Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:17])[CH:6]=[C:7]([CH3:16])[C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.N1C=CC=CC=1.[F:24][C:25]([F:31])([F:30])[S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:17][S:26]([C:25]([F:31])([F:30])[F:24])(=[O:28])=[O:27])[CH:6]=[C:7]([CH3:16])[C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1cc(O)cc(C)c1CN1CCCCC1
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(OS(=O)(=O)C(F)(F)F)cc(C)c1CN1CCCCC1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
To a stirred solution 3-methoxy-5-methyl-4-piperidin-1-ylmethylphenol (563 mg, 2.4 mmol) and pyridine (0.77 mL, 10.0 mmol) in DCM (20 mL) at 0° C. was added trifluoromethanesulfonyl chloride (0.81 mL, 4.8 mmol). After the addition was complete the reaction was allowed to warm to ambient temperature. The mixture was diluted with DCM (20 mL) and washed with water (10 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford an oil that was purified by flash chromatography (silica, 40 g column, ISCO, 0-100% ethyl acetate in cyclohexane) to afford the title compound as a red oil (698 mg, 58%). NMR (CDCl3, 300 MHz): 6.82 (d, J=2.4 Hz, 1H), 6.73 (d, J=2.4 Hz, 1H), 4.28 (s, 2H), 3.96 (s, 3H), 3.67-3.35 (m, 1H), 2.99-2.66 (m, 1H), 2.47 (s, 3H), 2.21-1.75 (m, 4H), 1.73-1.35 (m, 4H).
Reaction SMILES: CNC1N=C(C2C=CC=CN=2)C=C(C2C=NC=CC=2)C=1[C:21]1[CH:22]=[N:23][N:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=1.Br[C:33]1[CH:34]=[C:35]([C:39]2[CH:44]=[C:43]([NH:45][CH3:46])[N:42]=[C:41]([C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[N:48]=3)[CH:40]=2)[CH:36]=[N:37][CH:38]=1>>[CH3:46][NH:45][C:43]1[N:42]=[C:41]([C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[N:48]=2)[CH:40]=[C:39]([C:35]2[CH:36]=[N:37][CH:38]=[C:33]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)[CH:34]=2)[CH:44]=1
Reactant: CNc1cc(-c2cncc(Br)c2)cc(-c2cccc(C)n2)n1
Reactant: CNc1nc(-c2ccccn2)cc(-c2cccnc2)c1-c1cnn(C2CCNCC2)c1
Product: CNc1cc(-c2cncc(-c3cnn(C4CCNCC4)c3)c2)cc(-c2cccc(C)n2)n1

Procedure:
This compound is prepared analogously to Methyl-[5″-(1-piperidin-4-yl-1H-pyrazol-4-yl)-[2,2′;4′,3″]terpyridin-6′-yl]-amine (Example 2.183) by replacing (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (Example 2.1, step1) with (5″-Bromo-6-methyl-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (Example 1.27).
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17](B(O)O)=[CH:18]4)=[CH:13][C:12]=3[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[C:33]1[S:37][C:36]([C:38]([O:40][CH3:41])=[O:39])=[CH:35][CH:34]=1>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:33]5[S:37][C:36]([C:38]([O:40][CH3:41])=[O:39])=[CH:35][CH:34]=5)=[CH:18]4)=[CH:13][C:12]=3[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: OB(O)c1ccc2cc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)cc2c1
Reactant: COC(=O)c1ccc(Br)s1
Product: COC(=O)c1ccc(-c2ccc3cc(OCc4ccccc4)c(C45CC6CC(CC(C6)C4)C5)cc3c2)s1
Yield: 65.5 %

Procedure:
Following the procedure of Example 1(c), but reacting 1.5 g (3.6 mmol) of 7-(l-adamantyl)-6-benzyloxy-2-naphthylboronic acid with 400 mg (1.8 mmol) of methyl 5-bromo-2-thiophenecarboxylate, 600 mg (65%) of the expected compound were obtained, which compound had a melting point of 170°-1° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[C:28]([O:32][C:33]([NH:35][C:36]1[CH:44]=[C:43]2[C:39]([CH2:40][N:41]([CH2:46][C:47](O)=[O:48])[C:42]2=[O:45])=[CH:38][CH:37]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[C:28]([O:32][C:33]([NH:35][C:36]1[CH:44]=[C:43]2[C:39]([CH2:40][N:41]([CH2:46][C:47]([O:10][C@H:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]4[CH2:25][CH2:24]4)[CH:12]=3)[CH2:8][C:7]3[C:6]([Cl:26])=[CH:5][N+:4]([O-:27])=[CH:3][C:2]=3[Cl:1])=[O:48])[C:42]2=[O:45])=[CH:38][CH:37]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(=O)N(CC(=O)O)C2
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (Compound 7, 60 mg, 0.143 mmol), 2-(6-(tert-butoxycarbonylamino)-1-oxoisoindolin-2-yl)acetic acid (65.6 mg, 0.214 mmol), DMAP (20.93 mg, 0.171 mmol), and EDC (82 mg, 0.428 mmol) were dissolved in DMF (5 ml). The reaction was stirred at RT overnight. The reaction mixture was diluted with water, and the precipitate was washed with water, dissolved in EtOAc and extracted with HCl 1N, Na2CO3 sat. sol. and brine. The organic phase was dried over Na2SO4 and concentrated under vacuum to give (S)-4-(2-(2-(6-(tert-butoxycarbonylamino)-1-oxoisoindolin-2-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (70 mg, 0.099 mmol, 69% yield). MS/ESI+ 306.12 [MH]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[N-:11]=[N+:12]=[N-:13].[Na+].C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[N:11]=[N:12][NH:13][N:10]=2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Fc1ccc(Cc2nn[nH]n2)cc1
Temperature: 90 °C

Procedure:
To a solution of (4-fluorophenyl)acetonitrile (5.00 g, 37.0 mmol) in 100 mL of toluene was added sodium azide (7.22 g, 111 mmol), triethylamine (15.5 mL, 111 mmol), and concentrated aqueous HCl solution (9.25 mL, 111 mmol). The reaction was heated at 90° C. overnight. The solution was cooled to room temperature and extracted with water and 1N NaOH solution. The combined aqueous layers were washed with ether (3×), acidified with concentrated aqueous HCl solution, and the resulting precipitate was collected by filtration and rinsed with 0.1N HCL solution. The resulting solid was azeotroped from toluene to provide 5-(4-fluorobenzyl)-2H-tetrazole. ESI+MS: 178.9 [M+H]+.
Reaction SMILES: [I-:1].[CH2:2]([C:6]1[CH:15]=[CH:14][C:13]2[N+:12]3[CH:16]=[C:17]4[CH:26]=[CH:25][C:24]5[CH:23]=[C:22](F)[CH:21]=[CH:20][C:19]=5[N:18]4[C:11]=3[CH:10]=[CH:9][C:8]=2[CH:7]=1)[CH2:3][CH2:4][CH3:5].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.CN1CCCC1=O>CCOCC>[I-:1].[CH2:2]([C:6]1[CH:15]=[CH:14][C:13]2[N+:12]3[CH:16]=[C:17]4[CH:26]=[CH:25][C:24]5[CH:23]=[C:22]([N:28]6[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]6)[CH:21]=[CH:20][C:19]=5[N:18]4[C:11]=3[CH:10]=[CH:9][C:8]=2[CH:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ccc2c(ccc3n4c(ccc5cc(F)ccc54)c[n+]23)c1
Reactant: C1CCNCC1
Agent: [I-]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: CCCCc1ccc2c(ccc3n4c(ccc5cc(N6CCCCC6)ccc54)c[n+]23)c1

Procedure:
A mixture of 4.7 g. of 3-butyl-10-fluoroimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide, 5.0 ml. of piperidine and 50 ml. of N-methyl-2-pyrrolidinone is heated at reflux for 16 hours, then cooled and diluted with 400 ml. of ether. The resulting precipitate of 3-butyl-10-(1-piperidinyl)imidazo[1,2-a:3,4-a']diquinolin-15-ium iodide is collected by filtration; m.p. 266°-267° C. (dec.), after crystallization from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:18][CH2:17][CH2:16][CH:15]=[C:14]2[C:13](=[O:19])[NH:12][C:11](=[O:20])[CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH:23]1([CH2:27]CS([O-])(=O)=O)[CH2:26][CH2:25][CH2:24]1>CN(C)C=O>[CH:23]1([CH2:27][N:12]2[C:11](=[O:20])[CH2:10][C:9]3([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[C:14](=[CH:15][CH2:16][CH2:17][CH2:18]3)[C:13]2=[O:19])[CH2:26][CH2:25][CH2:24]1
Reactant: O=S(=O)([O-])CCC1CCC1
Reactant: COc1cccc(C23CCCC=C2C(=O)NC(=O)C3)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(C23CCCC=C2C(=O)N(CC2CCC2)C(=O)C3)c1
Reaction time: 10 h

Procedure:
The procedure in Example 9, Part A was followed in which 4a-(m-methoxyphenyl)-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline (10.74 g) in 135 ml of anhydrous dimethylformamide was added to a 55% suspension of sodium hydride in mineral oil (2.15 g) in 90 ml of dimethylformamide at 70° C. Cyclobutylmethylmesylate (9 g) was added and the reaction heated at 80°-90° C. for 6 hours, then at 25° C. for 10 hours. This gave, after chromatography, a crystalline product (6 g), mp 89°-93° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.CC(C)([O-])C.[Na+].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[N:22]1([C:2]2[N:7]=[C:6]([C:8]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]3[C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNCC1
Reactant: O=C(c1cccc(Br)n1)N1CCCCC1c1cccnc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: O=C(c1cccc(N2CCCCC2)n1)N1CCCCC1c1cccnc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 64.3 %

Procedure:
(6-bromopyridin-2-yl)(2-(pyridin-3-yl)piperidin-1-yl)methanone (60 mg, 0.173 mmol), piperidine (18 mg, 0.208 mmol), Pd2(dba)3 (3 mg, 0.003 mmol), xantphos (6 mg, 0.010 mmol), and sodium-tert-butoxide (25 mg, 0.260 mmol) were suspended in toluene (3 ml), and then stirred at 100° C. under nitrogen stream for 3 hours. A saturated aqueous ammonium chloride solution of (15 ml) was added to the resulting reaction liquid, followed by extraction with MC (15 ml×2). The organic layer was dried over anhydrous magnesium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (90% EtOAc/Hexanes), to obtain 39 mg of pale yellow oil (64%). MS (ESI): 351 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4](Cl)[N:3]=1.C(O)CCC.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1
Reactant: CCC(CC)n1cnc2c(Cl)nc(Cl)nc21
Reactant: Nc1ccccc1
Solvent: CCCCO
Solvent: CC(C)O
Product: CCC(CC)n1cnc2c(Nc3ccccc3)nc(Cl)nc21
Reaction time: 22 h

Procedure:
The operation is carried out as in Stage 2 of Example 3 starting from 200 mg (0.77 mmoles) of the product obtained in Stage 1 of Example 3 and 4 ml of butanol and using 0.088 ml (0.96 mmoles) of aniline in place of the benzylamine. Agitation is carried out at ambient temperature then the reaction medium is taken to a temperature of 80 to 85° C. for 22 hours, left to return to ambient temperature, diluted with 4 ml of isopropanol, left for two days at a temperature of approximately 0° C., followed by separating, washing with 10 ml of isopropanol and drying at a temperature of approximately 50° C.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[ClH:15].C(N(CC)CC)C.[C:23]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].[N:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]2[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44](=O)[NH:43][N:42]=2)=[CH:36][CH:35]=1>ClCCl>[ClH:15].[ClH:15].[C:23]([C:27]1[CH:28]=[CH:29][C:30]([NH:31][C:44]2[C:45]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:41]([CH2:40][C:37]3[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=3)=[N:42][N:43]=2)=[CH:32][CH:33]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: O=c1[nH]nc(Cc2ccncc2)c2ccccc12
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 210 °C
Reaction time: 4.5 h

Procedure:
In the manner described in Example 45, a mixture of 1.80 g (12.68 mmol) phosphorus pentoxide, 1.73 g (12.6 mmol) triethylamine hydrochloride, 1,9 ml (12.5 mmol) 4-tertbutylaniline, and 1 g (4.2 mmol) 4-(4-pyridylmethyl)-1(2H)-phthalazinone is stirred for 4.5 h at 210° C. The frozen melt is then dissolved in dichloromethane using an ultrasonic bath, filtered off from undissolved components, and the filtrate evaporated in the RE. The oil-like residue is distributed between dichloromethane and a mixture of 20 ml water and 5 ml conc. ammonia, and the organic phase dried over anhydrous sodium sulfate, filtered and evaporated under vacuum. The residue is then stirred with 10 ml acetonitrile, filtered off from some non-transformed 4-(4-pyridylmethyl)-1(2H)-phthalazinone, and the filtrate evaporated under vacuum. Flash chromatography of the residue on silica gel with a particle size of 0.04-0.06 mm using a toluene/acetone mixture (7:3) yields a resin (free base of the title compound), which is dissolved in a mixture of 4 ml methanol and 1.5 ml of 3 N methanolic HCl. After evaporation under vacuum, recrystallization of the residue from methanol/ether, drying under HV (6 h, 80° C.), and equilibration for 16 h at 20° C. and in room atmosphere, title compound is obtained with a water content of 4.47%; m.p. 196-200° C.; ESI-MS: (M+H)+=369.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[C@@H:15]([CH:16]([CH3:18])[CH3:17])[CH2:14][NH:13][C:12]3=[O:19])=[N:7][C:6]=12.CS(O[CH2:25][C@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])(=O)=O>>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[C@@H:15]([CH:16]([CH3:17])[CH3:18])[CH2:14][N:13]([CH2:25][C@H:26]4[CH2:30][CH2:29][CH2:28][N:27]4[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[C:12]3=[O:19])=[N:7][C:6]=12
Reactant: CC(C)[C@H]1CNC(=O)N1c1ccn2ncc(Br)c2n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COS(C)(=O)=O
Product: CC(C)[C@H]1CN(C[C@H]2CCCN2C(=O)OC(C)(C)C)C(=O)N1c1ccn2ncc(Br)c2n1
Yield: 50 %

Procedure:
(R)-tert-butyl 2-(((S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrrolidine-1-carboxylate (94 mg, 50%) was prepared by the procedure described in Example 38, Step 1, using (S)-1-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-5-isopropylimidazolidin-2-one and (R)-tert-butyl 2-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:18]([O:20][C:21](=[O:47])[CH2:22][C:23]1([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35](B4OC(C)(C)C(C)(C)O4)=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)[CH2:25][CH2:24]1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:47])[CH2:22][C:23]1([C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:2]4[S:3][CH:4]=[CH:5][C:6]=4[CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:34][CH:33]=3)=[CH:30][CH:31]=2)[CH2:24][CH2:25]1)[CH3:19]
Reactant: CCOC(=O)CC1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Reactant: OC(CCCc1ccccc1)c1ccsc1Br
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4sccc4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 2, using the following starting materials: 1-(2-bromo-thiophen-3-yl)-4-phenyl-butan-1-ol and {1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([N+:13]([O-:15])=O)=[C:8]([NH2:12])[CH:9]=2)[CH2:4]1.[N:17]#[C:18][NH2:19].[CH]Cl.[OH-].[Na+]>O>[CH3:16][N:2]([CH3:1])[CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]3[N+:13]([O-:15])=[N:17][C:18]([NH2:19])=[N:12][C:8]=3[CH:9]=2)[CH2:4]1
Reactant: CN(C)C1Cc2cc(N)c([N+](=O)[O-])cc2C1
Reactant: N#CN
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)C1Cc2cc3nc(N)n[n+]([O-])c3cc2C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 43.6 %

Procedure:
A mixture of nitroaniline 110 (0.50 g, 2.3 mmol) and cyanamide (0.4 g, 9.0 mmol) were mixed together at 80° C., cHCl (5 mL) added dropwise and the mixture heated at 100° C. for 3 h. A further aliquot of cyanamide (0.4 g, 9.0 mmol) and cHCl (1 mL) was added and the mixture stirred at 100° C. for 1 h. The mixture was cooled to 50° C., 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100° C. for 3 h. The mixture was cooled, diluted with water (30 mL), filtered, washed with water (2×10 mL), and dried. The residue was filtered through a short plug of silica, eluting with 10% MeOH/DCM, and the solvent evaporated to give 1-oxide 111 (246 mg, 44%) as a yellow powder: mp (MeOH/DCM) 212-216° C.; 1H NMR [(CD3)2SO] δ 7.93 (s, 1H, H-9), 7.34 (s, 1H, H-5), 7.11 (br s, 2H, NH2), 3.03-3.18 (m, 3H, H-7, CH2), 2.79-2.89 (m, 2H, CH2), 2.22 [s, 6H, N(CH3)2]; 13C NMR [(CD3)2SO] δ 159.9, 152.0, 148.6, 140.5, 128.9, 120.0, 114.1, 67.0, 43.2 (2), 37.0, 36.1. Anal. calcd for C12H15N5O.½H2O: C, 56.7; H, 6.3; N, 27.5. Found: C, 56.9; H, 6.0; N, 27.4%.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][C:29]1[NH:33][CH:32]=[N:31][C:30]=1[C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1>>[CH3:28][C:29]1[NH:33][CH:32]=[N:31][C:30]=1[C:34]1[CH:40]=[CH:39][C:37]([NH:38]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:36][CH:35]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: Cc1[nH]cnc1-c1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(-c2nc[nH]c2C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(5-methyl-imidazol-4-yl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol/ammonia=10:1:0.01) C27H22N4O3
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH2:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:54]/[O:55][CH3:56])/[C:12]([NH:14][CH:15]2[C:52](=[O:53])[N:17]3[C:18]([C:36]([O:38]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:37])=[C:19]([C:22]4[C:25](=[O:26])[C:24](=[O:27])[C:23]=4[O:28]CC4C=CC=CC=4)[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1.C1(OC)C=CC=CC=1>[N+](C)([O-])=O.C(Cl)Cl.Cl>[NH2:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:54]/[O:55][CH3:56])/[C:12]([NH:14][CH:15]2[C:52](=[O:53])[N:17]3[C:18]([C:36]([OH:38])=[O:37])=[C:19]([C:22]4[C:23](=[O:28])[C:24](=[O:27])[C:25]=4[OH:26])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(OCc4ccccc4)c(=O)c3=O)CS[C@H]12)c1csc(N)n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(c3c(O)c(=O)c3=O)CS[C@H]12)c1csc(N)n1
Reaction time: 2 h
Yield: 7.7 %

Procedure:
A solution of aluminum chloride (82 mg, 0.612 mmol) in nitromethane (1 mL) was added rapidly to a stirred, cooled (ice/H2O bath) solution of diphenylmethyl 7-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(2-benzyloxy-3,4-dioxo-1-cyclobutenyl)-3-cephem-4-carboxylate (50 mg, 0.068 mmol) and anisole (66 mg, 0.612 mmol) in CH2Cl2 (1 mL). The mixture was stirred with cooling for 0.33 hr and then for 2 hrs at ambient temperatures. The solution was cooled and diluted with dilute aqueous hydrochloric acid to precipitate a solid which was collected and discarded. The aqueous filtrate was washed with ethyl acetate. The aqueous layer was applied to a Michel-Miller HPLPLC column (22×130 mm) containing Partisil Prep 40 ODS-3. The column was eluted with a mixture of H2O-acetonitrile-acetic acid (90:10:0.5). The appropriate fractions were combined and the organic solvents removed. Lyophilization of the aqueous solution afforded the title compound (2.5 mg, 7.7 % yield) as a bright yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][CH:12]([CH2:15][CH3:16])[CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+]>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][OH:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCC(N)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCC(CO)Nc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 223.0 g (1.58 mol) of 1-fluoro-4-nitrobenzene, 168.5 g (1.89 mol) of 2-amino-1-butanol and 146.8 g (1.06 mol) of potassium carbonate in 630 ml of water was refluxed for 2 hours.
Reaction SMILES: O.O.[Sn](Cl)Cl.Cl.[C:7]([C:11]1[CH:12]=[C:13]([CH:29]=[CH:30][CH:31]=1)[O:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][C:18]([N+:25]([O-])=O)=[C:17]([CH3:28])[CH:16]=1)([CH3:10])([CH3:9])[CH3:8]>CO>[C:7]([C:11]1[CH:12]=[C:13]([CH:29]=[CH:30][CH:31]=1)[O:14][C:15]1[C:20]([C:21]([F:24])([F:22])[F:23])=[CH:19][C:18]([NH2:25])=[C:17]([CH3:28])[CH:16]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: Cc1cc(Oc2cccc(C(C)(C)C)c2)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: Cc1cc(Oc2cccc(C(C)(C)C)c2)c(C(F)(F)F)cc1N
Temperature: 25 °C
Yield: 63.5 %

Procedure:
Initially, at room temperature, 37.55 g (166.41 mmol) of tin(II) chloride dihydrate and then, with ice-cooling and slowly, 100 ml of concentrated hydrochloric acid are added to a solution of 19.60 g (55.47 mmol) of 4-(3-tertbutylphenoxy)-5-trifluoromethyl-2-methylnitrobenzene in 100 ml of methanol. The mixture is heated under reflux for 4 h, cooled to room temperature, concentrated, water is added and the residue is filtered off and dried under reduced pressure. The crude product is purified by column chromatography. (13.2 g, purity 86%, yield 63.5%, log P (pH 2.3)=4.67).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:40])([CH3:39])[CH2:9][C:10]2[N:11]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=[C:13]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[N:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:47][N:48]1[CH:52]=[C:51](B2OC(C)(C)C(C)(C)O2)[CH:50]=[N:49]1>C1(C)C=CC=CC=1.CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:13]1[N:14]=[C:10]([CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:51]3[CH:50]=[N:49][N:48]([CH3:47])[CH:52]=3)=[CH:3][CH:4]=2)([OH:40])[CH3:39])[N:11]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:12]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(C)(O)c2ccc(Br)cc2)n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cn1cc(-c2ccc(C(C)(O)Cc3nc(CC(C)(C)C)cn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)cn1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Palladium tetrakis(triphenylphosphine) (50 mg, 0.04 mmol) was added to a degassed, ambient temperature solution of 2-(4-bromophenyl)-1-[4-(2,2-dimethylpropyl)-1-trityl-1H-imidazol-2-yl]propan-2-ol (500 mg, 0.84 mmol), potassium carbonate (151 mg, 1.1 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (193 mg, 0.9 mmol) in toluene/methanol (10:1) (4.4 mL). After stirring at 90° C. for 2 hr, the reaction mixture was washed with water and brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 20-100% ethyl acetate/hexane afforded 1-[4-(2,2-dimethylpropyl)-1-trityl-1H-imidazol-2-yl]-2-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]propan-2-ol.