Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=O)[CH2:5][C:4](=[O:9])[CH2:3]1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O.[F:21][C:22]([F:30])([F:29])[C:23]1[CH:27]=[C:26]([NH2:28])[NH:25][N:24]=1>C(O)C>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]1[C:5]2[C:4](=[O:9])[CH2:3][C:2]([CH3:1])([CH3:10])[CH2:7][C:6]=2[NH:28][C:26]2=[N:25][NH:24][C:23]([C:22]([F:30])([F:29])[F:21])=[C:27]12
Reactant: COc1ccccc1C=O
Reactant: Nc1cc(C(F)(F)F)n[nH]1
Reactant: CC1(C)CC(=O)CC(=O)C1
Solvent: CCO
Product: COc1ccccc1C1C2=C(CC(C)(C)CC2=O)Nc2n[nH]c(C(F)(F)F)c21
Temperature: 150 °C
Yield: 16.2 %

Procedure:
5,5-Dimethylcyclohexane-1,3-dione (824 mg, 5.88 mmol), 2-methoxybenzaldehyde (800 mg, 5.88 mmol) and 3-(trifluoromethyl)-1H-pyrazol-5-amine (1199 mg, 7.93 mmol) were mixed together in a microwave vial and ethanol (14.7 mL, 0.4 M) was added to it. The reaction mixture was heated in microwave for 15 min at 150° C. The mixture was cooled and the solvent was evaporated. The resultant mixture was then purified by column chromatography over silica gel (hexane/ethyl acetate: 100/0 to 20/80) to afford the desired product as a white solid (372.0 mg). 1H NMR (300 MHz, MeOD) δ 7.19 (d, J=7.4 Hz, 1H), 7.12-7.03 (m, 1H), 6.78 (dd, J=13.8, 7.4 Hz, 2H), 5.39 (s, 1H), 3.67 (s, 3H), 2.56 (d, J=16.8 Hz, 1H), 2.42 (d, J=16.7 Hz, 1H), 2.24 (d, J=16.5 Hz, 1H), 2.04 (d, J=16.5 Hz, 1H), 1.08 (s, 3H), 0.97 (s, 3H). LRMS (ESI+) (M+): 391.82.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[CH:9](O)=[O:10]>>[CH:2]1[N:1]=[CH:9][N:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=12.[CH:9]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:10]
Reactant: NCc1ccccn1
Reactant: O=CO
Product: O=CNCc1ccccn1
Product: c1ccn2cncc2c1

Procedure:
A mixture of 32.4 g. of 2-aminomethylpyridine and 96 ml. of 97% formic acid is heated under reflux for 3.5 hrs. The resulting solution is subjected to vacuum distillation, the desired product, 2-formamidomethylpyridine, being isolated as a yellow oil crystallizes to a solid having a melting point at about room temperature.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[BH3-]C#N.[Na+].[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([N:24]2[CH:33]3[CH:28]([CH2:29][CH2:30][CH2:31][CH:32]3[N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[NH:27][CH2:26][CH2:25]2)=[O:23])[CH:17]=[CH:18][C:19]=1[Cl:20].C([O-])([O-])=O.[Na+].[Na+]>CO.C(O)(=O)C>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([N:24]2[CH:33]3[CH:28]([CH2:29][CH2:30][CH2:31][CH:32]3[N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[N:27]([CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:26][CH2:25]2)=[O:23])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Reactant: O=Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCN(Cc2ccccn2)C2CCCC(N3CCCC3)C21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridine-2-carbaldehyde (268 mg, 2.5 mmol) was dissolved in MeOH (5 ml) and NaBH3CN (157 mg, 2.5 mmol) was added. The pH was adjusted to 5 with concentrated acetic acid. 2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (98 mg, 0.25 mmol), dissolved in MeOH (15 ml), was then added to the mixture and the mixture was stirred at room temperature overnight. After addition of saturated Na2CO3 solution (15 ml), the mixture was stirred at room temperature for 15 minutes. The precipitate formed was filtered off. The aqueous phase of the filtrate was extracted five times with CH2Cl2 and the combined organic phases were dried over Na2SO4 and evaporated in vacuo. The residue was purified four times by flash chromatography (in each case Ø 2 cm, l=15 cm, V=5 ml; 1. CH2Cl2/MeOH/NH3 9.5:0.5:0.1, 2. CH2Cl2/MeOH/NH3 9.5:0.5:0.1, 3. CH2Cl2/MeOH/NH3 9.75:0.25:0.15, 4. CH2Cl2/MeOH/NH3 9.5:0.5:0.15). The crude product was then purified by preparative HPLC (as described under Example 14 in MeOH/H2O/Et2NH 80:20:0.1). MeOH was evaporated off from the product fraction, the aqueous phase was extracted by shaking three times with CH2Cl2 and the combined organic phases were dried over Na2SO4 and evaporated. A yellowish resin was isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1.[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:33])[CH3:32])[C:26]=1[N:34]=[C:35]=[O:36])([CH3:24])[CH3:23]>>[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:32])[CH3:33])[C:26]=1[NH:34][C:35](=[O:36])[N:12]([CH2:11][C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])[C:13]1[CH:14]=[CH:15][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:17][CH:18]=1)([CH3:23])[CH3:24]
Reactant: COc1ccc(CNc2ccc(C(C)C)cc2)c(OC)c1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: COc1ccc(CN(C(=O)Nc2c(C(C)C)cccc2C(C)C)c2ccc(C(C)C)cc2)c(OC)c1
Yield: 93.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(2,4-dimethoxyphenyl)methyl](4-isopropylphenyl)amine (1.0 g) and 2,6-diisopropylphenyl isocyanate (1.2 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(2,4-dimethoxyphenyl)methyl]-N-(4-isopropylphenyl)urea (1.6 g) was obtained.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[CH:11]([OH:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].[O]N(S(=O)([O-])=O)S(=O)([O-])=[O:22].[K+].[K+].C(OCC)C>CN(C)C=O.O>[CH3:8][C:7]1[C:2](=[O:1])[C:3]([CH:11]([OH:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH3:10])[C:5](=[O:22])[C:6]=1[CH3:9]
Reactant: Cc1cc(C)c(C(O)CCCCCO)c(O)c1C
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1=C(C)C(=O)C(C(O)CCCCCO)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(2'-hydroxy-3',4',6'-trimethylphenyl)-1,6-hexanediol (formula III-3 wherein R=H3C, X=H, Y=OH, n=4 in the free form) (0.32 part) in dimethyl formamide (20 volume parts) was added all at once a mixture of Fremy's salt (0.5 part) and potassium biphosphate (0.5 part) in water (50 volume parts). The mixture was stirred for 3 hours at room temperature. The reaction product was taken up with diethyl ether. The diethyl ether layer was washed with water and dried over anhydrous sodium sulfate. The residue upon removal of the solvent was subjected to chromatography on silica gel and eluted with ethyl acetate-diethyl ether (4:1) to give 2,3,5-trimethyl-6-(1',6'-dihydroxyhexyl)-1,4-benzoquinone (formula IV-3 wherein R=H3C, n=4, in the free form) (0.26 part) as a yellow oil.
Reaction SMILES: S1C=CC=C1.[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH:15]1[C:20]([NH2:22])=[O:21].[H][H]>[Pt].CO.C(O)C>[C:7]1([CH2:6][N:17]2[CH2:18][CH2:19][NH:14][CH:15]([C:20]([NH2:22])=[O:21])[CH2:16]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [H][H]
Reactant: NC(=O)C1CNCCN1
Reactant: O=Cc1ccccc1
Agent: [Pt]
Solvent: c1ccsc1
Solvent: CCO
Solvent: CO
Product: NC(=O)C1CN(Cc2ccccc2)CCN1
Yield: 55 %

Procedure:
To 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol were added 2.2 parts of benzaldehyde, 2.6 parts of 2-piperazinecarboxamide and 120 parts of methanol. The whole was hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The solid residue was boiled in 64 parts of acetonitrile. The mixture was filtered and the filtrate was allowed to crystallize at room temperature. The product was filtered off and dried, yielding 2.4 parts (55%) of 4-(phenylmethyl)-2-piperazinecarboxamide; mp. 168.3° C. (intermediate 36).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C@:13]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([NH2:17])[CH2:14][CH:15]=[CH2:16])[CH3:9])=[CH:4][CH:3]=1.CCN(CC)CC.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:14]([C@:13]1([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH2:12][CH2:11][N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH3:9])[C:33](=[O:35])[NH:17]1)[CH:15]=[CH2:16]
Reactant: C=CC[C@@](N)(CCN[C@@H](C)c1ccc(Br)cc1)c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)N1
Reaction time: 3 h
Yield: 20.3 %

Procedure:
To a solution of (R)—N1—((S)-1-(4-bromophenyl)ethyl)-3-(4-fluorophenyl)hex-5-ene-1,3-diamine (12 g, 31 mmol) in CH2Cl2 (100 mL) and Et3N (36 g, 0.36 mmol) was added triphosgene (3.50 g, 11.8 mmol) at 0° C. The resulting mixture was stirred for 3 h. The mixture was washed with water. The organic layer was separated, and concentrated to give the crude product, which was purified by column chromatography to afford (R)-4-allyl-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)tetrahydropyrimidin-2(1H)-one (1.0 g, 8%). 1H NMR (CDCl3): δ=1.49 (t, 3H), 2.00 (m, 2H), 2.35 (m, 2H), 2.76 (m, 2H), 5.18 (m, 2H), 5.31 (m, 2H), 5.72 (q, 1H), 6.95 (m, 4H), 7.18 (m, 2H), 7.254 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([OH:13])=[O:12].[N+](=[CH2:17])=[N-]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:13][CH3:17])=[O:12]
Reactant: COC(=O)/C=C/[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)/C=C/[C@H]1[C@@H](C(=O)OC)C1(C)C

Procedure:
Using the procedure of Example 7, 1.26 g of (1R,cis) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylic acid and 12.7 ml of 0.5 M/l of diazomethane in methylene chloride were reacted to obtain 0.678 g of methyl (1R,cis) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =-4°±2° (c=0.6% in chloroform).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[O:24]=[C:25]([CH2:31][CH3:32])[CH2:26][CH2:27][C:28](Cl)=[O:29].S(Cl)(Cl)=O.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:28](=[O:29])[CH2:27][CH2:26][C:25](=[O:24])[CH2:31][CH3:32])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(NCc2ccccc2)cc1
Reactant: CCC(=O)CCC(=O)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)CCC(=O)N(Cc1ccccc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
To a solution of 22.8 g (0.1 mol) of 4-nitro-N-(phenylmethyl)benzenamine and 7.9 g (0.1 mol) of pyridine in 150 mL of methylene chloride cooled to 0° C. add slowly a solution of 16.3 g (0.11 mol) of 4-oxohexanoyl chloride (prepared from the acid and thionyl chloride or oxalyl chloride). When the addition is complete stir the solution and allow to warm slowly to room temperature. Follow the progress of the reaction by thin-layer chromatography on silica gel. At the completion of the reaction wash the solution with two 25 mL portions of 5% hydrochloric acid solution, two 25 mL portions of 5% sodium carbonate solution and 50 mL of saturated sodium chloride solution. Dry the organic phase over anhydrous sodium sulfate. Remove the drying agent by filtration and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [CH2:1]=[O:2].[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])([CH3:6])([CH3:5])[CH3:4].CC1C=CN=CC=1.[Sn](Cl)Cl>C1(C)C=CC=CC=1.C(OCC)C>[C:3]([C:7]1[C:8]([OH:13])=[C:9]([CH:10]=[CH:11][CH:12]=1)[CH:1]=[O:2])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1O
Reactant: C=O
Agent: Cl[Sn]Cl
Solvent: Cc1ccccc1
Solvent: Cc1ccncc1
Solvent: CCOCC
Product: CC(C)(C)c1cccc(C=O)c1O
Temperature: 95 °C
Reaction time: 6 h
Yield: 39.5 %

Procedure:
9.0 g (300 mmol) of para-formaldehyde in 200 ml of toluene were introduced into a 500 ml three-necked flask fitted with magnetic stirrer, reflux condenser and nitrogen/vacuum connection, and 15.4 ml (100 mmol) of 2-tert-butylphenol (Aldrich), 3.9 ml (40 mmol) of 4-methylpyridine and 1.89 g (10 mmol) of tin(II) chloride were added. The batch was subsequently allowed to stir at 95° C. for six hours. The isolated product was taken up in diethyl ether, and the solution was washed with sodium chloride solution, dried over sodium sulfate and evaporated in a rotary evaporator, giving the product in a yield of 39.5%.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[C:21]2[N:27]([CH3:40])[C:28](=[O:39])[C:29]([C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=4[Cl:38])=[CH:30][C:20]3=2)[N:16]=1)C1C=CC=CC=1.C1(SC)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>FC(F)(F)C(O)=O>[NH2:10][CH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[C:21]2[N:27]([CH3:40])[C:28](=[O:39])[C:29]([C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=4[Cl:38])=[CH:30][C:20]3=2)[N:16]=1
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CNC(=O)OCc5ccccc5)n4)ccc3n(C)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CN)n4)ccc3n(C)c21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
780 mg (1.3 mmol) of compound A {4-[3-(2,4-dichlorophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]thiazol-2-ylmethyl}carbamic acid benzyl ester are dissolved in 12 ml of trifluoroacetic acid. 8 ml (10.3 mmol) of thioanisole are added and the mixture is stirred at ambient temperature for 16 hours. It is poured into a saturated K2CO3 solution and the mixture is extracted with EtOAc. The organic phase is adsorbed onto silica and purification is carried out on a silica column, elution being carried out with EtOAc and then with 90/10/1 EtOAc/MeOH/NH3.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10])[N:6]2[C:17](=[O:20])[CH:18]([NH2:19])[C@H:5]2[S:4]1.C(N(CC)CC)C.CN(C)C1C=CC=CC=1.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:42][C:43](Cl)=[O:44]>ClCCl>[CH3:2][CH:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:14])[Cl:15])=[O:10])[N:6]2[C:17](=[O:20])[CH:18]([NH:19][C:43](=[O:44])[CH2:42][C:38]3[S:37][CH:41]=[CH:40][CH:39]=3)[C@H:5]2[S:4]1
Reactant: O=C(Cl)Cc1cccs1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S1
Temperature: -15 °C
Yield: 86.8 %

Procedure:
2,2,2-Trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (3.0 g) was suspended in dried dichloromethane (50 ml) and then dissolved by adding triethylamine (0.72 g) and dimethylaniline (1.9 g) under cooling at -15° C. To a solution was dropwise added a solution of (2-thienyl)acetyl chloride (2.0 g) in dried dichloromethane (10 ml) under stirring and cooling at the same temperature, and the mixture was stirred for 1.5 hours at the same temperature. After the reaction, the reaction mixture was in turn washed with 5% hydrochloric acid, water, 5% sodium bicarbonate aqueous solution and water and then dried. After the solvent was distilled off, the residue was dissolved in ether, allowed to stand, after which the precipitated crystals were collected by filtration and dried to give crystals of 2,2,2-trichloroethyl 2-methyl-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylate (3.2 g), mp 161° to 162° C. (dec.).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1)=[O:3].[C:11](Cl)(=[O:18])[CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>>[C:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:18])[CH2:12][CH2:13][CH2:14][C:15]([NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:2](=[O:3])[CH3:1])[CH:5]=2)=[O:16])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1cccc(N)c1
Reactant: O=C(Cl)CCCC(=O)Cl
Product: CC(=O)c1cccc(NC(=O)CCCC(=O)Nc2cccc(C(C)=O)c2)c1

Procedure:
N,N′-bis(3,5-diacetylphenyl)(isophthalic acid diamide), mp 283-4° C. Also analogously, N,N′-bis(3-acetylphenyl)pentanediamide, mp 174-5° C. was prepared from 3-aminoacetophenone and glutaryl dichloride.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[Br:10][C:11]1[N:12]=[N:13][C:14](Br)=[CH:15][CH:16]=1.C(N(CC)CC)C>C1COCC1>[Br:10][C:11]1[N:12]=[N:13][C:14]([N:6]2[CH2:7][CH2:8][CH:3]([N:2]([CH3:9])[CH3:1])[CH2:4][CH2:5]2)=[CH:15][CH:16]=1
Reactant: CN(C)C1CCNCC1
Reactant: Brc1ccc(Br)nn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C1CCN(c2ccc(Br)nn2)CC1
Temperature: 70 °C
Yield: 89.7 %

Procedure:
N,N-dimethylpiperidin-4-amine (0.505 g, 3.94 mmol), 3,6-dibromopyridazine (0.511 g, 2.15 mmol), and triethylamine (0.599 mL, 4.30 mmol) were combined in 5 mL of THF. The solution was heated at 70° C. for 17 hours. The solution was cooled to room temperature and then purified on CombiFlash column (dry loaded), eluting with 10% methanol/0.5% NH4OH (˜28% in water)/DCM isocratic. The fractions containing the product were combined and concentrated under vacuum to give compound 201 (0.550 g, 89.8% yield) as an off white solid. 1H NMR (500 MHz, MeOD-d3) δ 7.51 (1 H, d, J=9.8 Hz), 7.24 (1 H, d, J=9.8 Hz), 4.45 (2 H, d, J=13.7 Hz), 2.98 (2 H, td, J=13.0, 2.2 Hz), 2.61 (1 H, tt, J=11.5, 3.8 Hz), 2.38 (6 H, s), 1.99-2.07 (2 H, m), 1.45-1.58 (2 H, m, J=12.5, 12.2, 12.2, 4.2 Hz) ppm; LCMS-ESI (POS), M/Z, M+1: Found 285.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15])([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=1)=[O:15])([O-:11])=[O:10]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1cccc(F)c1
Product: O=C(Nc1cccc(F)c1)c1ccccc1[N+](=O)[O-]
Yield: 76.1 %

Procedure:
Using the procedure described in Example 93, Part A, 3-fluoroaniline (15.6 mmol) and 2-nitrobenzoyl chloride (17.2 mmol) yielded 3.09 g (76%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([O:10]C)[C:5]([O:12]C)=[CH:4][CH:3]=1.B(Br)(Br)Br.O(CC)CC.Cl>ClCCl>[F:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([OH:10])[C:5]([OH:12])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c(C=O)c1OC
Agent: BrB(Br)Br
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1c(F)ccc(O)c1O
Temperature: -60 °C
Reaction time: 4 h

Procedure:
To a solution of 6-fluoro-2,3-dimethoxy-benzaldehyde (18.0 g, 97.74 mmol) in anhydrous dichloromethane (100 mL) under nitrogen at −60° C. was added dropwise BBr3.OEt2 (195 mL, 195.48 mmol) over 30 min and the solution was allowed to warm up to r.t and stirred for 4 h. The reaction mixture was cooled to −60° C. and 2N HCl (250 mL) was carefully added drop wise. The mixture was stirred at r.t overnight. The two layers were separated and the aqueous layer extracted with DCM. The combined organic layers were washed with water, sat. NaHCO3 solution, water and brine and dried over MgSO4. The solvent was removed in vacuo to provide the title compound which was used in the next step without further purification. Yield 11.15 g (74%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.53 (s, 1H), 10.23 (s, 1H), 7.11 (dd, J=8.8, 5.3 Hz, 1H), 6.57 (t, J=9.6 Hz, 1H), 5.48 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −132 ppm.
Reaction SMILES: [CH2:1]([C:4]1([C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1)[CH:2]=[CH2:3].[F:22][C:23]1[CH:24]=[C:25]([N:38]2[CH2:42][CH:41]([CH2:43][NH:44][C:45](=[O:47])[CH3:46])[O:40][C:39]2=[O:48])[CH:26]=[CH:27][C:28]=1B1OC(C)(C)C(C)(C)O1.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.CN(C=O)C.O>[CH2:1]([C:4]1([C:15]2[CH:20]=[CH:19][C:18]([C:28]3[CH:27]=[CH:26][C:25]([N:38]4[CH2:42][CH:41]([CH2:43][NH:44][C:45](=[O:47])[CH3:46])[O:40][C:39]4=[O:48])=[CH:24][C:23]=3[F:22])=[CH:17][CH:16]=2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(c2ccc(Br)cc2)Cn2cc([N+](=O)[O-])nc2O1
Reactant: CC(=O)NCC1CN(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)C(=O)O1
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: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC1(c2ccc(-c3ccc(N4CC(CNC(C)=O)OC4=O)cc3F)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The title compound was synthesized according to the reaction scheme shown in FIG. 21. To a mixture of 2-Allyl-2-(4-bromo-phenyl)-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazole (80 mg, 0.229 mmol), N-{3-[3-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (104 mg, 0.274 mmol), Pd(PPh3)4 (53 mg, 0.046 mmol) and K2CO3 (240 mg, 0.458 mmol) was added anhydrous DMF/H2O (4 mL/0.4 mL, 4.4 mL total) under N2. The reaction mixture was stirred for 2 h at 80° C., cooled to rt, quenched with water, diluted with EtOAc, washed with brine and water. The organic layers were separated, dried (MgSO4) and concentrated. Column chromatography provided 63 mg of yellow solid. 1H NMR (400 MHz, DMSO-d) δ 8.26 (t, J=5.8 Hz, 1H), 7.60 (m, 2H), 7.41 (m, 2H), 5.61 (m, 1H), 5.16 (m, 2H), 4.74 (m, 1H), 4.65 (d, J=11.2 Hz, 1H), 4.48 (d, J=11.2 Hz, 1H), 4.15 (d, J=9.0 Hz, 1H), 3.76 (m, 1H), 3.41 (d, J=1.3 Hz, 2H), 3.02 (m, 2H); ESI MS m/z 522 (M+H+)
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9])=[C:6]([S:15]([N:18]=[C:19]=[O:20])(=[O:17])=[O:16])[CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[N:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([O:30][CH3:31])[N:23]=1>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9])=[C:6]([S:15]([NH:18][C:19]([NH:21][C:22]2[N:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([O:30][CH3:31])[N:23]=2)=[O:20])(=[O:16])=[O:17])[CH:5]=[CH:4][CH:3]=1
Reactant: COCCOC(=O)c1c(F)cccc1S(=O)(=O)N=C=O
Reactant: COc1nc(N)nc(OC)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCOC(=O)c1c(F)cccc1S(=O)(=O)NC(=O)Nc1nc(OC)nc(OC)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
7.1 g of β-methoxyethyl 6-fluoro-2-isocyanatosulfonylbenzoate in 20 ml of methylene chloride were added over 10 minutes at 25° C. to a stirred mixture of 4 g of 2-amino-4,6-dimethoxy-1,3,5-triazine in 40 ml of DMF under nitrogen; the temperature rose to 32° C. After the mixture had been stirred for 14 hours at 25° C., the solvent was removed under reduced pressure and the residue was stirred with ether and twice with 3N HCL. It was then taken up in acetone, insoluble mater was separated off and the filtrate was concentrated to dryness. 7 g of the compound shown in the title, of melting point 179° C.-182° C. were obtained.