Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[C:18]2[N:19]([CH3:24])[N:20]=[CH:21][C:22]=2[Br:23])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(N(C)C)=O.Cl[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]>CS(C)=O>[CH:35]([O:34][C:32](=[O:33])[NH:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:12]([C:18]2[N:19]([CH3:24])[N:20]=[CH:21][C:22]=2[Br:23])[CH:13]=1)([CH3:37])[CH3:36]
Reactant: CC(C)OC(=O)Cl
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCN1CCCCCC1
Solvent: CS(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)OC(=O)Nc1ccc(OCCN2CCCCCC2)c(-c2c(Br)cnn2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of 4-(2-azepan-1-yl-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenylamine (0.06 g, 0.1539 mmol) 2.0 mL of DMA was added isopropyl chloroformate (0.021 g, 0.1687 mmol), and the mixture was stirred at ambient temperature overnight. The reaction mixture was diluted to 5.0 mL with DMSO and purified by RP-HPLC. The proper fractions were collected and evaporated to ¼ volume and the aqueous was neutralized with 1N NaOH to a pH 9.0. Next, the product was extracted with ethyl acetate (2×, 30 mL). The pooled organic layer was dried with sodium sulfate, filtered and evaporated to dryness to afford [4-(2-Azepan-1-yl-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-carbamic acid isopropyl ester as a colorless solid in 69% yield. LCMS m/z (%)=478 (M+H 79Br, 100), 480 (M+H 81Br, 98). 1H NMR (400 MHz, DMSO-d6) δ: 8.79 (bs, 1H), 8.69 (bs, 1H), 7.59 (s, 1H), 7.34 (d, J=2.62 Hz, 1H), 7.21-7.31 (m, 1H), 7.14 (d, J=9.04 Hz, 1H), 4.02-4.12 (m, 1H), 3.92-4.12 (m, 2H), 3.67 (s, 3H), 2.69-2.78 (m, 2H), 2.53-2.59 (m, 2H), 1.4-1.58 (bs, 8H), 1.26 (d, J=6.82 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([CH2:26][N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)=[CH:22][CH:21]=4)[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:34]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:34])[N:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)=[CH:24][CH:25]=3)[N:14]=2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: CN1CCN(Cc2ccc(Nc3nccc(-c4c[nH]nc4-c4ccc(Cl)cc4)n3)cc2)CC1
Product: CN1CCN(Cc2ccc(Nc3nccc(-c4cnn(C)c4-c4ccc(Cl)cc4)n3)cc2)CC1

Procedure:
The title compound is prepared as described in Example 54 starting from {4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl)}-[4-(4-methyl-piperazin-1-yl-methyl)-phenyl]-amine (Example 32) and methanol.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])=[C:8]2[C:12]([O-:14])=[O:13])[CH3:3].[Na+].[C:23]([O:29][CH2:30]I)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25].C(OCC)(=O)C>CN(C)C=O>[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])=[C:8]2[C:12]([O:14][CH2:30][O:29][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:13])[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3ccccc3O)C[C@H]12
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3ccccc3O)C[C@H]12
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
A solution of sodium (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(hydroxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (106 mg) in dry dimethylformamide (4.5 ml) was cooled with ice, and thereto pivaloyloxymethyl iodide (123 mg) was added. The mixture was stirred for 1 hour at the same temperature. Ethyl acetate and ice water were added to the reaction solution, and the mixture was separated with a separating funnel. After the organic layer was washed with a cold saturated aqueous sodium chloride solution (4 times), it was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and then the residue was purified by silica gel column chromatography (chloroform/methanol) to give [(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(hydroxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (36 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[C:4]([CH3:11])[CH:3]=1.[N:12]([O-])=O.[Na+].[OH-].[Na+]>Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[N:10]=[N:12][N:8]([CH3:9])[C:6]=2[CH:7]=1
Reactant: O=N[O-]
Reactant: CNc1cc(Br)cc(C)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(Br)cc2c1nnn2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
To a solution of 5-bromo-N1,3-dimethylbenzene-1,2-diamine (Step 85.2) (2.5 g, 11.62 mmol) in HCl cc (15 mL, 494 mmol) cooled down to 0° C. was slowly added a solution of NaNO2 (0.962 g, 13.95 mmol) in water (25 mL). The resulting mixture was allowed to warm up and stir at RT for 2 hr. NaOH was added until basic pH, a precipitate occurred. The resulting solid was filtrated off, washed with water and dried under reduced pressure to afford the title product (2.5 g, 9.95 mmol, 86% yield) as beige solid. tR: 0.93 min (LC-MS 2); ESI-MS: 228 [M+H]+ (LC-MS 2).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][N:27]=[N:26][CH:25]=1)CCC>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:24]3[CH:29]=[CH:28][N:27]=[N:26][CH:25]=3)[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]=2[C:6]([CH3:14])=[CH:7]1)([CH3:13])[CH3:12]
Reactant: COC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnnc2)cc2c1c(C)cn2C(C)C
Temperature: 105 °C

Procedure:
To a 50 ml round bottom flask was added; methyl 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylate (150 mg, 0.484 mmol), PdCl2(dppf)-CH2Cl2 adduct (39.5 mg, 0.048 mmol) and 1,4-Dioxane (4836 μl) followed with 4-(tributylstannyl)pyridazine (179 mg, 0.484 mmol) and a magnetic stir bar. The flask was equipped with a reflux condenser and an exhaust bubbler and heated to 105° C. The reaction solution changed to a dark brown at 30 minutes. LCMS (105 C—3 h) showed the reaction to be complete. The reaction solvent was removed in-vacuo and the remaining residue taken up with DMSO. (1.5 ml). The DMSO solution was purified by reverse phase HPLC using a Phenomenex Gemini 100×30 mm column, neutral acetonitrile and 0.1% formic acid in water, 40-70%, 10 min gradient. The desired fractions were dried in a Genovac EZ-2 evaporator and the solid residues combined. The product, methyl 1-isopropyl-3-methyl-6-(pyridazin-4-yl)-1H-indole-4-carboxylate, was obtained as a white solid. 1H NMR (400 MHz, METHANOL-δ4) 9.68 (δ, J=1.26 Hz, 1H), 9.19 (d, J=5.56 Hz, 1H), 8.20 (d, J=1.52 Hz, 1H), 8.13 (dd, J=2.53, 5.56 Hz, 1H), 7.98 (d, J=1.52 Hz, 1H), 7.48 (s, 1H), 4.96 (dt, J=6.60, 13.33 Hz, 1H), 4.00 (s, 3H), 2.39 (s, 3H), 1.56 (d, 6H). MS(ES) [M+H]+ 310.2.
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:27]2[N:28]=[C:29]([NH:32]C=O)[S:30][CH:31]=2)[C:7]([NH:9][C@@H:10]2[C:25](=[O:26])[N:12]3[C:13]([C:22]([OH:24])=[O:23])=[C:14]([CH2:17][O:18][C:19](=[O:21])[NH2:20])[CH2:15][S:16][C@H:11]23)=[O:8])[CH2:3][CH2:2]1.Cl.C(=O)(O)[O-].[Na+]>CO.O1CCCC1>[NH2:32][C:29]1[S:30][CH:31]=[C:27]([C:6](=[N:5][O:4][CH:1]2[CH2:2][CH2:3]2)[C:7]([NH:9][C@@H:10]2[C:25](=[O:26])[N:12]3[C:13]([C:22]([OH:24])=[O:23])=[C:14]([CH2:17][O:18][C:19](=[O:21])[NH2:20])[CH2:15][S:16][C@H:11]23)=[O:8])[N:28]=1
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NOC3CC3)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NOC3CC3)c3csc(N)n3)[C@H]2SC1
Temperature: 0 °C
Yield: 45.5 %

Procedure:
A mixture of 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (2.0 g) and concentrated hydrochloric acid (1.2 ml) in a mixture of methanol (15 ml) and tetrahydrofuran (15 ml) was warmed at 33° to 35° C. for 1.5 hours. The mixture was poured into ice-water, adjusted to pH 7.5 with saturated aqueous solution of sodium bicarbonate and washed with ethyl acetate. The aqueous solution was adjusted to pH 2 with 1N hydrochloric acid and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate to give 7β-[2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (0.86 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][CH2:9][CH2:8][CH:7]=1)=[O:5])[CH3:2].[C-:11]#[N:12].[Na+].O>CN(C)C=O>[C:11]([C@H:7]1[C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:10][CH2:9][CH2:8]1)#[N:12]
Reactant: [C-]#N
Reactant: CCOC(=O)C1=CCCS1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1SCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 22.2 %

Procedure:
To a stirred solution of 5-ethoxycarbonyl-2,3-dihydrothiophene (500 mg) in dimethylformamide (3 ml), sodium cyanide (187 mg) was added under nitrogen atmosphere and the mixture was stirred for 2 days at room temperature. Water was added to the mixture and extracted with diethyl ether. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 130 mg (24%) of trans-4-cyano-5-ethoxycarbonyltetrahydrothiophene.
Reaction SMILES: [OH:1][NH:2]/[C:3](/[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[CH:9]2)=[N:4]\[H].Cl.C(N=C=NCCCN(C)C)C.[O:27]=[C:28]1[C:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][CH2:31][CH2:30][N:29]1[CH2:46][C:47](O)=O.CN(C)C=O>ClC(Cl)C>[NH:11]1[C:12]2[C:8](=[CH:7][C:6]([C:3]3[N:4]=[C:47]([CH2:46][N:29]4[CH2:30][CH2:31][CH2:32][C:33]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:28]4=[O:27])[O:1][N:2]=3)=[CH:14][CH:13]=2)[CH:9]=[N:10]1
Reactant: [H]/N=C(\NO)c1ccc2[nH]ncc2c1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1N(Cc2nc(-c3ccc4[nH]ncc4c3)no2)CCCC1(c1ccccc1)c1ccccc1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
(Z)—N-hydroxy-1H-indazole-5-carboximidamide (0.055 g, 0.312 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.120 g, 0.624 mmol) and 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (0.097 g, 0.312 mmol; Example 68E) were stirred together in dichloroethane (1 mL) at room temperature for 20 minutes. N,N-Dimethylformamide (0.2 mL) was added and stirring was continued for 2 hours and a dark solution resulted. The reaction was heated to 85° C. and stirred overnight. The reaction was cooled, concentrated, loaded onto a GraceResolv™ 4 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes (Flow=18 mL/minute) over 30 minutes. The material obtained was subjected to a second chromatography on a GraceResolv™ 4 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 0.5% methanol/dichloromethane to 7.5% methanol/dichloromethane (Flow=18 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.30 (s, 1H), 8.01 (dd, J=1.2, 8.8, 1H), 7.75 (d, J=8.7, 1H), 7.45-7.07 (m, 10H), 4.92 (s, 2H), 3.66 (t, J=6.3, 2H), 2.76-2.57 (m, 2H), 1.78 (s, 2H).
Reaction SMILES: C1(O)C=CC=CC=1.C1(S)C=CC=CC=1.C[O:16][C:17]1[CH:22]=[C:21]([N:23]2[CH:27]=[CH:26][CH:25]=[N:24]2)[CH:20]=[CH:19][C:18]=1[C:28]1[N:29]=[N:30][C:31]([O:34][CH:35]2[CH2:39][CH2:38][NH:37][CH2:36]2)=[CH:32][CH:33]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[N:23]1([C:21]2[CH:20]=[CH:19][C:18]([C:28]3[N:29]=[N:30][C:31]([O:34][CH:35]4[CH2:39][CH2:38][NH:37][CH2:36]4)=[CH:32][CH:33]=3)=[C:17]([OH:16])[CH:22]=2)[CH:27]=[CH:26][CH:25]=[N:24]1
Reactant: COc1cc(-n2cccn2)ccc1-c1ccc(OC2CCNC2)nn1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: Oc1ccccc1
Product: Oc1cc(-n2cccn2)ccc1-c1ccc(OC2CCNC2)nn1
Yield: 107 %

Procedure:
Following GENERAL METHOD 3-1 for phenol deprotection using thiophenol, 3-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-6-(pyrrolidin-3-yloxy)pyridazine (91 mg, 0.24 mmol) was treated with thiophenol (30 mg, 0.27 mmol) and K2CO3 (30 mg, 0.22 mmol) in NMP (1.6 mL) for 15 min at 190° C. After HPLC purification (0.1% trifluoroacetic acid as modifier), the product-containing fractions were free based by catch and release using SiliaBond Propylsulfonic Acid® (2 g, MeOH as eluent and a 2 N ammonia solution in MeOH to release the material). Solvent was concentrated under reduced pressure and a pale brown solid (83 mg, 68%) was afforded. LCMS Rt=0.48 min (LCMS method Q); [M+H]: 324.1457; 1H NMR (400 MHz, CHLOROFORM-d) δ 13.62 (bs, 1H), 7.97 (d, J=2.5 Hz, 1H), 7.97 (d, J=9.5 Hz, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.39-7.43 (m, 1H), 7.38 (d, J=2.5 Hz, 1H), 7.12 (d, J=9.5 Hz, 1H), 6.44-6.51 (m, 1H), 5.74 (ddt, J=7.0, 5.0, 2.5 Hz, 1H), 3.24-3.31 (m, 2H), 3.17-3.24 (m, 1H), 3.02 (ddd, J=11.0, 8.5, 5.5 Hz, 1H), 2.20-2.33 (m, 1H), 2.02-2.11 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@H:5]([CH2:7][OH:8])[CH2:4][C@H:3]1[CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:17][S:18]([O:8][CH2:7][C@H:5]1[CH2:6][N:2]([CH3:1])[C@H:3]([CH2:9][O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH2:4]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: CN1C[C@H](CO)C[C@H]1COc1cccnc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C[C@H](COS(C)(=O)=O)C[C@H]1COc1cccnc1

Procedure:
To a 386 mg (1.84 mmol) sample of 3-(trans-1-methyl-4-hydroxymethyl-2(S)-pyrrolidinylmethoxy)pyridine (from Example 48a above) dissolved in 12 mL of methylene chloride were added 262 μL (3.38 mmol) of methanesulfonyl chloride, 470 μL of triethylamine and a catalytic amount of DMAP, and the reaction mixture was stirred for 5 hours at room temperature. The reaction was quenched with water, the product extracted from the mixture, the solvent removed, and the product purified by column chromatography on silica gel, eluting with 20:1 chloroform:methanol to afford 320 mg of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([Br:22])[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOC(C)=O.[H][H]>[Pt]=O.CCO>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([Br:22])[C:9]1=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=c1c(Br)c(C#Cc2ccccc2)ccn1Cc1ccccc1
Agent: O=[Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=c1c(Br)c(CCc2ccccc2)ccn1Cc1ccccc1

Procedure:
A mixture of 1-benzyl-3-bromo-4-(phenylethynyl)pyridin-2(1H)-one (0.3 g), and platinum oxide (0.05 g) in a solvent mixture of EtOAc (10.0 mL) and EtOH (10.0 mL) was stirred in an atmosphere of hydrogen at 15 psi in a Fischer porter bottle for 45 min. The catalyst was removed by filtration, and filtrate was concentrated. The resulting residue was purified by silica gel flash chromatography using 25% EtOAc in hexanes as the eluent. The appropriate fractions (visualized under an UV lamp) were combined and concentrated under reduced pressure. 1H-NMR (CD3OD) δ: 7.56 (d, 1H, J=6.8 Hz), 7.31-7.17 (m, 10H), 6.24 (d, 1H, J=6.8 Hz), 5.19 (s, 2H), 2.96 (m, 2H), and 2.91 (m, 2H); ES-MS m/z=368 (MH+); HR-MS m/z (MH+) calcd C20H19NOBr 368.0650, found 368.0630.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:15][C:16]1[NH:20][N:19]=[N:18][N:17]=1>O1CCCC1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>[N:1]1([C:6]2[N:11]=[C:10]([C:12]([NH:15][C:16]3[NH:20][N:19]=[N:18][N:17]=3)=[O:14])[CH:9]=[N:8][CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cncc(N2CCCC2)n1
Reactant: Nc1nnn[nH]1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1nnn[nH]1)c1cncc(N2CCCC2)n1

Procedure:
To a suspension of 2.90 g of 6-(1-pyrrolidinyl) pyrazine-2-carboxylic acid in 45 ml of tetrahydrofuran, 2.30 ml of triethylamine and 2.00 ml of pivaloyl chloride were added dropwise successively at 0 ° C. under stirring. After stirring for 1 hour at 0 ° C., 1.40 g of 5-amino-1H-tetrazole was added to the mixture, and the reaction mixture was stirred for 1 hour at room temperature, and then refluxed for 12 hours, The reaction mixture was evaporated, and water was added to the residue. The precipitate was collected by filtration, and recrystalized from dimethylsulfoxide affording 1.63 g of the desired compound as yellow needles. The obtained crystal was consistent with that of (a)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[OH:11].[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([N+:13]([O-:15])=[O:14])[C:5]=1[OH:11]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc(Cl)ccc1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
Methyl-5-Chloro-2-hydroxylbenzoate (30 g, 160 mmol) is suspended in sulfuric acid (140 mL) and cooled to 0° C. in an ice bath. Nitric acid (13 mL) in sulfuric acid (30 mL) is added drop wise to the suspension over 30 minutes while maintaining the reaction temperature at 0° C. The reaction is warmed to room temperature and stirred for 4 hours. An additional 6 mL of nitric acid is added drop wise to the reaction over 30 minutes and the reaction is heated to 45° C. for 16 hours. The reaction is poured onto crushed ice, and the resulting yellow precipitate collected and washed with copious amount of water and dried in vacuo to give the title compound (33 g 142 mmol, 89%). LCMS (ESMS): m/z 232.7 (M+H+).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][NH:16][C:17](=[S:20])SC)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>O.C(O)C>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[C:17](=[S:20])[NH:23][N:22]=[N:21]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CSC(=S)NCCCN1CCN(c2ccccc2)CC1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: S=c1[nH]nnn1CCCN1CCN(c2ccccc2)CC1
Reaction time: 4.5 h
Yield: 25.2 %

Procedure:
To a solution of methyl N-[3-(4-phenyl-1-piperazinyl)propyl]dithiocarbamate (12.9 g) in a mixture of water (20 m) and ethanol (30 m) was added sodium azide (3.6 g). The resulting mixture was refluxed with stirring for 4.5 hours. The reaction mixture was concentrated under reduced pressure. After the addition of water to the residue, the mixture was washed successively with ethyl acetate and diethyl ether and then evaporated. To the residue was added ethanol (100 m) and the mixture was filtered. The filtrate was evaporated under reduced pressure. The residue was recrystallized from isopropyl alcohol twice to give 1-[3-(4-phenyl-1-piperazinyl)propyl]-4,5-dihydro-1H-tetrazole-5-thione (3.2 g), mp. 200° to 205° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:23](O)=[O:24])[O:20][C:21]=3[CH3:22])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[S:26]([C:30]1[CH:35]=[CH:34][C:33]([O:36]C(=O)C)=[CH:32][CH:31]=1)(=[O:29])(=[O:28])[NH2:27].C[O-].[Na+]>CO.O>[OH:36][C:33]1[CH:34]=[CH:35][C:30]([S:26]([NH:27][C:23]([C:19]2[O:20][C:21]([CH3:22])=[C:17]([CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[CH:14][CH:13]=3)[CH:18]=2)=[O:24])(=[O:28])=[O:29])=[CH:31][CH:32]=1
Reactant: CC(=O)Oc1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2ccc(OCc3cc(C(=O)NS(=O)(=O)c4ccc(O)cc4)oc3C)cc2)cc1
Yield: 20.6 %

Procedure:
4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (4) (50 mg) was reacted with acetic acid 4-sulphamoyl-phenyl ester (64 mg) in an analogous manner to that described in Example 2A. The acetic ester intermediate was hydrolysed with sodium methoxide (80 mg) in a mixture of methanol (10 mL) and water (1 mL) for 1 hour. The solution was concentrated in vacuo then partitioned between dichloromethane (10 mL) and water (10 mL). The organic layer was washed with brine (10 mL)r dried, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (starting at 30% acetonitrile and increasing at a rate of 1% per minute up to 98% acetonitrile) to give compound 13 as a white solid (15 mg). LC/MS System C: Rt=3.50 mins, m/z (ES−)=492 (M− for C26H23N2O7S).
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([S:28]([C:31]([F:36])([F:35])[CH:32]([F:34])[F:33])(=[O:30])=[O:29])[NH:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23]C(C)(C)C)=[CH:19][CH:18]=2)=[CH:8][CH:7]=1)(C)(C)C.FC(F)(F)C(O)=O>O>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]=[C:14]([S:28]([C:31]([F:35])([F:36])[CH:32]([F:34])[F:33])(=[O:29])=[O:30])[NH:15][C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[CH:10][CH:11]=1
Reactant: CC(C)(C)Oc1ccc(-c2nc(S(=O)(=O)C(F)(F)C(F)F)[nH]c2-c2ccc(OC(C)(C)C)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=S(=O)(c1nc(-c2ccc(O)cc2)c(-c2ccc(O)cc2)[nH]1)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4,5-bis(4-t-butoxyphenyl)-2-(1,1,2,2-tetrafluoroethylsulfonyl)imidazole and trifluoroacetic acid is stirred overnight at room temperature. The reaction mixture is poured into water, and work-up affords as product 4,5-bis(4-hydroxyphenyl)-2-(1,1,2,2-tetrafluoroethylsulfonyl)imidazole.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].CO.[CH:11]([C:15]1[C:16]([CH3:34])=[CH:17][C:18]([I:33])=[C:19]([CH:32]=1)[O:20][C:21](=[CH:24]NC1C=CC=CC=1)[C:22]#[N:23])=[CH:12][CH:13]=[CH2:14]>C(O)C>[CH:11]([C:15]1[C:16]([CH3:34])=[CH:17][C:18]([I:33])=[C:19]([CH:32]=1)[O:20][C:21]1[C:22]([NH2:23])=[N:4][C:3]([NH2:5])=[N:2][CH:24]=1)=[CH:12][CH:13]=[CH2:14]
Reactant: N=C(N)N
Reactant: C=CC=Cc1cc(OC(C#N)=CNc2ccccc2)c(I)cc1C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: C=CC=Cc1cc(Oc2cnc(N)nc2N)c(I)cc1C

Procedure:
To a suspension of guanidine hydrochloride (3.10 g, 32.5 mmol) in 10 mL ethanol was added a solution of 25% NaOMe in methanol (7.0 mL, 32.5 mmol). The resulting solution was added to the crude 2-(5-buta-1,3-dienyl-2-iodo-4-methyl-phenoxy)-3-phenylamino-acrylonitrile of step 4, and the mixture was heated to reflux under nitrogen for 16 hours. The reaction mixture was cooled, concentrated under reduced pressure, diluted with water, and extracted with methylene chloride. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica (10% MeOH/methylene chloride+0.1% NH4OH), and recrystallized from EtOAc to give 2.1 g of 5-(5-buta-1,3-dienyl-2-iodo-4-methyl-phenoxy)-pyrimidine-2,4-diamine, MP=195-197° C.