Hz, 1H) 7.28 (d, J=5.02 Hz, 1H) 8.01 (d, J=8.53 Hz, 1H) 8.25 (d, J=5.27 Hz, 1H) 8.39 (s, 1H).