Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:11]([Si:15]([CH3:18])([CH3:17])Cl)([CH3:14])([CH3:13])[CH3:12].N1C=CN=C1.O>CN(C=O)C.CCOC(C)=O>[Si:15]([O:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH:3]=1)[NH2:1])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:18])[CH3:17]
Reactant: Cc1ccc(CO)cc1N
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(CO[Si](C)(C)C(C)(C)C)cc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (3-amino-4-methylphenyl)methanol (1.0 g, 7.3 mmol) in DMF (7.3 mL) was added tert-butyldimethylchlorosilane (1.2 g, 8.1 mmol) and imidazole (0.65 g, 9.5 mmol). The reaction stirred at room temperature for 18 hours and then was poured into a separatory funnel with water and EtOAc. The mixture was extracted with EtOAc and the extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by silica gel column chromatography (0-40% EtOAc/heptane) afforded the title compound.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[CH3:29])[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC=C(Cl)C=2C)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[Cl:28][C:24]1[C:23]([CH3:29])=[C:22]([N:15]([CH2:16][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:30])=[O:3])=[CH:8][N:9]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(Cl)c2C)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: Cc1c(Cl)cccc1NCC1CCCC1
Product: Cc1c(Cl)cccc1N(CC1CCCC1)C(=O)Nc1ncc(SCC(=O)O)s1

Procedure:
The title compound was prepared via {2-[3-(3-chloro-2-methyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(3-chloro-2-methyl-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: Br[C:2]1[CH:39]=[CH:38][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:28]2[C@H:30]([C:31]([O:33]CC)=[O:32])[C:29]2([CH3:37])[CH3:36])=[CH:4][CH:3]=1.[CH3:40][O:41][C:42]1[N:47]=[CH:46][C:45](B(O)O)=[CH:44][N:43]=1>>[CH3:40][O:41][C:42]1[N:47]=[CH:46][C:45]([C:2]2[CH:39]=[CH:38][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]5[CH:27]=[CH:26][C:25]6[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=6)[N:19]=5)=[CH:15][C:10]=4[N:9]=[C:8]3[C@@H:28]3[C@H:30]([C:31]([OH:33])=[O:32])[C:29]3([CH3:37])[CH3:36])=[CH:4][CH:3]=2)=[CH:44][N:43]=1
Reactant: CCOC(=O)[C@H]1[C@@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)C1(C)C
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2ccc(Cn3c([C@@H]4[C@H](C(=O)O)C4(C)C)nc4cc(OCc5ccc6ccccc6n5)ccc43)cc2)cn1

Procedure:
The title compound was prepared using similar methods to those in Example 110 using racemic cis-ethyl 3-(1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)-2,2-dimethylcyclopropanecarboxylate and 2-methoxypyrimidine-5-boronic acid in Step A. MS (ESI): mass calcd. for C35H31N5O4, 585.24; m/z found, 586.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.69 (s, 2H), 8.24 (d, J=8.5, 1H), 8.11 (d, J=8.5, 1H), 7.87-7.83 (m, 1H), 7.79-7.74 (m, 1H), 7.71 (d, J=8.5, 1H), 7.60-7.55 (m, 1H), 7.52 (d, J=8.3, 2H), 7.41-7.39 (m, 1H), 7.31-7.29 (m, 1H), 7.21 (d, J=8.3, 2H), 7.17-7.14 (m, 1H), 5.49 (s, 2H), 5.45 (s, 2H), 4.06 (s, 3H), 2.38-2.35 (m, 1H), 2.23-2.21 (m, 1H), 1.24 (s, 3H), 1.04 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[C:7]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:6][CH:5]=1.C1COCC1.[OH-].[Li+].Cl>O>[C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:8]2[C:7]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:6][CH:5]=[C:4]([CH:9]=2)[C:3]([OH:24])=[O:2])=[CH:15][CH:14]=1)#[N:17]
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(C#N)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2cc(C(=O)O)cnc2OCC(F)(F)F)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
In a 25 mL round-bottomed flask, the above prepared 5-(4-cyano-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid methyl ester (0.891 g, 2.65 mmol, Eq: 1.00) was combined with THF (7 mL) and water (3.5 mL) to give a light yellow biphasic system. Lithium hydroxide (127 mg, 5.3 mmol, Eq: 2) was added and the reaction mixture was stirred at 40° C. for 3 hours when TLC indicated the reaction to be complete. Work up: 10 mL H2O and 7 mL HCl 1N were added, the mixture extracted with AcOEt (2×50 mL), the organic layers were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo. Trituration with heptane/EtOAc 9:1 afforded finally 794 mg of the desired title product as a white solid; MS (EI) 321.2 (M−H)−.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:19][C:20]([CH3:25])([CH3:24])[C:21](Cl)=[O:22]>ClCCl>[C:21]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)(=[O:22])[C:20]([CH3:25])([CH3:24])[CH3:19]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CCN(C(=O)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
Ethyl isonipecotate (20 mL, 130 mmol) was dissolved in 130 mL of dichloromethane and cooled to 0° C. and triethyl amine (19.9 mL, 143 mmol) was added. Trimethylacetyl chloride (16.8 mL, 136 mmol) was added dropwise and the reaction was allowed to warm to rt and stirred for 16 h. The reaction mixture was washed with hydrochloric acid solution (1.0 M, aq), sodium bicarbonate (sat., aq.) and sodium chloride (sat., aq.). The organic layer dried over magnesium sulfate, filtered and the solvent removed to provide 29.5 g (94%) of 20a as a pale orange liquid. LC-MS m/z 242 [M+H]+.
Reaction SMILES: CS[C:3]([N:7]1[CH2:11][C:10]([CH3:13])([CH3:12])[CH:9]=[N:8]1)=[N:4][CH2:5][CH3:6].[S:14]([NH2:24])(=[O:23])([C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)=[O:15]>C(#N)C>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([S:14]([N:24]=[C:3]([N:7]2[CH2:11][C:10]([CH3:12])([CH3:13])[CH:9]=[N:8]2)[NH:4][CH2:5][CH3:6])(=[O:15])=[O:23])=[CH:17][CH:18]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CCN=C(SC)N1CC(C)(C)C=N1
Solvent: CC#N
Product: CCNC(=NS(=O)(=O)c1ccc(N)cc1)N1CC(C)(C)C=N1
Yield: 0.3 %

Procedure:
0.75 g (1 mol equiv.) N-Ethyl-4,4-dimethyl-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester and 0.65 g (1.0 mol equiv.) sulfanilamide were added to 10 mL acetonitrile. The reaction mixture was refluxed overnight, and volatiles were removed underreduced pressure. The residue was taken up in ethyl acetate and extracted with 2N NaOH. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Purification by flash chromatography on silica gel (Et2O:EtOAc=1:1) afforded 1.13 g (86%) 4-amino-N-[(4,4-dimethyl-4,5-dihydro-pyrazol-1-yl)-ethylamino-methylene]-benzenesulfonamide. 1H NMR (400 MHz, CDCl3) δ 1.15 (t, J=7.2 Hz, 3H), 1.20 (s, 6H), 3.43-3.51 (m, 2H), 3.74 (br.s., 2H), 3.98 (br.s., 2H), 6.66 (d, J=8.6 Hz, 2H), 6.71 (s, 1H), 7.71 (d, J=8.6 Hz, 2H).
Reaction SMILES: C[O:2]S([O-])(=O)=O.[NH2:7][C:8]1[C:21]2[C:20](=O)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:23])[C:12]=2[C:11]([NH2:24])=[C:10]2[C:25]([O:27][C:28](=[O:29])[C:9]=12)=[O:26].[CH3:30][N:31]([CH2:33][CH2:34][NH2:35])[CH3:32]>C(O)(=O)C>[CH3:30][N:31]([CH2:33][CH2:34][N:35]=[C:20]1[C:21]2[C:8]([NH2:7])=[C:9]([C:28]([OH:2])=[O:29])[C:10]([C:25]([OH:27])=[O:26])=[C:11]([NH2:24])[C:12]=2[C:13](=[O:23])[C:14]2[C:19]1=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:32]
Reactant: CN(C)CCN
Reactant: Nc1c2c(=O)oc(=O)c2c(N)c2c(=O)c3ccccc3c(=O)c12
Reactant: COS(=O)(=O)[O-]
Solvent: CC(=O)O
Product: CN(C)CCN=C1c2ccccc2C(=O)c2c(N)c(C(=O)O)c(C(=O)O)c(N)c21
Reaction time: 4 h

Procedure:
Synthesis of a dye with formula XVI, R'=R"=CH3, n=2, A-=CH3SO4 was performed as described below. A solution of 1,4-diaminoanthraquinone-2,3-dicarboxylic anhydride (3.08 g) and dimethylaminoethylamine (1.32 g) in acetic acid (30 ml) is heated to boiling and boiled for 4 hours to form a reaction mixture. Then, the reaction mixture is cooled, and the resultant precipitate is filtered, washed with ethyl alcohol, and dried to yield 3.6 g of 1,4-diaminoanthraquinone-2,3-dicarboxylic acid dimethylaminoethylimide.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.[CH:21]([S:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27])([CH3:23])[CH3:22].C(OCC)(=O)C>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[S:24][CH:21]([CH3:23])[CH3:22])[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: COc1ccc(Cn2nnc3c(Cl)nc(Cl)nc32)cc1
Reactant: CC(C)Sc1ccccc1N
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nnc3c(Nc4ccccc4SC(C)C)nc(Cl)nc32)cc1
Temperature: 25 °C

Procedure:
A solution of 5,7-dichloro-3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (0.03 g) and 2-(isopropylthio)aniline (0.1 g) in dioxane (10 mL) was heated at 100° C. for 10 h. It was then cooled down to room temperature and ethyl acetate (20 mL) was added. The mixture was washed with saturated sodium bicarbonate (10 mL), and dried over sodium sulfate. Solvent was removed under reduced pressure and the remaining residue was purified on a silica gel column (ethyl acetate:hexane=1:10) to give desired product. ESMS calculated for C21H21ClN6OS (m/z): 440.1; found (M+H+): 441.1.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[C:17]2[C:12](=[N:13][C:14]([C@@H:24]([NH2:26])[CH3:25])=[C:15]([C:18]3[N:22]([CH3:23])[N:21]=[CH:20][CH:19]=3)[CH:16]=2)[CH:11]=[CH:10]1.Cl[C:28]1[C:33]([C:34]#[N:35])=[C:32]([CH3:36])[N:31]=[C:30]([S:37][CH3:38])[N:29]=1.CCN(CC)CC>C1COCC1>[CH3:36][C:32]1[C:33]([C:34]#[N:35])=[C:28]([NH:26][C@H:24]([C:14]2[N:13]=[C:12]3[CH:11]=[CH:10][N:9]([CH3:8])[C:17]3=[CH:16][C:15]=2[C:18]2[N:22]([CH3:23])[N:21]=[CH:20][CH:19]=2)[CH3:25])[N:29]=[C:30]([S:37][CH3:38])[N:31]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnn1C
Reactant: CSc1nc(C)c(C#N)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CSc1nc(C)c(C#N)c(N[C@@H](C)c2nc3ccn(C)c3cc2-c2ccnn2C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottomed flask was added (S)-1-(1-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine 2,2,2-trifluoroacetate (364 mg, 0.986 mmol) in THF (6400 μL) along with 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carbonitrile (197 mg, 0.986 mmol) and Et3N (302 μL, 2.168 mmol). The reaction mixture was stirred at room temperature overnight and was subsequently purified on silica, eluting with a gradient of EtOAc/hexanes (2:8 to 9:1) to give the title compound as a clear film (270 mg, 65.5%). ESI-MS m/z [M+H]+ calc'd for C21H22N8S 419.17; found 419.4.
Reaction SMILES: [H-].[Na+].I[CH2:4][CH2:5][CH3:6].[Si:7]([O:14][CH2:15][C:16]1[N:20]=[CH:19][NH:18][N:17]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].O>CN(C=O)C>[Si:7]([O:14][CH2:15][C:16]1[N:17]([CH2:4][CH2:5][CH3:6])[N:18]=[CH:19][N:20]=1)([C:10]([CH3:13])([CH3:11])[CH3:12])([CH3:9])[CH3:8].[Si:7]([O:14][CH2:15][C:16]1[N:20]=[CH:19][N:18]([CH2:4][CH2:5][CH3:6])[N:17]=1)([C:10]([CH3:13])([CH3:11])[CH3:12])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OCc1nc[nH]n1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1cnc(CO[Si](C)(C)C(C)(C)C)n1
Product: CCCn1ncnc1CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 43 %
Yield: 31 %

Procedure:
To a stirred mixture of sodium hydride (60% dispersion in oil, 1.5 g, 37.5 mmol) and 1-iodopropane (4.4 ml, 45 mmol) in anhydrous DMF (100 ml), cooled under nitrogen to 0° C., was added dropwise over 10 min a solution of 3-(tert-butyldimethylsilanyloxymethyl)-1H-1,2,4-triazole (prepared as described in EP-A-421210) (8.0 g, 37.5 mmol) in anhydrous DMF (25 ml). The mixture was stirred under nitrogen at 0° C. for 25 min, more sodium hydride (60% dispersion in oil, 0.45 g, 11.3 mmol) was added, and the mixture was stirred for another 30 min. Water (300 ml) was then added and the mixture was extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with brine (100 ml), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 40-50% EtOAc/hexane; and alumina, 15% EtOAc/hexane) to yield 4.10 g (43%) of 5-(tert-butyldimethylsilanyloxymethyl)-1-propyl-1H-1,2,4-triazole and 2.97 g (31%) of 3-(tert-butyldimethylsilanyloxymethyl)-1-propyl-1H-1,2,4-triazole as colourless oils.
Reaction SMILES: [Cl:1]CC1C=CC(NC(C2CCOC3C=CC(C4C=CC(C)=CC=4)=CC=3C=2)=O)=CC=1.C[N:31](C)[CH:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1>CN(C)C=O>[Cl-:1].[O:38]=[C:35]1[CH2:36][CH2:37][CH:32]([NH3+:31])[CH2:33][CH2:34]1
Reactant: CN(C)C1CCC(=O)CC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Solvent: CN(C)C=O
Product: [Cl-]
Product: [NH3+]C1CCC(=O)CC1
Reaction time: 14 h
Yield: 384.6 %

Procedure:
To a solution of N-(4-chloromethylphenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (214 mg, 0.530 mmol) in N,N-dimethylformamide (1 ml) was dropwise added a solution of 4-dimethylaminocyclohexanone (112 mg, 0.795 mmol) in N,N-dimethylformamide (1 m). Under nitrogen atmosphere, the mixture was stirred for 14 hours. The solvent was evaporated to give crude product, which was washed with ether to give N,N-dimethyl-N-(((7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-yl)carbonyl)amino)benzyl)-N-(4-oxocyclohexyl)ammonium chloride (Compound 2) (305 mg) as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:17]1[CH:16]=[C:15]([CH3:18])[CH:14]=[CH:13][C:12]=1[CH3:11])=[O:6]
Reactant: Cc1ccc(C)cc1
Reactant: O=C(O)c1ccccc1Cl
Product: Cc1ccc(C)c(C(=O)c2ccccc2Cl)c1
Reaction time: 4.5 h
Yield: 55 %

Procedure:
The HF-catalyzed condensation of 2-chlorobenzoic acid with p-xylene was also investigated. Condensation was carried out at 60° C. for 4.5 hours. 2-chloro-2',5'-dimethylbenzophenone product was isolated in 55% yield. Upon repeating the reaction at 80° C. for 4.5 hours, the conversion was slightly increased to afford the product in 60% yield. The results appear to show that p-xylene is not as reactive as m-xylene in this reaction.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][CH2:24][NH:25][S:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:28])=[O:27].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[C:32]([O:31][C:30](=[O:36])[NH:29][S:26](=[O:28])(=[O:27])[NH:25][CH2:24][CH2:23][O:22][NH:21][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])([CH3:35])([CH3:33])[CH3:34]
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCCON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.200 g, 0.723 mmol) in DCM (6.0 mL) was added tert-butyl{[2-(aminooxy)ethyl]sulfamoyl}carbamate 78 (0.276 g, 1.085 mmol), 1-hydroxybenzotriazole (0.147 g, 1.086 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.208 g, 1.086 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 79 (0.35 g, 93%) as a white solid.
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=CN=3)CC3CC(CC(C3)C1)C2.[C:25]12([CH2:35][O:36][C:37]3[C:45]([Cl:46])=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][C:38]=3[Cl:47])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2.COC[CH2:51][S:52]([NH2:55])(=[O:54])=[O:53].CS(N)(=O)=O>>[C:25]12([CH2:35][O:36][C:37]3[C:45]([Cl:46])=[CH:44][C:40]([C:41]([NH:55][S:52]([CH3:51])(=[O:54])=[O:53])=[O:42])=[CH:39][C:38]=3[Cl:47])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2
Reactant: O=C(O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)c(Cl)c1
Reactant: COCCS(N)(=O)=O
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)c(Cl)c1
Yield: 74 %

Procedure:
Following the procedure as described in Example 271 and making variations as required to replace 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with 4-(adamantan-1-ylmethoxy)-3,5-dichlorobenzoic acid and to replace 2-methoxyethanesulfonamide with methyl sulfonamide. Purification by silica gel column chromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gave the title compound as a colorless solid (0.72 g, 74%): 1H NMR (300 MHz, DMSO-d6) δ 12.20 (br s, 1H), 8.01 (s, 2H), 3.55 (s, 2H), 3.33 (s, 3H), 1.99-1.91 (m, 3H), 1.72-1.57 (m, 12H); MS (ES−) m/z 430.1, 432.1 (M−1).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1.[Cl:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][NH:22][C:23]2=[O:26])=[CH:18][CH:17]=1.Br[C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>C(Cl)(Cl)Cl.[Cu](I)I.CO>[Cl:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][N:22]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[C:23]2=[O:26])=[CH:18][CH:17]=1
Reactant: Brc1cccnc1
Reactant: O=C1NCCc2ccc(Cl)cc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: O=C1c2cc(Cl)ccc2CCN1c1cccnc1
Temperature: 110 °C
Yield: 42.2 %

Procedure:
Copper iodide (15.6 mg, 0.0824 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (28.3 mg, 0.2472 mmol) and potassium phosphate (437.3 mg, 2.0604 mmol) were added to 1,4-dioxane (20 mL) degassed with argon for 30 minutes. The reaction mixture was purged with argon for a further 20 minutes followed by the addition of 7-chloro-3,4-dihydro-2H-isoquinolin-1-one (I-1d: 150 mg, 0.82417 mmol) and 3-bromo-pyridine (88.9 mL, 0.9065 mmol). The reaction mixture was heated to reflux at 110° C. for 12 hours. The reaction was monitored by TLC (10% methanol in CHCl3). The reaction mixture was filtered and the filtrate was concentrated. Purification by column chromatography on silica gel (10% methanol in CHCl3) afforded 90 mg of the product (42.2% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]([C:19]3[C:20]([NH2:26])=[N:21][CH:22]=[C:23](Br)[CH:24]=3)=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:33][N:34]1[C:42]2[C:37](=[CH:38][C:39](B(O)O)=[CH:40][CH:41]=2)[CH:36]=[CH:35]1>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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]([C:19]3[C:20]([NH2:26])=[N:21][CH:22]=[C:23]([C:39]4[CH:38]=[C:37]5[C:42](=[CH:41][CH:40]=4)[N:34]([CH3:33])[CH:35]=[CH:36]5)[CH:24]=3)=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnc(-c3cc(Br)cnc3N)o2)CC1
Reactant: Cn1ccc2cc(B(O)O)ccc21
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: Cn1ccc2cc(-c3cnc(N)c(-c4nnc(C5CCN(C(=O)OC(C)(C)C)CC5)o4)c3)ccc21
Temperature: 100 °C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
To a solution of 4-[5-(2-amino-5-bromo-pyridin-3-yl)-[1,3,4]oxadiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.1 g, 2.59 mmol) in dioxane (20 mL) and water (10 mL) were added K2CO3 (1.07 g, 7.77 mmol) and N-methylindole-5-boronic acid (0.50 g, 2.85 mmol) in a sealed tube. The reaction mixture was degassed with argon for 20 min, then Pd(PPh3)4 (0.15 g, 0.13 mmol) was added to the reaction mixture. The reaction mixture was stirred for 18 h at 100° C. The reaction was diluted with water (100 mL), extracted with ethyl acetate (2×150 mL) and organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude compound. Crude compound was purified by column chromatography using 100-200 mesh silica gel compound eluted with 60% ethyl acetate in petroleum ether to afford 900 mg of the title compound which is further purified by washing with 20% chloroform in hexane to afford the title compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)[CH3:2].S(Cl)([Cl:21])=O>C(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([Cl:21])=[O:13])=[CH:10][CH:9]=1)[CH2:17][CH3:18])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCN(CC)CCCOc1ccc(C(=O)O)cc1
Solvent: ClCCl
Product: CCN(CC)CCCOc1ccc(C(=O)Cl)cc1

Procedure:
A solution of the compound from Example 2(ii)(6 g, 24 mmol) in DCM was stirred at 0° C. Thionyl chloride was added drop-wise and the reaction was heated at reflux for 24 hrs. The reaction was allowed to cool and the solvents removed under vacuum to afford the expected compound as a pungent crude solid. 5.9 g, 100%. The solid was used without further purification.
Reaction SMILES: [C:1](#N)C.C=O.[CH3:6][NH:7][CH3:8].[C:9]1([C:15]2[N:16]=[C:17]3[C:22]([C:23]([NH:25][CH:26]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=4)[C:27]#[N:28])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]3[CH:36]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)(=O)C>[CH3:6][N:7]([CH2:1][C:36]1[N:18]2[CH:19]=[CH:20][CH:21]=[C:22]([C:23]([NH:25][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[C:27]#[N:28])=[O:24])[C:17]2=[N:16][C:15]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:8]
Reactant: CNC
Reactant: N#CC(NC(=O)c1cccn2cc(-c3ccccc3)nc12)c1cccc(F)c1
Reactant: CC#N
Agent: C=O
Solvent: CC(=O)O
Product: CN(C)Cc1c(-c2ccccc2)nc2c(C(=O)NC(C#N)c3cccc(F)c3)cccn12
Temperature: 0 °C
Yield: 40.8 %

Procedure:
To acetonitrile (10 ml) were added 37% formaldehyde (0.3 ml) and acetic acid (0.4 ml), and 50% aqueous solution of dimethylamine (0.3 ml) was added slowly thereto at 0° C. with stirring. To the mixture was added α-(2-phenyl-imidazo[1,2-a]pyridin-8-ylcarbonylamino)-(3-fluorophenyl)acetonitrile (1.0 g, 2.7 m moles), and the mixture was reacted at 50° C. for 2 hours and further stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was neutralized with saturated aqueous solution of NaHCO3. The solution was extracted with dichloromethane, and the extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel (eluent: chloroform) to give the object compound (0.47 g, yield 40.8%) as crystals. m.p. 123°-124° C.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([C:13](=[O:16])[CH2:14][CH3:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(C)C>C(OCC)(=O)C.CCCCCC>[OH:4][C:5]1[CH:6]=[C:7]([C:13](=[O:16])[CH2:14][CH3:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: CCC(=O)c1ccc(OC)c(OC(C)C)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCC(=O)c1ccc(OC)c(O)c1

Procedure:
Concentration of fraction B (Rf 0.6 in 1:1 v/v ethyl acetate/hexane) afforded the starting ether 10 (207 mg, 50% recovery) as a white solid that was identical, as judged by 1H NMR spectroscopic analysis, with authentic material.