Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Br[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1.O>CO>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)=[N:15][CH:16]=1
Reactant: Brc1ccc(Br)nc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CO
Solvent: O
Product: Brc1ccc(N2CCN(c3ccncc3)CC2)nc1
Temperature: 200 °C
Yield: 50.3 %

Procedure:
A mixture of 1-(4-pyridyl)piperazine (3.26 g, 20 mmol) and 2,5-dibromopyridine (2.36 g) was heated gradually on an oil bath up to 200° C. At approximately 150° C. a clear, slightly coloured melt was obtained and at approximately 180° C. a vigorous reaction set in which caused the melt to darken markedly. The now-dark melt was heated at 200° C. for 10 minutes then allowed to cool to room temperature. The solid reaction mixture was dissolved in methanol (100 mL) and poured into water (100-150 mL). The resultant precipitate was collected, washed with water, dried, then recrystallised from hot aqueous methanol to give the product (1.6 g, 25% yield) as a buff-coloured solid: m.p. 176-180° C.; NMR (DMSO-d6), 3.32 (4H, m), 3.50 (4H, m), 6.72 (2H, m), 6.75 (1H, d), 7.59 (1H, dd), 8.05 (3H, m); Found: MH+, 319/321; C14H15BrN4 requires MH+, 319/321.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.C[O:21][C:22](=[O:31])[C:23]([CH3:30])([CH3:29])[CH2:24][C:25](=O)[CH2:26][CH3:27]>C(O)(C)(C)C>[Br:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:10]3[C:15](=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:26]([CH3:27])=[C:25]2[CH2:24][C:23]([CH3:30])([CH3:29])[C:22]([OH:31])=[O:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(N(N)Cc2ccc(Br)cc2)cc1
Reactant: CCC(=O)CC(C)(C)C(=O)OC
Agent: Cl
Solvent: CC(C)(C)O
Product: COc1ccc2c(c1)c(C)c(CC(C)(C)C(=O)O)n2Cc1ccc(Br)cc1

Procedure:
Following the method of Example 2, but using 1-[4-bromobenzyl]-1-(4-methoxy phenyl) hydrazine hydrochloride and methyl-2,2-dimethyl-4-oxohexanoate as the starting materials, using t-butanol as the solvent, the title compound was prepared.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:24])[CH2:20][S:21]([CH3:23])=[O:22])=[C:15]([NH:25][CH3:26])[CH:14]=1.C(=O)([O-])O.[Na+]>ClCCl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:24])[CH2:20][S:21]([CH3:23])(=[O:6])=[O:22])=[C:15]([NH:25][CH3:26])[CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNc1cc(F)ccc1C(=O)CS(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNc1cc(F)ccc1C(=O)CS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-chloroperoxybenzoic acid (8.29 g) in dichloromethane (200 ml) was added to a solution of 1-(4-fluoro-2-methylaminophenyl)-2-methylsulphinylethanone (10.0 g), prepared in a similar manner to that described in Example 1, in dichloromethane (175 ml) over a period of 7 minutes whilst maintaining the temperature below 30°. The mixture was stirred at ambient temperature for 2 hours, saturated aqueous sodium hydrogen carbonate solution (244 ml) was added and the mixture stirred at ambient temperature for a further 2 hours. The dichloromethane layer was isolated and the aqueous layer extracted with dichloromethane (2×60 ml). The organic phases were combined, dried (magnesium sulphate) and evaporated in vacuo to give a solid which was crystallised from acetone to give 1-(4-fluoro-2-methylaminophenyl)-2-methylsulphonylethanone, m.p. 143.5°-145°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:15]([CH3:31])([CH3:30])[CH2:14]2)[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]2[CH2:42][C:41]([CH3:44])([CH3:43])[N:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:39]([CH3:55])([CH3:54])[CH2:38]2)[N:3]=1.[OH-].[Na+].Cl[CH2:59][CH:60]([OH:63])[CH2:61][OH:62]>>[O:63]1[CH2:59][CH:60]1[CH2:61][O:62][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:15]([CH3:31])([CH3:30])[CH2:14]2)[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]2[CH2:42][C:41]([CH3:44])([CH3:43])[N:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:39]([CH3:55])([CH3:54])[CH2:38]2)[N:3]=1
Reactant: OCC(O)CCl
Reactant: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)nc(OCC3CO3)n2)CC1(C)C

Procedure:
The title compound is prepared by the reaction of 2-chloro-4,6-bis[N-(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine with sodium hydroxide and 3-chloro-1,2-propanediol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][CH:7]=1.[OH-].[Li+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1ccc(Cc2ccc(Cl)c(Cl)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(Cc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a solution of ethyl 4-(3,4-dichlorobenzyl)benzoate (Preparation 170, 240 mg, 0.78 mmol) in THF/MeOH/water (4:3:2, 7.2 mL) was added lithium hydroxide (65 mg, 1.56 mmol) and the mixture was stirred at room temperature for 4 hours. The solvent was evaporated in vacuo and the residue acidified with 1M hydrochloric acid solution. The crude product was extracted with chloroform/methanol, and the extract dried over Na2SO4 and the solvent evaporated in vacuo to give the title compound as a white solid (160 mg, 73%)
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=23)=[N:5]1)#[N:2].C(N(CC)CC)C.[SH2:33].O>N1C=CC=CC=1>[O:10]=[C:9]1[CH:8]=[CH:7][C:6]([C:11]2[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=23)=[N:5][N:4]1[CH2:3][C:1](=[S:33])[NH2:2]
Reactant: S
Reactant: N#CCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Solvent: O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)Cn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O

Procedure:
Into a mixture of 3-(2-cyanomethyl-3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (2.0 g) and triethylamine (1.02 ml) in pyridine (10 ml) was introduced hydrogen sulfide at 50° C. for 6 hours. The mixture was poured into water. The resulting solid was collected by filtration to give 3-(3-oxo-2-thiocarbamoylmethyl-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (2.18 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[C:12]([C:19]([NH:21][O:22][CH2:23][CH2:24][O:25]C=C)=[O:20])=[N:13][N:14]([CH3:18])[C:15](=[O:17])[CH:16]=1.Cl>CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[C:12]([C:19]([NH:21][O:22][CH2:23][CH2:24][OH:25])=[O:20])=[N:13][N:14]([CH3:18])[C:15](=[O:17])[CH:16]=1
Reactant: C=COCCONC(=O)c1nn(C)c(=O)cc1Nc1ccc(SC)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: CSc1ccc(Nc2cc(=O)n(C)nc2C(=O)NOCCO)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
To a solution of 4-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridazine-3-carboxamide (30 mg, 0.077 mmol) in EtOR/THF (2 mL/2 mL) was added 1 N aqueous HCl (0.15 mL, 0.15 mmol, 1 N aqueous solution) at room temperature. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was neutralized to pH 7, diluted with EtOAc (3×), washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (100% EtOAc to 100% CH2Cl2 to 2.5 to 3 to 5% MeOH in CH2Cl2) to afford 6 mg (22%) of the desired product. MS APCI (−) m/z 367 (M−1) detected; 1H NMR (400 MHz, CD3OD) δ 7.35 (t, 1H), 7.18 (dd, 1H), 7.14 (dd, 1H), 5.92 (s, 1H), 4.06 (t, 2H), 3.79 (t, 2H), 3.74 (s, 3H), 2.51 (s, 3H).
Reaction SMILES: CN(C)C=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.S([O-])([O-])(=O)=O.[Na+].[Na+].[Br:27][C:28]1[CH:29]=[C:30]([NH:36][C:37](=[O:43])/[CH:38]=[CH:39]\[C:40]([OH:42])=O)[CH:31]=[C:32]([Br:35])[C:33]=1[OH:34]>O>[Br:27][C:28]1[CH:29]=[C:30]([N:36]2[C:37](=[O:43])[CH:38]=[CH:39][C:40]2=[O:42])[CH:31]=[C:32]([Br:35])[C:33]=1[OH:34]
Reactant: O=C(O)/C=C\C(=O)Nc1cc(Br)c(O)c(Br)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C=CC(=O)N1c1cc(Br)c(O)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
In a reactor, 70 ml of dimethylformamide, 8.3 g (0.058 moles) of phosphorus pentoxide and 7.1 g (0.05 moles) of sodium sulfate were charged, to which 36.5 g (0.10 mole) of N-(3,5-dibromo-4-hydroxyphenyl) maleamic acid were gradually added at 25° C. with vigorous stirring. Thereafter, the reaction was continued at 60° C. for 3 hours. After cooling to room temperature, the resulting reaction mixture was added with water to precipitate N-(3,5-dibromo-4-hydroxyphenyl) maleimide in the form of crystals. The crystals were then separated by filtration, washed with water and dried to obtain 26.3 g (0.0757 moles) of N-(3,5-dibromo-4-hydroxyphenyl) maleimide (yield 75.7%).
Reaction SMILES: [NH2:1][C:2](=[O:40])[CH2:3][C:4]1[CH:39]=[CH:38][CH:37]=[CH:36][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]3)=[CH:21][CH:20]=2)[N:9]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:27]1[CH2:28][CH:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:10]3[N:9]=[C:8]([CH2:7][CH2:6][C:5]4[CH:36]=[CH:37][CH:38]=[CH:39][C:4]=4[CH2:3][C:2]([NH2:1])=[O:40])[C:13]([C:14]([F:16])([F:15])[F:17])=[CH:12][N:11]=3)=[CH:20][CH:21]=2)[CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CNC3)cc2)ncc1C(F)(F)F
Yield: 99.7 %

Procedure:
A solution of tert-butyl 3-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate (A82) (0.346 g, 0.623 mmol) and trifluoroacetic acid (1 mL) in DCM (10 mL) was stirred at room temperature for 22 hours. The volatiles were removed in vacuo and 2 M aqueous NaOH (15 mL) was added to the residue. Water (20 mL) was added and the resulting suspension sonicated for 2 minutes, filtered and the filter cake washed with water and dried to give the title compound 20 as a white solid (0.283 g, 99%); 1H NMR (300 MHz, d6-DMSO) δ 10.26 (s, 1H), 8.69 (s, 1H), 7.78 (d, J=8.6 Hz, 2H), 7.43 (s, 1H), 7.36 (d, J=8.6 Hz, 2H), 7.25-7.15 (m, 4H), 6.92 (s, 1H), 4.21 (brs, 2H), 4.06-3.99 (m, 3H), 3.50 (s, 2H), 3.12-3.05 (m, 5H). LCMS-B: rt 5.442 min; m/z 456 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:24][CH:25]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:34])[N:27]=3)[CH2:18]2)[N:3]=1.[NH2:35][NH2:36]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:35][NH:36]3)=[CH:14][CH:15]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:24][CH:25]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:34])[N:27]=3)[CH2:18]2)[N:3]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(N3CCOC(c4nc(-c5ccccc5Cl)c[nH]4)C3)nc(N)n2)cc1F
Solvent: CCO
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCOC(c3nc(-c4ccccc4Cl)c[nH]3)C2)n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
A mixture of 4-(2-amino-6-{2-[4-(2-chlorophenyl)-1H-imidazol-2-yl]-4-morpholinyl}-4-pyrimidinyl)-2-fluorobenzonitrile (50 mg, 0.105 mmol) and hydrazine (0.167 mL, 5.25 mmol) in ethanol (2 mL) was heated at 120° C. under microwave conditions with stirring for 1 hour. The reaction mixture was filtered and concentrated, and the resulting residue dried in vacuo to afford the title compound (40 mg) as a yellow solid. LC-MS (ES) m/z=488 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 3.10-3.16 (m, 1H), 3.22-3.28 (m, 1H), 3.71-3.76 (m, 1H), 4.04-4.07 (m, 1H), 4.30-4.34 (m, 1H), 4.65-4.68 (m, 1H), 4.73 (m, 1H), 5.38 (s, 2H), 6.20 (s, 2H), 6.71 (s, 1H), 7.21-7.25 (m, 1H), 7.33-7.37 (m, 1H), 7.46-7.48 (m, 1H), 7.60-7.63 (m, 1H), 7.69-7.73 (m, 2H), 7.99 (s, 1H), 8.11-8.13 (m, 1H), 11.52 (s, 1H), 12.53 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:29][N:30]([CH3:40])[C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH3:29][N:30]([CH3:40])[C:31]1[N:36]=[CH:35][C:34]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=3[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]3[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=3[CH:10]=2)=[CH:33][CH:32]=1
Reactant: CN(C)c1ccc(B(O)O)cn1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N(C)C)nc2)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared in a similar manner as described for example 13 from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (100 mg, 0.225 mmol) and [6-(dimethylamino)-3-pyridinyl]boronic acid (49 mg, 0.292 mmol). The final product was collected as a white solid (49 mg, 44%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (s, 1H) 8.57-8.65 (m, 2H) 8.35 (s, 1H) 8.01-8.06 (m, 2H) 7.83 (s, 1H) 6.76 (d, J=8.84 Hz, 1H) 5.92 (s, 1H) 5.13 (dt, J=13.14, 6.57 Hz, 1H) 4.42 (br. s., 1H) 4.41 (br. s., 1H) 3.09 (s, 6H) 2.54 (m, 2H) 2.14 (s, 3H) 1.51-1.58 (m, 2H) 1.50 (s, 3H) 1.49 (s, 3H) 0.88 (t, J=7.33 Hz, 3H). LC-MS (ES) m/z=487.4 [M+H]+
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][C:18]2=[O:36])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37]N=NNC1C=CC(C)=CC=1>C1C=CC=CC=1>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[O:36][CH3:37])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(=O)CS[C@H]12
Reactant: CN=NNc1ccc(C)cc1
Solvent: c1ccccc1
Product: COC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1

Procedure:
A solution of 0.050 g of 7β-phenylacetylamino-cepham-3-one-4ξ-carboxylic acid diphenylmethyl ester and 0.020 g of 1-methyl-3-(4-methylphenyl)-triazene in 5 ml of benzene is boiled for 2 hours under reflux. After cooling, the mixture is evaporated under reduced pressure and the residue is purified by thin layer chromatography (silica gel; 1×20 cm; system: toluene/ethyl acetate, 3:1). The zone (Rf~0.18) which is visible under ultraviolet light (λ=254μ) is eluted with acetone and 3-methoxy-7β-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained, ultraviolet absorption spectrum (in ethanol): λmax =264μ (ε=6,300); infrared absorption spectrum (in methylene chloride): Characteristic bands at 2.94μ, 5.63μ, 5.83μ, 5.94μ, 6.26μ and 6.68μ.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11](O)=[CH:10][N:9]=1>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:1][C@@H:2]2[CH2:6][CH2:5][NH:4][CH2:3]2)=[CH:10][N:9]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: O[C@H]1CCNC1
Product: Clc1ccc(O[C@@H]2CCNC2)cn1

Procedure:
By the procedure of Example 2, employing the appropriate 3-(S)-hydroxypyrrolidine in place of 3-hydroxypyrrolidine and 2-chloro-5-hydroxypyridine in place of 3-hydroxypyridine, 2-chloro-5-(3-(R)-pyrrolidinyloxy)-pyridine was produced as a clear oil: 1H NMR (300 MHz, CD3OD) δ 8.10 (1H, s), 7.50 (1H, dd, J=2.3, 8.8 Hz), 7.40 (1H, d, J=8.8 Hz), 5.28 (1H, s), 3.63-3.31 (4H, m), 2.34 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.C([Li])CCC.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([B:18]([OH:23])[OH:19])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cc(-c2cccc(F)c2)c(Cl)cc1I
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1B(O)O
Reaction time: 0.67 h
Yield: 66.1 %

Procedure:
A round-bottom flask was charged with 2-chloro-3′-fluoro-4-iodo-5-methoxy-1,1′-biphenyl (1.68 g, 4.63 mmol), triisopropyl borate (1.399 ml, 6.02 mmol), and THF (23.17 ml). The flask was cooled in a dry ice-acetone bath for 10 min, then n-butyllithium (2.5 M in hexane) (2.409 ml, 6.02 mmol) was added drop wise over 1 min. After 40 min, a solution of 2 N aq. NaOH (25 mL) was added. The resulting biphasic mixture was stirred for 10 min, and then partitioned between water and ether. The layers were separated, and the ethereal layer was extracted with water (2×). The combined aq. extracts were washed with ether, and the ethereal layer was back-extracted with water. The combined aq. layers were acidified with 3N aq. HCl (50 mL), and the aq. mixture was extracted with DCM (3×). The combined DCM-layers were dried over sodium sulfate, filtered, and concentrated to give (2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)boronic acid (0.859 g, 3.06 mmol, 66.1% yield) as an oily solid. m/z (ESI) 281.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[Br:10][C:11]1[C:12]2[N:13]([CH:17]=[C:18]([CH2:20][CH2:21][C:22]#[CH:23])[N:19]=2)[CH:14]=[CH:15][CH:16]=1>>[Br:10][C:11]1[C:12]2[N:13]([CH:17]=[C:18]([CH2:20][CH2:21][C:22]#[C:23][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=3)[N:19]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: C#CCCc1cn2cccc(Br)c2n1
Reactant: FCc1cccc(Br)n1
Product: FCc1cccc(C#CCCc2cn3cccc(Br)c3n2)n1
Yield: 10.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 190(F), from 2-bromo-6-(fluoromethyl)pyridine (180 mg, 0.97 mmol) and 8-bromo-2-(but-3-ynyl)-imidazo[1,2-a]pyridine (242 mg, 0.97 mmol). The crude residue was purified over silicagel chromatography 25 g silicagel column Cyclohexane/AcOEt: from 100/0 to 60/40 as eluent) to afford 36 mg of 8-bromo-2-(4(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 10%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[BH4-].[Na+].O>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH2:7][OH:8])[CH:11]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(Br)cc(CO)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of dimethyl 5-bromoisophthalate (5.4 g, 20 mmol) in methanol (300 mL) at 0° C. was slowly added sodium tetrahydroborate (10 g, 0.28 mol). The mixture was stirred at rt for 3 h, and then treated with water (300 mL). The volatiles were removed in vacuo and the aqueous phase was extracted with CH2Cl2 (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The resulting oil was purified by flash chromatography to afford the title compound.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C)[N:17]=3)=[CH:14][C:13]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[N:17]=3)=[CH:14][C:13]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3cccc(OC)n3)c2s1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3cccc(O)n3)c2s1
Temperature: 50 °C

Procedure:
To a solution of 1-ethyl-3-[7-(6-methoxy-pyridin-2-yl)-5-pyridin-3-yl-benzothiazol-2-yl]-urea (0.04 g, 0.098 mmol) in dry DCM was added BBr3 (0.50 ml) under nitrogen atmosphere at 0° C. The reaction mixture was then heated at 50° C. for 6 h under nitrogen atmosphere. Since the starting material was not consumed (TLC monitoring), toluene (5 mL) was added into the reaction mixture and heated at 120° C. for 16 h. After the completion of the reaction (TLC monitoring), the reaction mixture was cooled to 0° C. and quenched with ice-cold water. Toluene was distilled off, added water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The crude residue was purified over silica gel (100-200 M) using DCM-MeOH (96:4) to provide the title compound as off white solid (2.5 mg, 6%).
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>>[CH:33]1([C:36]([N:2]2[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]3[C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[C:27]6[O:26][CH2:25][O:24][C:23]=6[CH:22]=[CH:21][C:20]=5[O:28][CH2:29][CH:30]5[CH2:32][CH2:31]5)[C:13]=4[NH:12][CH:11]=3)=[O:9])[CH2:3]2)=[O:37])[CH2:35][CH2:34]1
Reactant: O=C(Cl)C1CC1
Reactant: O=C(N[C@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: Cl
Product: O=C(N[C@H]1CCN(C(=O)C2CC2)C1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-pyrrolidin-3-ylamide hydrochloride (example A143) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [S:1]1[C:5]([CH:6]([NH:8][OH:9])[CH3:7])=[CH:4][C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2.O([NH:21][C:22]([NH:24][C:25](N)=[O:26])=[O:23])C1C=CC=CC=1>O1CCOCC1>[C:22]([NH:24][C:25](=[O:26])[N:8]([OH:9])[CH:6]([C:5]1[S:1][C:2]2[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=2[CH:4]=1)[CH3:7])(=[O:23])[NH2:21]
Reactant: NC(=O)NC(=O)NOc1ccccc1
Reactant: CC(NO)c1cc2ccccc2s1
Solvent: C1COCCO1
Product: CC(c1cc2ccccc2s1)N(O)C(=O)NC(N)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of urea (7.27 g, 119 mmol) was added phenyl chloroformate (8.9 g, 57 mmol) followed by pyridine (30 mL). The resulting mixture became highly exothermic and soon solidified. This solid residue was dispersed and washed well with pyridine and ethylacetate to afford the intermediate N-phenoxycarbamoyl urea. A solution of N-(1-benzo[b]thien-2-yl)ethylhydroxylamine (0.50 g, 2.6 mmol) and N-phenoxycarbamoyl urea (0.46 g, 2.6 mmol) in dioxane (12 mL) was heated at 50° C. for 18 h. The mixture was then brought to 75° C. for 24 h. The reaction was cooled to r.t. and concentrated in vacuo. The resulting residue was crystallized in ethanol:hexanes to afford the desired product. (R1 =NHCONH2, A=CHCH3, X=S [2-isomer], Y=H, M=H).