Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](/[CH:21]=[CH:22]/[C:23](=[O:25])[CH3:24])=[CH:15][C:14]=3[F:26])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.C(Cl)Cl>[Pd].CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH2:22][C:23](=[O:25])[CH3:24])=[CH:15][C:14]=3[F:26])=[O:9])=[CH:27][CH:28]=1
Reactant: CC(=O)/C=C/c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)CCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 0.75 h
Yield: 8 %

Procedure:
To a mixture of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(E)-3-oxo-1-butenyl]-3-quinolinecarboxamide from Example No. 153 (100 mg) and Et3N (0.35 mL) in 80 mL 3:1 CH2Cl2 :MeOH is added Pd/C (10%, 20 mg). The reaction mixture is placed under the Parr hydrogenator at 29 psi H2 and monitored by mass spectroscopy for complete reduction of the alkene. The old palladium catalyst is replaced with fresh palladium catalyst each time the reaction was taken off the Parr. In this case, the reaction is taken off the Parr once. The reaction is complete in 45 min. The reaction mixutre is filtered over celite to remove the palladium. The filtrate is concentrated. The crude mixture was separated by HPLC to afford 38.7 mg (8%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[N:15]=[C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:13]3=[CH:12][C:11]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:6][CH:5]=1)(O)=[O:2].Cl.[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH2:33].C(N=C=NCCCN(C)C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:29][N:30]([CH2:31][CH2:32][NH:33][C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[N:15]=[C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:13]3=[CH:12][C:11]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:6][CH:5]=1)=[O:2])[CH3:34]
Reactant: CCOC(=O)c1cc2c(nc1COc1ccc(C(=O)O)cc1)CCCCC2
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(nc1COc1ccc(C(=O)NCCN(C)C)cc1)CCCCC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 52.7 %

Procedure:
In an atmosphere of argon, ethyl 2-(4-carboxyphenoxymethyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (1.22 g, 3.31 mmol) was dissolved in methylene chloride (5.0 ml), and the solution was mixed with N,N-dimethylethylenediamine hydrochloride (0.44 ml, 4.01 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) hydrochloride (954.2 mg, 4.98 mmol) at 0° C. and then stirred at room temperature for 15 hours. The reaction solution was diluted with chloroform, mixed with saturated sodium bicarbonate aqueous solution and then extracted with chloroform. The thus obtained organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (chloroform:methanol=10:1) to obtain the title compound (767.2 mg, 52.7%) as pale yellow amorphous.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10]([C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH3:18])=O)=[N:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[CH3:18])=[N:9][N:8]=2)[CH:7]=1
Reactant: CN1CCCC[C@H]1C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCCC[C@H]1c1nnc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a solution of Intermediate 62a (331 mg, 1.31 mmol), Ph3P (688 mg, 2.63 mmol) and Et3N (731 μL, 5.25 mmol) in THF (13.0 mL) at 0° C. was added hexachloroethane (622 mg, 2.63 mmol). The reaction was stirred at RT overnight then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was taken up in MeOH and loaded onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave the title compound (250 mg, 81%). LCMS (Method 4): Rt 0.31 min, m/z 235.1 [MH+].
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[CH3:19][CH:20]([S-:22])[CH3:21].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:19][CH:20]([S:22][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]1)[CH3:21]
Reactant: CC(C)[S-]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)SC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
tert-Butyl 4-(methanesulfonyloxy)piperidine-1-carboxylate (Intermediate 239, 0.320 g, 1.15 mmol) and sodium 2-propanethiolate (0.147 g, 1.50 mmol) were combined in DMF (3 mL) and stirred at room temperature for 18 h. The mixture was then diluted with EtOAc (30 mL) and washed with water (3×10 mL). The organic layer was dried over sodium sulfate and concentrated to yield a yellow oil. This was purified by FCC, eluting with a gradient of 0-20% EtOAc in heptane to afford the title compound as a colourless oil (0.179 g, 60%). 1H NMR (500 MHZ, CDCl3) δ ppm 3.88 (2H, br s), 2.94 (1H, m), 2.86 (2H, m), 2.77 (1H, m), 1.83 (2H, d), 1.42 (2H, m), 1.38 (9H, s) and 1.20 (6H, d).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]1(Br)[CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C(#N)C>[CH:10]1([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=Cc1ccc(OC2CCCC2)cc1

Procedure:
A solution of 4-hydroxybenzaldehyde (100 mg, 0.819 mmol), cyclopentyl bromide (176 μl, 1.64 mmol), potassium carbonate (340 mg, 2.46 mmol), acetonitrile (4 mL) and potassium iodide (136 mg, 819 μmol) was stirred at 60° C. for 18 h. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give crude product 4-(cyclopentyloxy)benzaldehyde. This was used as crude in the following Step. Analytical LCMS (M+H)+: m/z=191.1.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)[C@H:10]1[CH2:14][O:13][S:12](=[O:15])[N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:34].[Na+].O.CCOC(C)=O>CC#N.O.[Ru](Cl)(Cl)Cl>[Si:1]([O:8][C@@H:9]([C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=1)[C@H:10]1[CH2:14][O:13][S:12](=[O:34])(=[O:15])[N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O[Si](C)(C)C(C)(C)C)c2ccc(C(F)(F)F)cc2)COS1=O
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O[Si](C)(C)C(C)(C)C)c2ccc(C(F)(F)F)cc2)COS1(=O)=O
Yield: 94.2 %

Procedure:
A mixture of tert-butyl (4R)-4-((S)-((tert-butyl(dimethyl)silyl)oxy)(4-(trifluoromethyl)phenyl)methyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (1.80 g, 3.63 mmol), sodium periodate (3.11 g, 14.5 mmol), ruthenium(III) chloride hydrate (0.0164 g, 0.0726 mmol) in CH3CN:water:EtOAc (51 mL:17 mL:9 mL) was put in a sonicator for 17 minutes. The dark mixture became a yellow suspension. HPLC-MS showed no more starting material. The reaction mixture was filtered through celite and the solid was washed with EtOAc. The organic phase was washed with water and brine, dried over Na2SO4, and then concentrated in vacuo. The residue was purified by chromatography on silica gel (0-4%-10% EtOAc-hexane) to provide the product as a white solid (1.75 g, 94%). LCMS (API-ES) m/z: 456 (M+H+-56).
Reaction SMILES: C([O:5][C:6](=[O:48])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([NH:15][CH:16]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=2)[CH2:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:37])=[O:29])=[CH:23][CH:22]=2)=[O:19])=[O:14])=[CH:9][CH:8]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:47][O:46][C:40]1[CH:39]=[C:38]([CH:16]([NH:15][C:13]([C:10]2[CH:9]=[CH:8][C:7]([C:6]([OH:48])=[O:5])=[CH:12][CH:11]=2)=[O:14])[CH2:17][C:18]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:37])=[O:29])=[CH:25][CH:26]=2)=[O:19])[CH:43]=[CH:42][C:41]=1[O:44][CH3:45]
Reactant: COc1ccc(C(CC(=O)Nc2ccc(NC(=O)Nc3ccccc3C)cc2)NC(=O)c2ccc(C(=O)OC(C)(C)C)cc2)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(CC(=O)Nc2ccc(NC(=O)Nc3ccccc3C)cc2)NC(=O)c2ccc(C(=O)O)cc2)cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-Butyl-4-{[(1-(3,4-dimethoxyphenyl)-3-{[4-({[(2-methylphenyl)amino]carbonyl}amino) phenyl]amino}-3-oxopropyl)amino]carbonyl}benzoate (30 mg, 0.05 mmol) was dissolved in DCM (10 mL) and TFA (0.18 mL, 2.30 mmol) was added at 0° C. and the reaction mixture was stirred at r.t. for 24 h. The solvent was removed in vacuum and the product was isolated (25 mg, 91%). M.p. 166° C. ESI-MS: 598[M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][C:30]1[CH:31]=[C:32]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:34]2[CH:33]=[C:32]([NH:45][S:46]([CH3:49])(=[O:47])=[O:48])[CH:31]=[C:30]([CH3:29])[CH:35]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: Cc1cc(NS(C)(=O)=O)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(NS(C)(=O)=O)cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 55.1 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (60 mg, 0.14 mmol) were added N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methane sulfonamide (141 mg, 45% purity, 0.20 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (11 mg, 0.01 mmol) and 136 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified by flash chromatography (50 to 100%, hexane-ethyl acetate) phase using SP1® Purification System to give 42 mg (55% yield) of the title compound as a white solid. Purity 98%.
Reaction SMILES: C([O:3][C:4]([CH:6]([O:8][C:9]1[N:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=1)[CH3:7])=[O:5])C.[OH-].[K+].Cl>C(O)C>[C:4]([CH:6]([O:8][C:9]1[N:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=1)[CH3:7])([OH:5])=[O:3]
Reactant: CCOC(=O)C(C)Oc1ncn(-c2ccccc2)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(Oc1ncn(-c2ccccc2)n1)C(=O)O
Temperature: 0 °C

Procedure:
A 2.5 g portion of the compound of Example 1 and 2.2 g of potassium hydroxide were added to 50 ml of ethanol, and the mixture was refluxed for 3 hours. It was then poured into ice-water and the mixture was made acid with concentrated hydrochloric acid. The solid was collected and crystallized from ethanol to obtain 0.9 g of the desired product, m.p. 140°-142°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([CH:23]=[O:24])[CH:22]=2)[O:19][C:18]([CH3:26])([CH3:25])[CH2:17][C:16]3([CH3:28])[CH3:27])=[CH:7][CH:6]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([CH2:23][OH:24])[CH:22]=2)[O:19][C:18]([CH3:25])([CH3:26])[CH2:17][C:16]3([CH3:28])[CH3:27])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C=O)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(C#Cc2cc(CO)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Reaction time: 2 h
Yield: 92.2 %

Procedure:
A stirred, cooled (ice bath) solution of {4-[8-formyl-2,2,4,4-tetramethyl chroman-6-ylethynyl]-phenyl}-acetic acid methyl ester (Compound 45, 0.21 g, 0.58 mmol) in methanol (4 mL) was treated with sodium borohydride (0.024 g, 0.64 mmol) and the resulting reaction mixture was stirred for 2 h. The reaction mixture was quenched with water and extracted with diethyl ether. The organic phase was washed with water (×1) and brine (×1), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title product as a colorless oil (0.21 g, 100%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[CH2:16][C:17]([NH2:19])=[O:18].C(N(CC)C(C)C)(C)C.[I-].[Na+]>C(#N)C>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:16][C:17]([NH2:19])=[O:18])[C@H:10]([CH3:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: NC(=O)CBr
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CC(N)=O
Yield: 88 %

Procedure:
A mixture of (R)-1-Boc-3-methylpiperazine (100 mg, 0.50 mmol), 2-bromoacetamide (103 mg, 0.75 mmol), N,N-diisopropylethylamine (129 mg, 1.00 mmol) and sodium iodide (7.5 mg, 0.050 mmol) in acetonitrile (2.0 ml) was subjected to microwave irradiation at 100° C. for 5 minutes. The mixture was filtered through a 5 g Strata™ SCX giga tube, eluting with dichloromethane, methanol and then 2 M ammonia in methanol, and purified by flash chromatography eluting with ethyl acetate to 17% (v/v) methanol in ethyl acetate to afford (R)-2-(4-Boc-2-methylpiperazin-1-yl)acetamide (114 mg, 0.44 mmol).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([C:13]2([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1.[B:21](OCCCC)([O:27]CCCC)[O:22]CCCC.Cl>C1COCC1.O>[C:18]([C:13]1([C:9]2[CH:8]=[C:7]([B:21]([OH:27])[OH:22])[CH:12]=[CH:11][CH:10]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1)([OH:20])=[O:19]
Reactant: O=C(O)C1(c2cccc(Br)c2)CCCC1
Reactant: CCCCOB(OCCCC)OCCCC
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(c2cccc(B(O)O)c2)CCCC1
Reaction time: 0.75 h

Procedure:
A solution of n-butyl lithium (2.5 M in hexanes, 5 mL, 12.48 mmol) in THF (30 mL) is chilled to −78° C., and a solution of 1-(3-bromo-phenyl)-cyclopentanecarboxylic acid [1.05 g, 3.9 mmol] in THF (10 mL) is added dropwise via syringe. The solution is stirred at temperature for 45 minutes and treated with tributyl borate (3.2 mL, 11.7 mmol). The reaction mixture is allowed to stir for 2.5 hours and then diluted with water (60 mL), acidified with 3M HCl and extracted twice with EtOAc (50 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford 3-(1-carboxy-cyclopentyl)-phenylboronic acid as a solid, which is used without further purification.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([O:21]N4C5C=CC=CC=5N=N4)=O)=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClCCl.[C:34]1([C@@H:40]([NH2:42])[CH3:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl.O>[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:42][C@H:40]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH3:41])=[O:21])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@H](N)c1ccccc1
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@@H](C)c1ccccc1
Reaction time: 8 h

Procedure:
To 100 mg of 1-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}oxy)-1H-benzotriazole were 1.7 ml of dichloromethane, 0.065 ml of (S)-(−)-1-phenylethylamine, and 0.07 ml of triethylamine, followed by stirring overnight. To the reaction mixture were added water and chloroform to carry out a layer separation operation, followed by drying over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography. To the obtained purified product was added diisopropyl ether, and the resulting solid was collected by filtration and dried to obtain 80 mg of 8-(cyclohexylmethoxy)-2-methyl-N-[(1S)-1-phenylethyl]imidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]1[C:23]([CH3:24])=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35](=[N:37]O)[NH2:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27].C(C1C=CC(S(N)(=O)=O)=CC=1)#N.CCN(C(C)C)C(C)C>>[CH3:7][O:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]1[N:16]=[CH:17][C:18]([C:19]2[O:21][N:37]=[C:35]([C:32]3[CH:31]=[CH:30][C:29]([S:26]([NH2:25])(=[O:27])=[O:28])=[CH:34][CH:33]=3)[N:36]=2)=[CH:22][C:23]=1[CH3:24]
Reactant: COCC1CCCN1c1ncc(C(=O)O)cc1C
Reactant: NC(=NO)c1ccc(S(N)(=O)=O)cc1
Agent: N#Cc1ccc(S(N)(=O)=O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCC1CCCN1c1ncc(-c2nc(-c3ccc(S(N)(=O)=O)cc3)no2)cc1C

Procedure:
Oxalyl chloride (122 mL; 1.44 mmol), Intermediate 29 (120 mg; 0.48 mmol), 4-(aminosulfonyl)-N′-hydroxybenzenecarboximidamide, prepared as described in WO 2006/013104 A1 from 4-cyanobenzene-1-sulfonamide (ABCR; CD10716), (103 mg; 0.48 mmol, 1 eq.) and DIEA (248 mL; 1.44 mmol) were reacted according to the procedure described for Example 38. Purification by column chromatography (from cHex/EtOAc, 50/50 to EtOAc) followed by recrystallisation from DCM/n-pentane afforded the title compound as a yellow solid. LC/MS (Method A): 430.3 (M+H)+. HPLC (Method A) Rt 2.80 min (purity 93.1%).
Reaction SMILES: [Na].S(O)(O)(=O)=[O:3].[CH2:7]([NH:15][C:16](N)=N)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[CH2:7]([N:15]=[C:16]=[O:3])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCNC(=N)N
Reactant: O=S(=O)(O)O
Agent: [Na]
Product: CCCCCCCCN=C=O

Procedure:
Proceeding in a manner similar to that described above in Example 18A, and using 2.3 g. of sodium, 22 g. of n-octylguanidine sulfate, and 15.5 g. of n-octyl isocyanate, there was obtained 26 g. of 1 -n-octylamidino-3-n-octylurea having the structural formula ##EQU69## as a white crystalline solid which melted at 60°-62°C. The solubility of this base in water at 25°C. was less than 0.25 per cent. IN 95 per cent ethyl alcohol it was soluble to the extent of 5 per cent; a precipitate formed when the 5 per cent ethanolic solution was diluted with four volumes of water.
Reaction SMILES: Cl[C:2]1[C:20]([Cl:21])=[C:19]([O:22][CH3:23])[CH:18]=[CH:17][C:3]=1/[C:4](=[N:15]\[OH:16])/[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[CH:7][C:6]=1[F:14].[H-].[Na+].O.C(OCC)C.CC(=O)CC>CN(C)C=O>[Cl:21][C:20]1[C:2]2[O:16][N:15]=[C:4]([C:5]3[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[CH:7][C:6]=3[F:14])[C:3]=2[CH:17]=[CH:18][C:19]=1[O:22][CH3:23]
Reactant: CCOc1ccc(/C(=N/O)c2ccc(OC)c(Cl)c2Cl)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOc1ccc(-c2noc3c(Cl)c(OC)ccc23)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 23.3 g of Z-2,3-dichloro-4'-ethoxy-2'-fluoro-4-methoxybenzophenone oxime in 175 ml dimethylformamide is added to 1.85 g of sodium hydride in 35 ml of dimethylformamide. After stirring 30 min at room temperature, the reaction is worked up with water and 1:1 diethyl ether/2-butanone. Concentration of the dried organic phase, trituration of the product with hexane and recrystallization from toluene/hexane gives 7-chloro-3-(4-ethoxy-2-fluorophenyl)-6-methoxy-1,2-benzisoxazole, mp 151°-152° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.C([Sn](CCCC)(CCCC)[C:18]([O:20][CH2:21][CH3:22])=[CH2:19])CCC.[F-].[K+].CC(OC)(C)C>CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([C:18]([O:20][CH2:21][CH3:22])=[CH2:19])[N:3]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C=C(OCC)c1cc(C(=O)OC)nc(Cl)n1
Temperature: 94 °C
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
Methyl 2,6-dichloropyrimidine-4-carboxylate (8.44 g, 40.77 mmol) and bis(triphenylphosphine)-palladium(II) chloride (0.572 g, 0.82 mmol) in DMF (80 mL) was degased. Tributyl(1-ethoxy-vinyl)tin (14.46 mL, 42.81 mmol) was added under argon. The mixture was heated at 94° C. for 1 h. The mixture was poured into a solution of potassium fluoride (30 g) in water (400 mL). MTBE (300 mL) was added and the mixture was stirred for 10 min. The mixture was filtered and the filter was washed with 200 mL of MTBE. The filtrate was washed with brine (100 mL), dried over sodium sulfate and the solvents were evaporated. The residue purified by column chromatography on silica eluting with DCM to give the title compound as a solid (7.40 g, 75%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:13][O:12][CH:11]3[CH:14]([O:17][CH3:18])[CH2:15][O:16][CH:10]23)[C:5]([Cl:19])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.Cl.[CH3:30][N:31]1[CH:35]=[C:34]([NH2:36])[CH:33]=[N:32]1>CCCCO>[Cl:19][C:5]1[C:6]([NH:8][CH:9]2[CH2:13][O:12][CH:11]3[CH:14]([O:17][CH3:18])[CH2:15][O:16][CH:10]23)=[N:7][C:2]([NH:36][C:34]2[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=2)=[N:3][CH:4]=1
Reactant: Cn1cc(N)cn1
Reactant: COC1COC2C(Nc3nc(Cl)ncc3Cl)COC12
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COC1COC2C(Nc3nc(Nc4cnn(C)c4)ncc3Cl)COC12
Yield: 42.7 %

Procedure:
A solution of 2,5-dichloro-N-(6-methoxyhexahydrofuro[3,2-b]furan-3-yl)pyrimidin-4-amine (430 mg, 1.4046 mmol), DIPEA (546.7 mg, 4.23 mmol) and 1-methylpyrazol-4-amine hydrochloride (283.3 mg, 2.12 mmol) in n-BuOH (10 mL) was stirred in a sealed tube at 150° C. for 23 h. The reaction solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the crude product as a white solid. The crude product was recrystallized from acetone to give the title compound as a white solid (220 mg, 42.6%).