Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21]N1C(OCC1C=CC=CC=1)=O.FC(F)(F)C(O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrCCCCCCC1C[CH2:72][N:71]([C:74]([O:76][CH2:77][C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)=[O:75])[CH2:70][CH2:69]1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:24][CH2:23][CH:22]1[CH2:21][CH2:72][N:71]([C:74]([O:76][CH2:77][C:78]2[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=2)=[O:75])[CH2:70][CH2:69]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Reactant: O=C(OCc1ccccc1)N1CCC(CCCCCCBr)CC1
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate and phenylmethyl 4-(6-bromohexyl)-1-piperidinecarboxylate. LCMS (System B): tRET=3.52 min; MH+ 539
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([CH3:19])[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][O:27][C:28]4[CH:41]=[CH:40][C:31]5[C@H:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:33][O:34][C:30]=5[CH:29]=4)[CH:21]=3)=[C:15]([CH3:42])[CH:14]=2)[CH2:9]1.C(N(CC)CC)C.[CH:50]1([C:53](Cl)=[O:54])[CH2:52][CH2:51]1>ClCCl>[CH:50]1([C:53]([N:8]2[CH2:11][CH:10]([O:12][C:13]3[CH:14]=[C:15]([CH3:42])[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][O:27][C:28]5[CH:41]=[CH:40][C:31]6[C@H:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:33][O:34][C:30]=6[CH:29]=5)[CH:21]=4)=[C:17]([CH3:19])[CH:18]=3)[CH2:9]2)=[O:54])[CH2:52][CH2:51]1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CNC5)cc4C)c3)ccc21
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CN(C(=O)C6CC6)C5)cc4C)c3)ccc21
Reaction time: 12 h
Yield: 94.4 %

Procedure:
The crude (S)-methyl 2-(6-((4′-(azetidin-3-yloxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 2,2,2-trifluoroacetate 14c (40 mg, 0.09 mmol) was dissolved in 3 mL of dichloromethane, followed by addition of triethylamine (0.1 mL, 0.26 mmol) and cyclopropanecarbonyl chloride 15a (14 mg, 0.13 mmol). The reaction solution was stirred for 12 hours. The resulting solution was mixed with 10 mL of dichloromethane, washed with saturated sodium chloride solution (5 mL), dried with anhydrous magnesium sulphate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound (S)-methyl 2-(6-((4′-((1-(cyclopropanecarbonyl)azetidin-3-yl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 15b (46 mg) as a red oil, which was directly used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([O:18][CH2:19][CH3:20])[CH:9]=2)[CH:5]=[C:4]([C:21]([F:24])([F:23])[F:22])[N:3]=1.[Br:25][C:26]1[N:27]=[CH:28][NH:29][CH:30]=1>>[Br:25][C:26]1[N:27]=[CH:28][N:29]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([O:18][CH2:19][CH3:20])[CH:9]=3)[CH:5]=[C:4]([C:21]([F:24])([F:23])[F:22])[N:3]=2)[CH:30]=1
Reactant: CCOc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F
Reactant: Brc1c[nH]cn1
Product: CCOc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chloro-4-(3-ethoxy-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example A.10) (0.5 g, 1.35 mmol) and commercially available 4-bromo-imidazole (0.30 g, 2.02 mmol) according to the general procedure IVa. Obtained as a white solid (0.47 g, 72%). MS (ISP) 483.0 [(M+H)+]; mp 147.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl.[Cl:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[CH:20][C:21]=1[Cl:22].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:15][C:16]1[CH:17]=[C:18]([S:23]([N:11]2[CH2:12][CH2:13][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH2:9][CH2:10]2)(=[O:24])=[O:25])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Fc1ccccc1N1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)c(Cl)c1)N1CCN(c2ccccc2F)CC1
Yield: 85.8 %

Procedure:
Sulfonylation of 1-(2-fluorophenyl)piperazine.HCl (325 mg, 1.5 mmol) with 3,4-dichlorobenzene-1-sulfonyl chloride (368.3 mg, 1.5 mmol) was carried out according to a similar procedure described for step 1A using anhydrous dichloromethane (3 mL) as solvent and diisopropylethylamine (0.575 mL, 3.3 mmol) as base. 1-[(3,4-dichlorophenyl)sulfonyl]-4-(2-fluorophenyl)piperazine was obtained in 85.8% yield (501 mg) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[OH:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.C([BH3-])#N.[Na+].Cl>C(O)(=O)C.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:32][C:31]4[CH:34]=[CH:35][C:28]([OH:27])=[CH:29][CH:30]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccc(O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (15 mg, 0.045 mmol), in 10-20% acetic acid in anhydrous methanol (0.20 mL)was added p-hydroxybenzaldehyde (16 mg, 0.14 mmol) and a freshly prepared solution of sodium cyanoborohydride (4.0 mg, 0.060 †mmol) in anhydrous methanol (0.24 mL). The mixture was shaken at room temperature for 14-18 h and then loaded onto an ion exchange resin (SCX, Varian). Elution with methanol (4 column volumes) followed by 2 N ammonia in methanol (2 column volumes) and concentration of the appropriate fractions provided the crude product. After drying the sample under vacuum for 12-20 h, the residue was dissolved in methanol and treated with hydrochloric acid (1-2 eq). The mixture was then concentrated in vacuo to give the title compound as the hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[N:7]3[N:13]=[C:14]([CH3:16])[CH:15]=[C:6]3[NH:5][C:4]=2[CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[N:7]3[N:13]=[C:14]([CH3:16])[CH:15]=[C:6]3[N:5]([CH3:17])[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc2[nH]c3cc(Cl)ncc3c(=O)n2n1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cc2n(C)c3cc(Cl)ncc3c(=O)n2n1
Reaction time: 24 h

Procedure:
23.5 g. of 6-chloro-2-methylpyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one of Example 3 are suspended in 200 ml. of dimethylformamide. 20 g. of potassium carbonate and 16 g. of methyl iodide are added. The mixture is stirred at 80° for 24 hours. After this time, the mixture is cooled and the precipitate filtered off. The crystalline product, 6-chloro-2,4-dimethylpyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one is washed several times with water and then recrystallized from dimethylformamide, yield: 18 g. (72%); m.p. >300°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10]3[N:11]([C:16]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][C:23]=4[F:28])=[O:20])=[CH:17][N:18]=3)[N:12]=[C:13](Cl)[CH:14]=2)[CH:5]=[C:4]([Cl:29])[CH:3]=1.[C@H:30]1([NH2:37])[CH2:35][CH2:34][C@H:33]([NH2:36])[CH2:32][CH2:31]1>CN1C(=O)CCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10]3[N:11]([C:16]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][C:23]=4[F:28])=[O:20])=[CH:17][N:18]=3)[N:12]=[C:13]([NH:36][C@H:33]3[CH2:34][CH2:35][C@H:30]([NH2:37])[CH2:31][CH2:32]3)[CH:14]=2)[CH:5]=[C:4]([Cl:29])[CH:3]=1
Reactant: Nc1cc(Cl)cc(Nc2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)n1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CN1CCCC1=O
Product: Nc1cc(Cl)cc(Nc2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)n1
Temperature: 110 °C

Procedure:
A mixture of 8-(6-amino-4-chloropyridin-2-ylamino)-6-chloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (42 mg, 0.073 mmol) and trans-cyclohexane-1,4-diamine (74.2 mg, 0.650 mmol) in NMP (0.4 mL) was heated at 110° C. overnight. The reaction mixture was then cooled to room temperature and purified by reversed-phase HPLC. The fractions containing the title compounds were lyophilized to dryness to afford 8-((6-amino-4-chloro-2-pyridinyl)amino)-6-((trans-4-aminocyclohexyl)amino)-N-(3-fluoro-4-pyridinyl)imidazo[1,2-b]pyridazine-3-carboxamide (16.5 mg, 25%). HPLC Rt=2.813 minutes (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm), [M+H]=511.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=2[F:27])[CH2:14][CH2:13]1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH2:28]([N:9]1[CH2:10][CH2:11][C:5]2[C:6](=[N:7][C:2]([Cl:1])=[C:3]([N:12]3[CH2:13][CH2:14][CH:15]([O:18][C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=4[F:27])[CH2:16][CH2:17]3)[N:4]=2)[CH2:8]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(OC2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1ccc(OC2CCN(c3nc4c(nc3Cl)CN(Cc3ccccc3)CC4)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl bromide was purified by filtration through a plug of basic alumina prior to use. A solution of 4-((1-(3-chloropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)oxy)-3-fluorobenzonitrile (200 mg, 0.521 mmol) and benzyl bromide (0.062 mL, 0.521 mmol) in ACN (2.60 mL) was heated at 80° C. for 3 h. The reaction mixture was allowed to cool to room temperature and sodium triacetoxyborohydride (331 mg, 1.563 mmol) was added. After stirring for 1 h at room temperature, the reaction mixture was quenched with saturated aqueous NaCl (1 mL). After bubbling ceased, the reaction mixture was purified by HPLC Method B, with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column was used, using a 35% to 70% ACN gradient to give the title compound, as a TFA salt, as a yellow oil (117.9 mg, 38.2%). ESI-MS m/z [M+H]+ 478.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:14]1[NH:15][C:16]([CH2:23][CH2:24][C:25](O)=O)=[C:17]2[C:22]=1[CH2:21][CH2:20][CH2:19][CH2:18]2.Cl[C:29]1C=CC(C2CCNCC2)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:25][CH2:24][CH2:23][C:16]3[N:15]([CH3:29])[N:14]=[C:22]4[C:17]=3[CH2:18][CH2:19][CH2:20][CH2:21]4)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1[nH]nc2c1CCCC2
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Clc1ccc(C2CCNCC2)cc1
Product: Cn1nc2c(c1CCCN1CCN(c3ccc(F)cc3)CC1)CCCC2

Procedure:
In the same manner as in Example 102 except that 3-(4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 9 and 1-(4-fluorophenyl)piperazine were used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine, 3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2-methyl-2H-indazole was obtained.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C1COCC1.O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(-c2ccc(C(=O)OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Yield: 71.1 %

Procedure:
A mixture of methyl 4-(4-butylphenyl)benzoate (89.0 g, 0.332 mol), NaOH (26.6 g, 0.664 mol) in THF/H2O (500 mL/100 mL) was heated to reflux overnight. After TLC showed the reaction was complete, THF was removed. The residue was adjusted pH ˜3-4 with 2 N HCl solution. The resulting mixture was filtered and the cake was washed with water, dried to give 4-(4-butylphenyl)benzoic acid (60.0 g, yield: 71.1%), as a white solid. (ESI) m/z 255.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[F:49][C:50]1[CH:58]=[C:57]([F:59])[C:56]([F:60])=[CH:55][C:51]=1[CH:52]([OH:54])[CH3:53]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:54][CH:52]([C:51]2[CH:55]=[C:56]([F:60])[C:57]([F:59])=[CH:58][C:50]=2[F:49])[CH3:53])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CC(O)c1cc(F)c(F)cc1F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC(C)c4cc(F)c(F)cc4F)cc3)c2cc1OC
Temperature: 25 °C
Yield: 52.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (87 mg) was added to toluene/triethylamine=10/1 (9 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (130 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2,4,5-trifluoro-α-methylbenzyl alcohol (80 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (77 mg, yield 49%).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[NH3:21]>C(Cl)Cl.CO>[NH2:21][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CBr)c2F)c1
Reactant: N
Solvent: CO
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reaction time: 2 h
Yield: 84 %

Procedure:
3-{[3-(Bromomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (1.0 g, 2.6 mmol) was dissolved in CH2Cl2 (5 mL) and added dropwise to ammonia in methanol (7N, 25 mL). The reaction mixture was stirred for 2 h then the solvent was evaporated. The resulting oil was purified by column chromatography (CH-2Cl2/MeOH) to afford the title compound (0.7 g, 84%). 1H NMR (400 MHz, DMSO-d6): δ ppm 7.79 (s, 2H), 7.45-7.56 (m, 4H), 7.42 (t, 1H), 3.75 (s, 2H). MS: m/z 311.1 (M+1).
Reaction SMILES: [Si]([N:5]=[N+:6]=[N-:7])(C)(C)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[C:11]([O:18][CH:19]([CH3:21])[CH3:20])[CH:10]=1>CCOC(C)=O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:16](=[O:17])[NH:7][N:6]=[N:5]2)=[C:11]([O:18][CH:19]([CH3:21])[CH3:20])[CH:10]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)Oc1cc(F)ccc1N=C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(F)ccc1-n1nn[nH]c1=O
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 81 %

Procedure:
This reaction with TMS-N3 was performed behind a blast shield. The crude 4-fluoro-1-isocyanato-2-isopropoxybenzene was placed under argon and trimethylsilylazide (16 mL, 118.2 mmol, 2 equiv) was added. The reaction mixture was heated to refluxed for ON under argon. After cooling to RT, the reaction mixture was concentrated under vacuum, and the residue was charged with saturated NaHCO3 (100 mL) and stirred vigorously for 5-10 min, then the basic reaction mixture was diluted with EtOAc. The layers were separated, and the organic layer was monitored by TLC to confirm that all the product had been extracted by the saturated NaHCO3 solution. EtOAc was added to the combined basic aqueous extracts, and the pH was adjusted to <3 using 6N HCl. The aqueous and organic layers were partitioned, and the aqueous layer was extracted with EtOAc 3×. The combined organic layers were dried over Na2SO4, filtered, and the solvent removed under vacuum to provide 1-(4-fluoro-2-isopropoxyphenyl)-1H-tetrazol-5(4H)-one (11.4 g, 81%) as a brown oil that was used without further purification.
Reaction SMILES: [I:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([N+:11]([O-])=O)=[CH:10][C:5]=2[O:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>[Fe].O1CCCC1.CO.O>[I:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc2c(I)c(-c3ccccc3)oc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc2c(I)c(-c3ccccc3)oc2c1
Temperature: 25 °C
Yield: 100 %

Procedure:
In a round bottom flask were combined 3-iodo-6-nitro-2-phenylbenzofuran (3.65 g, 10.0 mmol), ammonium chloride (0.802 g, 15.00 mmol) and iron powder (2.79 g, 50.0 mmol). To this was added a mixture of tetrahydrofuran/methanol/water (1:1:2 v-v, 100 mL). The mixture was heated to reflux for a total of four hours. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was dried (Na2SO4) filtered and concentrated to give the title compound 3.35 gm (100%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[C:13]([C:20]([O:22]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:21])=[C:14]([C:17](=[O:19])[CH3:18])[CH2:15][S:16][C@H:11]12)=[O:8].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>CCCCCCC>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[C:13]([C:20]([OH:22])=[O:21])=[C:14]([C:17](=[O:19])[CH3:18])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: CC(=O)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: CCCCCCC
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)C1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 5 °C

Procedure:
To a cooled (5° C.) stirred slurry of 0.100 g. of benzhydryl 7-(2-thienylacetamido)-3-acetyl-3-cephem-4-carboxylate in 1 ml. of anisole was added 1 ml. of cold trifluoroacetic acid. The ester immediately dissolved. The resulting colorless solution was stirred with cooling for 20 minutes after which time approximately 40 ml. of n-heptane was added. The resulting solution was evaporated in vacuo to a low volume causing the precipitation of a white solid. The solid was filtered from the mixture and subsequently dissolved in acetone. The acetone solution was filtered and then evaporated in vacuo to dryness. The residue was dissolved in ethyl acetate, and the resulting solution was extracted three times with cold sodium bicarbonate solution. The aqueous extracts were combined, layered with ethyl acetate and acidified with 1N.HCl. The ethyl acetate layer was separated, washed with brine and dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness gave 0.067 g. of the title product as a pale yellow solid which failed to crystallize from methylene chloride-hexane:
Reaction SMILES: [CH:1]([C:3]1[CH:52]=[CH:51][C:6]([C:7]([O:9][CH2:10][O:11][C:12]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([CH2:23][C:24]([NH:37][C:38]([O:40][CH2:41][C:42]3[O:43][C:44]4[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=4[CH:46]=3)=[O:39])([C:26](=[O:36])[NH:27][CH:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH3:29])[CH3:25])=[CH:15]2)=[O:13])=[O:8])=[CH:5][CH:4]=1)=O.[CH3:53][N:54]([CH3:59])[CH2:55][CH2:56][NH:57][CH3:58].C(O)(=O)C.C(=O)(O)[O-].[Na+].C(Cl)(Cl)[Cl:70]>>[ClH:70].[ClH:70].[CH3:53][N:54]([CH3:59])[CH2:55][CH2:56][N:57]([CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][O:11][C:12]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([CH2:23][C:24]([NH:37][C:38]([O:40][CH2:41][C:42]3[O:43][C:44]4[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=4[CH:46]=3)=[O:39])([C:26](=[O:36])[NH:27][CH:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH3:29])[CH3:25])=[CH:15]2)=[O:13])=[O:8])=[CH:51][CH:52]=1)[CH3:58]
Reactant: CC(NC(=O)C(C)(Cc1cn(C(=O)OCOC(=O)c2ccc(C=O)cc2)c2ccccc12)NC(=O)OCc1cc2ccccc2o1)c1ccccc1
Reactant: ClC(Cl)Cl
Reactant: CNCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(NC(=O)C(C)(Cc1cn(C(=O)OCOC(=O)c2ccc(CN(C)CCN(C)C)cc2)c2ccccc12)NC(=O)OCc1cc2ccccc2o1)c1ccccc1
Product: Cl
Reaction time: 0.5 h
Yield: 84 %

Procedure:
NaHB(OAc)3 (0.21 g, 1.0 mmol, 1.4 eq.) was added in three equal portions in 10 minutes to a cloudy solution of compound 19 (0.5 g, 0.713 mmol), N,N,N′-trimethylethylenediamine (0.316 mL, 1.07 mmol, 1.5 eq.) and acetic acid (0.061 mL, 1.07 mmol, 1.5 eq.) in dry chloroform (20 mL) under N2 in an ice bath. The reaction was stirred in ice bath for 30 minutes and room temperature for 20 hours to give a white suspension. Saturated sodium bicarbonate (20 mL) was added to the reaction mixture and stirred for 30 minutes. The organic layer was washed with saturated sodium bicarbonate (30 mL), saturated sodium chloride and dried over anhydrous sodium sulfate. The product was further purified by silica gel chromatography (2.5×6 cm) eluting with CHCl3/MeOH (10:0.5) to give compound 20f as a white foam (0.47 g, 84%).
Reaction SMILES: COC1C=CC(COC([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:33])[CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])[CH2:13][CH2:12]2)=O)=CC=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[N+:30]([C:27]1[CH:26]=[CH:25][C:24]([CH2:23][O:22][C:20]([NH:19][CH2:18][C:17]([N:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)=[O:33])=[O:21])=[CH:29][CH:28]=1)([O-:32])=[O:31]
Reactant: COc1ccc(COC(=O)N2CCN(C(=O)CNC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(NCC(=O)N1CCNCC1)OCc1ccc([N+](=O)[O-])cc1
Yield: 98.9 %

Procedure:
To 3.74 g of 1-(p-methoxybenzyloxycarbonyl)-4-(2-(p-nitrobenzyloxycarbonyl)aminoacetyl)piperazine were added 4.17 ml of anisole and, with cooling on an ice bath, 20 ml of trifluoroacetic acid, followed by 1 hour of reaction at room temperature. After removing trifluoroacetic acid by evaporation under a reduced pressure, the residue was adjusted to basic with a sodium hydroxide aqueous solution and extracted with chloroform, and an organic layer was washed with water and dried over sodium sulfate, followed by removal of the solvent under a reduced pressure and subsequent addition of n-hexane to a residue to collect a solid material by filtration, thereby obtaining 2.45 g of 1-(2-(p-nitrobenzyloxycarbonyl)aminoacetyl)piperazine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](SC)=[CH:4][C:3]=1[CH3:10].O[O:12][S:13]([O-:15])=O.[K+].S([O-])([O-])=O.[Na+].[Na+].[CH3:23]O.O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:13]([CH3:23])(=[O:15])=[O:12])=[CH:4][C:3]=1[CH3:10]
Reactant: CSc1ccc(Br)c(C)c1
Reactant: CO
Reactant: O=S([O-])OO
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: Cc1cc(S(C)(=O)=O)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a heterogenous solution of (4-bromo-3-methylphenyl)(methyl)sulfane (2.17 g, 9.99 mmol) in 55 mL of 10/1 MeOH/water at 0° C. was added oxone (6.14 g, 9.99 mmol). The solution was allowed to warm up to RT and stirred overnight. Saturated sodium sulfite (aq.) was added and the mixture was extracted with DCM (3×). The combined organic layers were washed with water and NaCl (sat.), dried over sodium sulfate, filtered and concentrated to afford 2.30 g of 1-bromo-2-methyl-4-(methylsulfonyl)benzene 2.30 g as a white solid.