Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:39][CH2:40][CH2:41][NH:42][C:43]1[N:48]=[C:47]([C:49]2[S:53][C:52]([C:54]([CH3:57])([CH3:56])[CH3:55])=[N:51][C:50]=2[C:58]2[C:59]([F:76])=[C:60]([NH:64][S:65]([C:68]3[CH:73]=[C:72]([F:74])[CH:71]=[CH:70][C:69]=3[F:75])(=[O:67])=[O:66])[CH:61]=[CH:62][CH:63]=2)[CH:46]=[CH:45][N:44]=1>CN(C=O)C.CCOC(C)=O>[F:75][C:69]1[CH:70]=[CH:71][C:72]([F:74])=[CH:73][C:68]=1[S:65]([NH:64][C:60]1[C:59]([F:76])=[C:58]([C:50]2[N:51]=[C:52]([C:54]([CH3:56])([CH3:55])[CH3:57])[S:53][C:49]=2[C:47]2[CH:46]=[CH:45][N:44]=[C:43]([NH:42][CH2:41][CH2:40][NH:39][C:1](=[O:5])[CH2:2][OH:3])[N:48]=2)[CH:63]=[CH:62][CH:61]=1)(=[O:67])=[O:66]
Reactant: O=C(O)CO
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(NCCN)n2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(NCCNC(=O)CO)n2)s1
Reaction time: 1 h
Yield: 46.4 %

Procedure:
A mixture of glycolic acid (0.040 g, 0.50 mmol), HATU (0.19 g, 0.50 mmol) and DIEA (0.09 ml, 0.50 mmol) in DMF (1 mL) was added to a stirring solution of N-{3-[5-{2-[(2-aminoethyl)amino]-4-pyrimidinyl}-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.15 g, 0.25 mmol) and DIEA (0.09 ml, 0.50 mmol) in DMF (1 mL). The reaction was stirred for 1 h. LCMS analysis indicated approximately 50% conversion to product. An additional 2.0 equivalents of activated glycolic acid was added and the reaction was allowed to stir for an additional 1 h. LCMS analysis indicated the starting material was still not completely consumed so an additional 2.0 equivalents of activated glycolic acid was added and the reaction was stirred for an addition 1 h. The reaction was diluted with EtOAc, washed with water (×5) and a saturated aqueous brine solution (×2). The organic layer was dried over MgSO4, filtered and the filtrate was concentrated onto silica gel and purified by flash chromatography to afford the title compound (0.072 g, 44% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.75 (br. s., 1H), 8.04 (d, J=5.1 Hz, 1H), 7.77-7.98 (m, 1H), 7.15-7.65 (m, 7H), 5.81-6.01 (m, 1H), 5.49 (t, J=5.2 Hz, 1H), 3.80 (d, J=5.3 Hz, 2H), 3.29 (br. s., 2H), 1.40 (s, 9H). MS (ES+): 621 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1
Reactant: C[O-]
Reactant: O=C(O)Cc1ccc(CBr)cc1
Agent: [Na+]
Solvent: CO
Product: COCc1ccc(CC(=O)O)cc1

Procedure:
4-(Bromomethyl)phenylacetic acid (4.85 g, 21.17 mmole), sodium methoxide (30% in methanol, ˜12 ml, ˜65 mmole)) and methanol (30 ml) were mixed and refluxed over night. The reaction mixture was allowed to cool down and was then acidified with HCL (1M). Methanol was evaporated. Water was added and the reaction mixture was extracted three times with dichloromethane. The combined organic phases was washed with brine and dried with NA2SO4. Evaporation gave 3.6 g, 94.4%, of the desired product.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][C:19](O)=[O:20])=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.[NH2:35][OH:36]>[Cl-].[Na+].O.CN(C=O)C>[CH:1]1[C:13]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][C:19]([NH:35][OH:36])=[O:20])=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CNC(=O)C=C1c2ccccc2-c2ccccc21
Reactant: NO
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(C=C1c2ccccc2-c2ccccc21)NCC(=O)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
2-(2-(9H-fluoren-9-ylidene)acetamido)acetic acid (279 mg, 1 mmol), triethylamine (151 mg, 1.5 mmol) and 20 ml of DMF were stirred at 0° C. while ethyl chloroformate (163 mg, 1.5 mmol) was added. The mixture was stirred at 0° C. for 2 hours, and then 50% aqueous solution of hydroxylamine (1.32 g, 20 mmol) was added. The mixture was stirred for 3 hours at room temperature, and then diluted with 1000 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (132 mg, 45%) as a yellow solid. LC-MS (m/z) 295 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:13])(C1C=CC=CC=1)[CH2:3][C:4](O)=[O:5].C(Cl)(=O)C(C)(C)C.C1(C(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Li])CCC.[O:45]1CC[NH:47][C:46]1=O>O1CCCC1.C(N(CC)CC)C>[CH:2]([C@H:3]1[CH2:4][O:5][C:46](=[O:45])[NH:47]1)([CH3:13])[CH3:1]
Reactant: CC(C)(CC(=O)O)c1ccccc1
Reactant: O=C1NCCO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Product: CC(C)[C@H]1COC(=O)N1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3,3-dimethyl-3-phenyl propionic acid (2.1 g, 12 mmol, from Reference Example 22) in anhydrous tetrahydrofuran (24 mL) is added under inert atmosphere triethylamine (2.0 mL) and the mixture is cooled to −78° C. in a dry-ice acetone bath. Pivaloyl chloride (1.5 mL, 13 mmol) is added dropwise, causing the immediate formation of a white precipitate. The reaction mixture is allowed to sit for 15 minutes at −78° C. and is then stirred at 0° C. in an ice-water bath. In a separate flask, a solution of (S)-4-isopropyl-2-oxazolidinone (1.5 g, 12 mmol) in anhydrous tetrahydrofuran (27 mL) is prepared under inert atmosphere and cooled to −35° C. in a dry-ice/acetone bath. A small amount of triphenylmethane (<5 mg) is added as an indicator of deprotonation. n-Butyllithium (1.6 M solution in hexanes, 7.7 mL, 12 mmol) is added dropwise via syringe. After 30 minutes of stirring at 0° C., the flask containing the mixed anhydride is re-cooled to −78° C. in a dry-ice/acetone bath. The solution of the lithium anion of the oxazolidinone is added to the mixed anhydride solution via cannula. The source flask is washed twice with tetrahydrofuran (4 mL×2) and these washings are also transferred via cannula to the mixed anhydride solution. The reaction mixture is stirred at −78° C. for 1 hour, 0° C. for 1 hour, and allowed to warm to room temperature overnight. The following morning, water (˜15 mL) is added and stirring is continued for 20 minutes. The aqueous phase is extracted thrice with diethyl ether. The combined extracts are washed with saturated aqueous sodium chloride, dried over sodium sulfate, decanted, and concentrated under reduced pressure to afford (3.6 g, >100% crude) of a pale yellow oil. The crude material is purified by flash chromatography (ethyl acetate/hexanes) to afford 1.5 g (44%) of a clear, colorless oil. MS (ES+): (M+H)=290.0
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([C:14](=[CH:20][N:21]([CH3:23])C)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([F:26])[C:6]([F:25])=[C:7]([F:24])[CH:8]=2)[N:3]=1.Cl.[F:28][CH2:29]CN.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>C(O)C>[CH2:18]([O:17][C:15]([C:14]1[C:12](=[O:13])[C:11]2[CH:10]=[C:9]3[CH:8]=[C:7]([F:24])[C:6]([F:25])=[C:5]([F:26])[C:4]3=[N:3][C:2]=2[N:21]([CH2:23][CH2:29][F:28])[CH:20]=1)=[O:16])[CH3:19]
Reactant: NCCF
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)c(F)c2nc1Cl
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn(CCF)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Yield: 75.4 %

Procedure:
3-Ethoxycarbonyl-1-(2-fluoroethyl)-7,8,9-trifluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under conditions similar to Example 3, but starting with ethyl 2-(2-chloro-6,7,8-trifluoro-3-quinolinecarbonyl)(dimethylamino)acrylate (3.9 g), 2-fluoroethylamine hydrochloride (3 g) and triethylamine (4.2 cc) in ethanol (100 cc). After the addition of DBU (1.8 cc), the solution is heated for 2 hours to 80° C. After the same treatment of the reaction mixture as in Example 24, 3-ethoxycarbonyl-7,8,9-trifluoro-1-(2-fluoroethyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (2.8 g) is obtained in the form of a yellow solid, m.p. 302°-304° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[C:21](=[O:22])[NH:20][C:19]([CH3:23])=[N:18][C:7]=3[CH2:8][N+:9]([O-])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[C:26]([O:29]C(=O)C)(=[O:28])[CH3:27]>>[C:26]([O:29][CH:8]1[C:7]2[N:18]=[C:19]([CH3:23])[NH:20][C:21](=[O:22])[C:6]=2[C:5]2[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=2[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:9]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc2c(c(=O)[nH]1)-c1ccc(Cl)cc1C(c1ccccc1)=[N+]([O-])C2
Product: CC(=O)OC1N=C(c2ccccc2)c2cc(Cl)ccc2-c2c1nc(C)[nH]c2=O

Procedure:
A mixture of 0.5 g (1.4 mmol) of 9-chloro-3-methyl-7-phenyl-5H-pyrimido[4,5-d][2]benzazepin-1(2H)-one 6-oxide and 10 mL of acetic anhydride was heated on a steam bath for 3 hr. The reaction mixture was concentrated at reduced pressure and the crystalline product separated. Recrystallization from methylene chloride gave the product as cream colored crystals, mp >320°.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:24]([CH3:25])=[C:23]([CH3:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[N:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[C:24]([CH3:25])=[C:23]([CH3:26])[S:22][C:12]=3[N:13]=2)=[CH:21][CH:20]=1
Reactant: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1C
Reactant: NCc1ccccc1
Product: Cc1sc2nc(-c3ccncc3)nc(NCc3ccccc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-4-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-benzylamino-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24](C(=O)C(F)(F)F)[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:49])[C:41]5[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N+:42]=5[O-:48])=[C:36]([O:50][CH3:51])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:52]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>C(O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:49])[C:41]5[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N+:42]=5[O-:48])=[C:36]([O:50][CH3:51])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:52]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)cc[n+]4[O-])c(OC)c2)CCN3C(=O)C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)cc[n+]4[O-])c(OC)c2)CCN3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]-3-methoxyphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.77 g) was dissolved in ethanol (200 ml), and to the solution, sodium borohydride (0.12 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The solvent was distilled off, and to the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]-3-methoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 9) (0.56 g) as yellow amorphous.
Reaction SMILES: [CH:1]1[C:11]2[C:10](=[C:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[CH2:14][CH2:13]3)[C:9]3[CH:25]=[CH:26][CH:27]=[CH:28][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[CH:1]1[C:11]2[C:10](=[C:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:14][CH2:13]3)[C:9]3[CH:25]=[CH:26][CH:27]=[CH:28][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCN1CCC(=C2c3ccccc3COc3ccccc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCN1CCC(=C2c3ccccc3COc3ccccc32)CC1
Yield: 96.3 %

Procedure:
A mixture of 3.70 g of ethyl 4-(dibenz[b,e]oxepin-11(6H)-ylidene)-1-piperidinepropionate, 9.9 ml of 2N sodium hydroxide aqueous solution and 40 ml of methanol was refluxed for 30 min and concentrated. Water was added to the residue, adjusted to pH 3 with 10% hydrochloric acid. The precipitate was collected by filtration and washed with water and ether to give 3.30 g of pale yellow crystals, which were recrystallized from a mixture of water and N,N-dimethylformamide to give 2.75 g of pale yellow crystals, mp 142°-143° C.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36]>>[NH2:26][C:24]1[C:25]2=[C:17]([C:14]3[CH:15]=[CH:16][C:10]4[S:9][C:8]([CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[N:12][C:11]=4[CH:13]=3)[CH:18]=[C:19]([CH:27]3[CH2:32][CH2:31][N:30]([CH2:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH2:29][CH2:28]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4sc(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)CN1CCC(c2cc(-c3ccc4sc(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Yield: 36.2 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 355 and using 5-(2-benzyl-1,3-benzothiazol-5-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and 2-chloro-N,N-dimethylacetamide as starting material, 21.6 mg (36.2%) of the desired product was isolated. 1H NMR (400 MHz, CD2Cl2) δ 8.06 (s, 1H), 7.92 (d, 1H), 7.91 (s, 1H), 7.49 (d, 1H), 7.43-7.36 (m, 5H), 6.59 (s, 1H), 5.43 (s, 2H), 4.47 (s, 2H), 3.32-3.23 (m, 1H), 3.21 (s, 2H), 3.10 (s, 3H), 3.09-3.03 (m, 2H), 2.92 (s, 3H), 2.40-2.32 (m, 2H), 2.16-2.12 (m, 2H), 1.94-1.82 (m, 2H); LC-MS m/z[M+H]+ 526.2, RT 2.30 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:13][CH2:12][CH:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:27])=[CH:21][CH:20]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Nc1ccc(Cl)cc1

Procedure:
Example 14 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-chloro-4-isocyanatobenzene (17.4 μl) to give the title compound (0.0275 g). LC-MS (System A): Rt 2.45 mins, Mass Spectrum m/z 428 [MH+].
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[CH:14]([C:20]([O:22][CH:23]([CH:25]4[CH2:27][CH2:26]4)[CH3:24])=[O:21])[C:15]([CH3:19])([CH2:17]Br)[S:16][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1>C1C=CC=CC=1>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:20]([O:22][CH:23]([CH:25]4[CH2:26][CH2:27]4)[CH3:24])=[O:21])=[C:15]([CH3:19])[CH2:17][S:16][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(OC(=O)C1N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1(C)CBr)C1CC1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC1=C(C(=O)OC(C)C2CC2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Yield: 62.5 %

Procedure:
A solution of 1-cyclopropylethyl 6-(2-phenylacetamido)-2-methyl-2-bromomethylpenam-3-carboxylate (0.5 g.) and pyridine (0.20 g.) in benzene (12 cc) was heated under reflux for 3 hours. After cooling, the benzene layer was washed with water, dried and then concentrated. The residue was subjected to chromatography on silica gel to yield crystals (0.26 g.) of 1-cyclopropylethyl 7-(2-phenylacetamido)-3-methyl-3-cephem-4-carboxylate, m.p. 108°-112° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][C:12]([CH3:20])([CH3:19])[C:11]=2[CH:10]=[C:9]([C:21](=[O:23])[CH3:22])[CH:8]=1)(=O)=O.[C:26]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27].[Cl-].[Li+].C(=O)([O-])[O-].[K+].[K+]>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:26]([C:30]1[CH:35]=[CH:34][C:33]([C:7]2[C:16]3[C:15]([CH3:17])([CH3:18])[CH2:14][CH2:13][C:12]([CH3:20])([CH3:19])[C:11]=3[CH:10]=[C:9]([C:21](=[O:23])[CH3:22])[CH:8]=2)=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: CC(=O)c1cc(OS(=O)(=O)C(F)(F)F)c2c(c1)C(C)(C)CCC2(C)C
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: [Cl-]
Product: CC(=O)c1cc(-c2ccc(C(C)(C)C)cc2)c2c(c1)C(C)(C)CCC2(C)C
Yield: 66 %

Procedure:
In a manner similar to that of Example 2 b, by reacting 1.3 g (3.4 mmol) of 3-acetyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthyl 1,1,1-trifluoromethanesulfonate with 600 mg (4.4 mmol) of 4-tert-butylphenylboronic acid, 450 mg (10.8 mmol) of lithium chloride, 4.6 mL (9.2 mmol) of 2 M potassium carbonate solution and 220 mg of tetrakis(triphenylphosphine)palladium. The desired product is obtained in the form of white crystals (m=812 mg; yield=66%; m.p.=134° C.).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21](F)[C:20]=1[CH3:29]>C1COCC1>[F:18][C:19]1[C:20]([CH3:29])=[C:21]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1
Reactant: Cc1c(F)ccc([N+](=O)[O-])c1F
Reactant: Nc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(F)ccc([N+](=O)[O-])c1Nc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 94.2 %

Procedure:
LiHMDS (1.0M in THF, 12.9 mL, 12.9 mmol) was added dropwise to a stirred solution of aniline (633 mg, 6.79 mmol) in anhydrous THF (10 mL) under a nitrogen atmosphere at −78° C. After 10 min stirring at −78° C., a solution of 1,3-difluoro-2-methyl-4-nitrobenzene (1.12 g, 6.47 mmol) in THF (5 mL) was added and stirring was continued for 30 min. The reaction mixture was quenched by addition of water and was diluted with EtOAc. The resulting emulsion was filtered through Celite® and the organic fraction separated, washed with brine and dried (MgSO4). The volatiles were removed in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in cyclohexane) to afford the title compound (1.5 g, 94%). 1H NMR (CDCl3, 400 MHz): δ 8.74 (1H, br s), 8.07 (1H, dd, J=9.34, 5.86 Hz), 7.30-7.23 (2H, m), 7.03 (1H, t, J=7.41 Hz), 6.85-6.78 (3H, m), 1.92 (3H, d, J=2.87 Hz).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([F:31])=[C:24]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])[CH:25]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[F:31][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)=[CH:25][C:24]=1[N:26]([CH3:30])[C:27](=[O:29])[CH3:28]
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Reactant: CC(=O)N(C)c1cc(C(=O)C=CN(C)C)ccc1F
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)N(C)c1cc(-c2ccnc3c(C(=O)c4cccs4)cnn23)ccc1F
Yield: 74.7 %

Procedure:
A mixture of 0.073 g (0.38 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.1 g (0.38 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-acetamide in 10 ml of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 ml of dichloromethane and 10 ml of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 112 mg of N-{2-fluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 75%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[Br:11]N1C(=O)CCC1=O>C1C=CC=CC=1>[N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(N=[N+]=[N-])cc1
Solvent: c1ccccc1
Product: [N-]=[N+]=Nc1ccc(CBr)cc1

Procedure:
To p-azidotoluene (2.2 mM) prepared as above was added N-bromosuccinimide (2.48 mM), and azo-isobutyronitrile (0.214 mM) in anhydrous benzene (5 ml). This was left to reflux for 5 hours, with the reaction being monitored by TLC. The organics were extracted into diethyl ether (3×15 ml), and water, dried over magnesium sulphate, and the excess solvent removed under vacuum. The p-azidobenzyl bromide formed was isolated using chromatographic techniques.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15]([C:17]1[S:21][C:20]([NH2:22])=[N:19][C:18]=1[C:23]([F:26])([F:25])[F:24])=[O:16])[CH3:13]>>[CH2:12]([O:14][C:15]([C:17]1[S:21][C:20]([NH:22][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[OH:11])=[N:19][C:18]=1[C:23]([F:25])([F:26])[F:24])=[O:16])[CH3:13]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: CCOC(=O)c1sc(N)nc1C(F)(F)F
Product: CCOC(=O)c1sc(NC(=O)c2cc(Br)ccc2O)nc1C(F)(F)F
Yield: 88.7 %

Procedure:
Using 5-bromosalicylic acid and 2-amino-4-(trifluoromethyl)thiazole-5-carboxylic acid ethyl ester as the raw materials, the same operation as the example 195(3) gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[C:4]=1Br.[CH2:22]([Li])CCC.CN(CCN(C)C)C.IC>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[C:4]=1[CH3:22]
Reactant: [Li]CCCC
Reactant: COc1ccc(-c2ccc3c(Br)c(OC)ccc3c2)cc1
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: COc1ccc(-c2ccc3c(C)c(OC)ccc3c2)cc1
Temperature: 25 °C
Yield: 88 %

Procedure:
To a solution of 2-methoxy-6-(4-methoxyphenyl)-1-bromonaphthalene in THF (25 mL) at 0° C. was slowly added n-butyl lithium (2 mL of 2.5N) and TMEDA (0.60 g, 5.13 mmol, freshly distilled from KOH). After thirty minutes at 0° C. iodomethane (7.3 g, 51.3 mmol, passed through basic alumina) was added and the stirring solution was allowed to warm to room temperature overnight. The reaction was poured into water (100 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with water, dried over magnesium sulfate, filtered, evaporation of the solvent, and purification by silica column chromatography (5% THF-hexanes) yielded 0.63 g (88%) of a white solid: mp 136-138° C.; 1H NMR (CDCl3): δ 3.87 (3H, s), 3.96 (3H, s), 7.02 (2H, d, J=8.74 Hz), 7.29 (1H, d, J=9.01 Hz), 7.60-7.80 (4H, m), 7.95 (1H, d, J=1.76 Hz), 8.00 (1H, d, J=8.86 Hz); MS (ESI) m/z279 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:8]=[C:7](S(C)(=O)=O)[CH:6]=[CH:5][C:3]=1[NH2:4].[C:13]([O-])(=[O:15])[CH3:14].[NH4+]>>[C:13]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:2]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: CS(=O)(=O)c1ccc(N)c(Cl)c1
Agent: [NH4+]
Product: CC(=O)Nc1ccccc1

Procedure:
2-Chloro-4-methylsulfonylaniline (2.06 g.) is diazotized and coupled with 3-(N-cyclohexyl-N-ethylamino)acetanilide (2.60 g.) in 40 ml. of 1:5 acid as described in Example 9, except that the coupling is buffered by the addition of ammonium acetate after the diazonium solution is added to the coupler. This azo compound, 2-(2-chloro-4-methylsulfonylphenylazo)-5-N-cyclohexyl-N-ethylamino)acetanilide, produces bright scarlet shades on polyester fibers.