Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=O)=[CH:7][CH:6]=1)(C)(C)C.[NH2:14][CH:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH3:16]>>[C:8]([N:14]([CH2:9][C:8]1[CH:7]=[CH:6][CH:5]=[CH:13][CH:12]=1)[CH:15]([CH3:16])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:12])([CH3:9])[CH3:7]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: CCCCCC(C)N
Product: CCCCCC(C)N(Cc1ccccc1)C(C)(C)C

Procedure:
The N-t-butylbenzyl-N-(1-methylhexyl)amine was synthesized in the same manner as in Example 2, procedures 1 and 2 using 4-t-butylbenzoyl chloride and 2-aminoheptane as starting materials.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][O:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:33]5[CH:32]=[CH:31][N:30]=[C:29]([O:28][CH3:27])[CH:34]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COc1cc(B(O)O)ccn1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccnc(OC)c5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-methoxy-4-pyridineboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 2): tR=1.15 min; Mass spectrum (ESI+): m/z=466 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[N:5][N:6]=1.[Li]CCCC.[CH2:12]([O:14][CH2:15][C:16](OCC)=[O:17])[CH3:13]>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:3][C:4]([C:16]([CH2:15][O:14][CH2:12][CH3:13])=[O:17])=[N:5][N:6]=1
Reactant: CCOCC(=O)OCC
Reactant: Cc1nnco1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOCC(=O)c1nnc(C)o1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the 2-methyl-1,3,4-oxadiazole (5.0 g, 59.5 mmol) in THF (100 mL) was added dropwise n-BuLi (23.79 mL, 59.5 mmol) in toluene under N2 at −78° C. After 1 h, ethyl ethoxyacetate (10.22 g, 77 mmol) was added. The reaction mixture was then allowed to warm to −40° C. and stirred for 2 h. The reaction mixture was then quenched with 65 mL of LON HCl and extracted with EtOAc. The organic layer was washed with water and then brine, dried over anhydrous Na2SO4, and concentrated. The resulting residue was purified on a flash chromatography column (Biotage™-40M) using a gradient of 0-100% of n-hexane/Et2O to give the desired product. 1H NMR (500 MHz, CD3OD): δ 1.27 (t, 3H), 2.64 (s, 3H), 3.69 (q, 2H), 4.88 (s, 2H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl.[OH-].[Na+]>O>[O:20]1[CH:18]([CH2:16][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:19]1
Reactant: ClCC1CO1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(CN(Cc2ccccc2)CC2CO2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At 0° C., 100 g (506.9 millimoles) of dibenzyl-amine (dissolved in 300 ml of methylene chloride) is added dropwise to a thoroughly stirred suspension of 234.51 g (2.53 mol) of epichlorohydrin and 200 ml of 32% sodium hydroxide solution. The mixture is stirred for 2 hours at 0° C. and then 3 hours at room temperature. The mixture is diluted with 31 of water and extracted 3 times with 500 ml of methylene chloride. The organic phases are combined, dried over magnesium sulfate, and evaporated under vacuum. The remaining oil is flash-chromatographed on silica gel (mobile phase: methylene chloride/hexane/acetone: 20/10/3).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[N:3]=1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](B2OC(C)(C)C(C)(C)O2)=[N:24]1>O>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:27]3[CH:28]=[CH:29][CH:30]=[C:31]4[C:26]=3[CH:25]=[N:24][NH:23]4)[N:7]=[C:6]3[N:8]([CH3:11])[N:9]=[CH:10][C:5]=23)[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Reactant: COc1ccc(Nc2nc(Cl)nc3c2cnn3C)cc1OC
Solvent: O
Product: COc1ccc(Nc2nc(-c3cccc4[nH]ncc34)nc3c2cnn3C)cc1OC

Procedure:
(6-Chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(3,4-dimethoxy-phenyl)-amine was reacted with indazole boronic acid pinacol ester in General Procedure A. Addition of water gave a solid which was purified by preparative HPLC to give 132. NMR: (CDCl3): 3.81 (s, 3H, CH3), 3.89 (s, H, ArH), 4.07 (s, 3H, CH3), 6.88 (d, H, ArH, J=8.52 Hz), 7.00 (dd, H, ArH, J=2.41 Hz, 8.46 Hz), 7.15-7.18 (m, 2H, 2×ArH), 7.43-7.47 (m, H, ArH), 7.54-7.56 (m, H, ArH), 8.33 (d, H, ArH, J=7.26 Hz), 9.08 (s, H, ArH), 10.1 (sbr, H, NH). MS: (ESI+) MH+=402.14
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1Cl)[C:5]#[N:6].[C:11](=[S:16])(OCC)[S-:12].[K+].Cl>CN(C=O)C.O>[C:5]([C:4]1[CH:7]=[CH:8][C:9]2[S:12][C:11]([SH:16])=[N:1][C:2]=2[CH:3]=1)#[N:6]
Reactant: CCOC(=S)[S-]
Reactant: N#Cc1ccc(Cl)c(N)c1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2sc(S)nc2c1
Temperature: 115 °C
Yield: 76.1 %

Procedure:
A mixture of 3-amino-4-chloro benzonitrile (13, 0.50 g, 3.28 mmol) and potassium O-ethyl dithiocarbonate (1.05 g, 6.55 mmol) in DMF (15 mL) was heated overnight at 110-120° C. under N2. After cooling, the reaction mixture was diluted with water and acidified with 1N HCl. The precipitate was collected by filtration, washed with water, and dried under vacuum to yield 14 (0.48 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](Cl)=[O:8])=[CH:4][CH:3]=1.[N:10]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH:14]=[CH:13][N:12]=[CH:11]1.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[O:8])=[CH:4][CH:3]=1
Reactant: NCCCCCn1ccnc1
Reactant: O=C(Cl)c1ccc(Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCCCn1ccnc1)c1ccc(Cl)s1
Reaction time: 20 h

Procedure:
A solution of 1.8 g. of 5-chlorothiophene-2-carbonyl chloride in 10 ml. of CH2Cl2 was added to a mixture of 1.52 g. of 1H-imidazole-1-pentanamine, 10 ml. of 1N NaOH and 50 ml. of CH2Cl2. The reaction mixture was stirred for 20 hours and then treated with 25 ml. of CH2Cl2 and 5 ml. of 1N NaOH. The layers were separated and the organic layer was washed with water, dried over MgSO4 and concentrated. The crystalline residue was washed with diethyl ether whereby the desired product, m.p. 123°-125° C., was obtained.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1([O:13][CH2:12][CH2:11][O:10]1)[CH3:9])[C:5]([OH:7])=O.[NH2:14][CH:15]1[C:32](=[O:33])[N:17]2[C:18]([C:29]([OH:31])=[O:30])=[C:19]([CH2:22][S:23][C:24]3[S:25][CH:26]=[N:27][N:28]=3)[CH2:20][S:21][C@H:16]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]1([O:13][CH2:12][CH2:11][O:10]1)[CH3:9])[C:5]([NH:14][CH:15]1[C:32](=[O:33])[N:17]2[C:18]([C:29]([OH:31])=[O:30])=[C:19]([CH2:22][S:23][C:24]3[S:25][CH:26]=[N:27][N:28]=3)[CH2:20][S:21][C@H:16]12)=[O:7]
Reactant: CON=C(C(=O)O)C1(C)OCCO1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)C1(C)OCCO1
Yield: 81.2 %

Procedure:
2-Methoxyimino-3,3-ethylenedioxybutyric acid (syn isomer, 15.1 g.) and 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (29.1 g.) were treated in a similar manner to that of Example 10-(2) to give 7-(2-methoxyimino-3,3-ethylenedioxybutyramido)-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 32.5 g.). Mp. 145° to 152° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][N:14]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:40]1[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH2:41]1>CO.Cl.O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][N:14]([S:30]([C:33]4[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=4)(=[O:32])=[O:31])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:40]1[CH2:41][CH2:42][NH:43][CH2:44][CH2:45]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)c(F)c4)cnc32)cc1
Yield: 98.5 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(2-fluoro-4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (product of step 1 of example 84) (130 mg, 0.179 mmol) was deprotected in methanol/HCl in dioxane (5/5 mL) to afford 110 mg (98.2% yield) of the titled compound. MS: m/z=624.4 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[O:7]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[C:24]1[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=1>COCCOC.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>[O:7]([C:14]1[CH:19]=[CH:18][C:17]([C:24]2[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: Nc1ncccc1Br
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncccc1-c1ccc(Oc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
A mixture of sodium carbonate (1.905 g), tetrakis(triphenylphosphine)palladium(0) (519 mg), 4-phenoxyphenylboronic acid (2.5 g) and 3-bromopyridin-2-amine (1.555 g) in 1,2-dimethoxyethane (60 mL) and water (12 mL) was stirred overnight at 80° C. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.289 g) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:21]=[C:20]3[C:15]([C:16](=[O:27])[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][NH:19]3)=[CH:14][C:13]=2[F:28])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:35](Br)[CH2:36][OH:37]>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:21]=[C:20]3[C:15]([C:16](=[O:27])[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][N:19]3[CH2:35][CH2:36][OH:37])=[CH:14][C:13]=2[F:28])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OCCBr
Reactant: CCOC(=O)c1c[nH]c2nc(N3CCN(C(=O)OCC)CC3)c(F)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCO)c2nc(N3CCN(C(=O)OCC)CC3)c(F)cc2c1=O
Temperature: 100 °C
Yield: 87.3 %

Procedure:
A mixture of ethyl 7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (10.5 g), dimethylformamide (100 ml), and potassium carbonate (7.4 g) was heated at 100° C. for 15 minutes. To the solution was added a solution of 10.1 g of ethylene bromohydrin in dimethylformamide (10 ml), and the mixture was heated at 100° C. for 45 minutes with stirring. After removal of the resulting inorganic substance by filtration, the filtrate was concentrated to dryness under reduced pressure. Water (80 ml) was added to the residue, and the resulting crystals were collected by filtration and recrystallized from ethanol to give 10.2 g of ethyl 7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-1-(2-hydroxyethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (mp 215°-217° C.). Thionyl chloride (5.0 g) was added to the solution of the resulting hydroxyethyl derivative (4.6 g) in chloroform (50 ml), and the mixture was refluxed under heating for 30 minutes. After cooling, the solution was treated with 30 ml of water and neutralized with a saturated sodium bicarbonate solution. The chloroform layer was separated, washed with water, and dried over anhydrous sodium sulfate. After removal of the solvent, the residue was chromatographed on silica gel with chloroform and the crystals resulting from the main fraction were recrystallized from ethyl acetate to give 4.7 g of ethyl 1-(2-chloroethyl)-7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (mp 143°-144° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:38][C:39]1[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([F:46])[C:40]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=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>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:16][CH:15]=1)=[O:29])=[C:8]([C:40]1[C:39]([F:38])=[CH:44][C:43]([F:45])=[CH:42][C:41]=1[F:46])[CH:7]=[CH:6]2
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: OB(O)c1c(F)cc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3c(F)cc(F)cc3F)ccc2c1
Temperature: 100 °C
Yield: 92.7 %

Procedure:
Dissolve trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (752 mg, 1.4 mmol), 2,4,6-trifluorophenylboronic acid (493 mg, 2.8 mmol), potassium phosphate (1.8 g, 8.4 mmol)) and tetrakis(triphenylphosphine)palladium (324 mg, 0.3 mmol) in dry dimethylformamide (DMF, 25 mL) and heat at 100° C. for 20 minutes. Purify reaction on an SCX column to yield 674 mg (93%) of the title compound. Mass spectrum (ion spray): m/z=520.2 (M+H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[O:12][CH3:13])=O.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20]>CCO>[Br:11][C:9]1[CH:8]=[CH:7][C:6]([O:12][CH3:13])=[C:5]([C:3]2[N:20]=[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]3[CH:2]=2)[CH:10]=1
Reactant: COc1ccc(Br)cc1C(=O)CBr
Reactant: Nc1ccccn1
Solvent: CCO
Product: COc1ccc(Br)cc1-c1cn2ccccc2n1
Temperature: 80 °C
Reaction time: 12 h
Yield: 6.2 %

Procedure:
To a mixture of 2-bromo-1-(5-bromo-2-methoxyphenyl)ethanone (500 mg, 1.6 mmol) in EtOH (5 mL), pyridin-2-amine (153 mg, 1.6 mmol) was added. The mixture was stirred at 80° C. for 12 hours, and then cooled to 25° C. After filtrated, the solid was dried in vacuo to provide 2-(5-bromo-2-methoxyphenyl)imidazo[1,2-a]pyridine (30 mg, yield: 5%). 1H-NMR(CDCl3, 400 MHz) δ 8.54 (s, 1H), 8.18 (s, 1H), 8.12˜8.13 (m, 1H), 7.62˜7.64 (m, 1H), 7.37˜7.40 (m, 1H), 7.16˜7.21 (m, 1H), 6.86˜6.88 (m, 1H), 6.76˜6.79 (m, 1H), 3.98 (s, 3H). MS (M+H)+: 303/305.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15]Cl)=[CH:9][CH:8]=1)C.[F:20][C:21]1[CH:35]=[CH:34][C:24]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:35]=[CH:34][C:24]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:15][C:14]#[C:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=3)=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(F)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(C#CCCl)cc1)OC
Product: CO[C@@H](Cc1ccc(C#CCOc2ccc(C(=O)c3ccc(F)cc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 5, Step A and 4-fluoro-4′-hydroxybenzophenone in a manner analogous to that described for Example 5, Step B. MS(ES) for C26H21FO[M+H]+: 433.2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]1([S:13]([C:16]2[C:17]([S:27][CH3:28])=[N:18][N:19]3[C:24](Cl)=[CH:23][C:22]([CH3:26])=[N:21][C:20]=23)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[C:7]1([S:13]([C:16]2[C:17]([S:27][CH3:28])=[N:18][N:19]3[C:24]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:23][C:22]([CH3:26])=[N:21][C:20]=23)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccccc1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: CSc1nn2c(N3CCOCC3)cc(C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
0.20 g (2.2 mmol) of morpholine was added to a solution of 0.25 g (0.85 mmol) of 3-benzenesulphonyl-7-chloro-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 10 l of DMF and stirred at 60° for 1 hr. The reaction solution was cooled to RT and evaporated in a high vacuum. The residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH 25:1) and crystallization from EtOH yielded 0.20 g (70%) of 3-benzenesulphonyl-5-methyl-2-methylsulphanyl-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine as colorless crystals, m.p. 206-208°.
Reaction SMILES: [N+](C1C=CC(O[C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:18]([CH2:20][CH:21](OC)OC)[CH3:19])=[O:17])=[CH:11][C:10]=2[N+:26]([O-:28])=[O:27])=CC=1)([O-])=O.Cl.[OH2:32]>>[CH3:19][N:18]1[CH:20]=[CH:21][N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:32][C:13]3[CH:12]=[CH:11][C:10]([N+:26]([O-:28])=[O:27])=[CH:9][CH:14]=3)=[C:10]([N+:26]([O-:28])=[O:27])[CH:11]=2)[C:16]1=[O:17]
Reactant: O
Reactant: COC(CN(C)C(=O)Nc1ccc(Oc2ccc([N+](=O)[O-])cc2)c([N+](=O)[O-])c1)OC
Agent: Cl
Product: Cn1ccn(-c2ccc(Oc3ccc([N+](=O)[O-])cc3)c([N+](=O)[O-])c2)c1=O

Procedure:
N-[4-(4-Nitrophenoxy)-3-nitrophenyl]-N'-(2,2-dimethoxyethyl)-N'-methylurea (0.02 mole), water (30 ml) and concentrated hydrochloric acid (3 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer and condenser. The mixture is refluxed for a period of about 30 minutes then cooled and extracted with ethyl acetate. The extract is washed with dilute aqueous sodium bicarbonate, with two portions of water and is then dried. The ethyl acetate is removed by mild warming under reduced pressure to yield the desired product 1-methyl-3-[4-(4-nitrophenoxy)-3-nitrophenyl]-4-imidazolin-2-one.
Reaction SMILES: Cl.[C:2]([C:5]1[C:6]([CH:16]2[CH2:19][CH2:18][CH2:17]2)=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])(=[NH:4])[NH2:3].Br[CH2:21][C:22](=O)[CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH:16]1([C:6]2[C:5]([C:2]3[NH:3][C:22]([CH2:23][CH3:24])=[CH:21][N:4]=3)=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH3:15])[CH:7]=2)[CH2:17][CH2:18][CH2:19]1
Reactant: COC(=O)c1cc(C(=N)N)c(C2CCC2)cc1C
Reactant: CCC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCc1cnc(-c2cc(C(=O)OC)c(C)cc2C2CCC2)[nH]1
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To a round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was added a solution of methyl 5-carbamimidoyl-4-cyclobutyl-2-methylbenzoate hydrochloride (compound 245.1, 350 mg, 1.11 mmol, 1.00 equiv, 90%) in ACN (50 mL). 1-Bromobutan-2-one (186 mg, 1.23 mmol, 1.00 equiv) and potassium carbonate (513 mg, 3.53 mmol, 3.00 equiv, 95%) were added to the reaction. The resulting solution was stirred overnight at 80° C. After cooling to ambient temperature, the mixture was diluted with ethyl acetate and washed with 3×30 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:5) as eluent to furnish 290 mg (83%) of methyl 4-cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoate as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:12])=[N:4][C:5](S(C)=O)=[N:6][C:7]=1[Cl:8].[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[C:3]([NH2:12])=[N:4][C:5]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[N:6][C:7]=1[Cl:8]
Reactant: CS(=O)c1nc(N)c(Br)c(Cl)n1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(-n2cccn2)nc(Cl)c1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
1 g (3.7 mmol) of 5-bromo-6-chloro-2-(methylsulfinyl)pyrimidine-4-amine (intermediate 2) was suspended in 10 ml of DMF. To this suspension were added 0.33 g (4.8 mmol) de pyrazole and 0.8 g of cesium carbonate. The reaction mixture was turned immediately light yellow color and allowed to stir at room temperature for about 1 to 2 hours. After nearly complete conversion to the corresponding monosubstituted derivative as was indicated by TLC the solution was poured onto 100 ml of cool water. The formed precipitated was filtered, washed with water and dried to afford 0.66 g (65%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1.[CH3:25][O:26][CH2:27][CH2:28]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([O:19][CH2:28][CH2:27][O:26][CH3:25])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1
Reactant: COCCO
Reactant: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(Cl)cc12
Product: COCCOC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c1
Yield: 70 %

Procedure:
The product was prepared from 3-{[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoic acid (21 mg, 0.055 mmol) (Intermediate 19) and 2-methoxyethanol (7.6 mg, 0.100 mmol) according to the General Procedure 7, described in Example 107. The title compound was obtained in 70% yield (16.9 mg). 1H NMR (500 MHz, CDCl3) δ ppm 2.47 (s, 3 H) 3.40 (s, 3 H) 3.67-3.70 (m, 2 H) 4.42-4.45 (m, 2 H) 6.92 (s, 1 H) 7.37 (dd, J=8.02, 7.74 Hz, 1 H) 7.45 (dd, J=8.73, 1.96 Hz, 1 H) 7.45 (ddd, J=8.02, 2.34, 1.17 Hz, 1 H) 7.72 (dd, J=8.73, 0.60 Hz, 1 H) 7.72 (dd, J=1.96, 0.60 Hz, 1 H) 7.74 (dd, J=2.34, 1.59 Hz, 1 H) 7.87 (ddd, J=7.74, 1.59, 1.17 Hz, 1 H). MS (ESI+) m/z 440 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[S:37](=[O:40])(=[O:39])[NH2:38])=[CH:27][CH:26]=2)[C:19]([CH3:41])=[C:18]3[CH3:42])=[O:14])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[C:43](Cl)(=[O:45])[CH3:44]>C(Cl)Cl>[C:43]([NH:38][S:37]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:20]2[C:21]3[C:17](=[CH:16][C:15]([C:13]([NH:12][C@H:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=4)[CH3:11])=[O:14])=[CH:23][CH:22]=3)[C:18]([CH3:42])=[C:19]2[CH3:41])=[CH:26][CH:27]=1)(=[O:39])=[O:40])(=[O:45])[CH3:44]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3S(N)(=O)=O)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)NS(=O)(=O)c1ccccc1-c1ccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the mixture of (S)—N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1-((2′-sulfamoyl-[1,1′-biphenyl]-4-yl)methyl)-1H-indole-5-carboxamide (0.058 g, 0.1 mmol) and TEA (0.03 mL, 0.2 mmol) in DCM (0.5 mL) was slowly added acetyl chloride (0.009 g, 0.11 mmol). The mixture was stirred at room temperature for 1 h.