Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][CH2:12][CH2:13][S:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][OH:18].C(N(CC)CC)C>C(Cl)Cl.O>[Cl:11][CH2:12][CH2:13][S:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[O:18]
Reactant: OCc1ccccc1SCCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1ccccc1SCCCl
Reaction time: 0.25 h
Yield: 91.7 %

Procedure:
A solution of 27.8 g of dimethylsulfoxide in 50 ml of methylene chloride is added to a solution of 22.6 g of oxalyl chloride in 450 ml of methylene chloride at -60° C. during one hour, and a solution of 32.7 g of 2-(2-chloroethylthio)benzylalcohol in 50 ml of methylene chloride is added thereto. The mixture is stirred for 15 minutes, and a solution of 71.8 g of triethylamine in 50 ml of methylene chloride is added to the mixture at -60° C. The mixture is stirred at the same temperature for 5 minutes and further stirred at room temperature for one hour. Water is added to the mixture, and the methylene chloride layer is collected therefrom. The methylene chloride solution is washed with water, dried and concentrated under reduced pressure to remove solvent. The residue is distilled under reduced pressure. 29.7 g of 2-(2-chloroethylthio)benzaldehyde are obtained as an oil. Yield: 91.6%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:24][C:25]1[CH:26]=[C:27]2[CH:33]=[CH:32][NH:31][C:28]2=[N:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C=O)C.ClCCl.CO>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:24][C:25]1[CH:26]=[C:27]2[CH:33]=[CH:32][NH:31][C:28]2=[N:29][CH:30]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Reactant: Oc1cnc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(Oc3cnc4[nH]ccc4c3)ncnc2cc1OCCCN1CCCCC1
Temperature: 95 °C
Reaction time: 6 h
Yield: 19.7 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (227 mg, 0.68 mmol), (prepared as described for the starting material in Example 67), 5-hydroxy-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.75 mmol), (prepared as described for the starting material in Example 182), and potassium carbonate (350 mg, 2.5 mmol) in DMF (4 ml) was stirred at 95° C. for 6 hours and allowed to cool to ambient temperature. The reaction mixture was treated with 1.0 N aqueous sodium hydroxide solution and allowed to stir at ambient temperature for a few minutes. The resulting precipitate was filtered off, washed with water and air dried to give a crude product. This was purified by column chromatography, eluting initially with dichloromethane/methanol (85/15) to isolate a less polar impurity and then with dichloromethane/methanol/0.88 ammonia (100/8/1) to isolate the target compound. The relevant fractions were combined and evaporated in vacuo to give a white solid which was triturated with acetone, filtered and dried to give 6-methoxy-7-(3-piperidinopropoxy)4-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)quinazoline (58 mg, 20%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:22]=[C:21]([N:23]2[CH:27]=[N:26][N:25]=[N:24]2)[CH:20]=[CH:19][C:4]=1[O:5][CH2:6][C:7]1[CH:11]=[N:10][N:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH:14]([CH3:18])[CH2:13]2)[N:8]=1.CS([C:32]1[N:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][N:33]=1)(=O)=O>>[F:2][C:3]1[CH:22]=[C:21]([N:23]2[CH:27]=[N:26][N:25]=[N:24]2)[CH:20]=[CH:19][C:4]=1[O:5][CH2:6][C:7]1[CH:11]=[N:10][N:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:32]3[N:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][N:33]=3)[CH:14]([CH3:18])[CH2:13]2)[N:8]=1
Reactant: CC1CC(n2ncc(COc3ccc(-n4cnnn4)cc3F)n2)CCN1
Reactant: CS(=O)(=O)c1ncc(C(F)(F)F)cn1
Agent: Cl
Product: CC1CC(n2ncc(COc3ccc(-n4cnnn4)cc3F)n2)CCN1c1ncc(C(F)(F)F)cn1

Procedure:
The title compound was synthesized from 4-(4-((2-fluoro-4-(1H-tetrazol-1-yl)phenoxy)methyl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidine hydrochloride and 2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine in a manner similar to that described in Example 9. The title compound was isolated as a mixture of four stereoisomers.
Reaction SMILES: Br.[Br:2][C:3]1[C:27]([F:28])=[CH:26][C:6]2[O:7][C:8]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:9]=3[C@H:10]3[C@H:15]([NH:16]C(=O)OC)[CH2:14][CH2:13][CH2:12][N:11]3[C:5]=2[CH:4]=1.[OH-].[Na+]>C(O)(=O)C>[Br:2][C:3]1[C:27]([F:28])=[CH:26][C:6]2[O:7][C:8]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:9]=3[C@H:10]3[C@H:15]([NH2:16])[CH2:14][CH2:13][CH2:12][N:11]3[C:5]=2[CH:4]=1
Reactant: COC(=O)N[C@@H]1CCCN2c3cc(Br)c(F)cc3Oc3cc(F)ccc3[C@@H]12
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: N[C@@H]1CCCN2c3cc(Br)c(F)cc3Oc3cc(F)ccc3[C@@H]12
Temperature: 100 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
A mixture of acetic acid (80 mL) and hydrogen bromide (48%, 40 mL) was added to methyl (±)-(cis)-(7-bromo-8,12-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamate (38.2 mmol), and the mixture stirred overnight at 100° C. After cooling down the reaction mixture was poured into a cold 1N NaOH solution (pH 9). It was extracted with ethyl acetate and the organic layer was washed with brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure to yield the crude title compound (12.7 g, 87%) which was used without further purification. (m/z)=381+383 (M+H)+.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[N+:13]([O-])([O-])=O.[NH4+:17].[CH:18](/[CH:25]=[CH:26]/O)=[CH:19]\[C:20]([C:22]([OH:24])=[O:23])=O>C1(C)C=CC=CC=1>[N:17]1[CH:26]=[CH:25][CH:18]=[CH:19][C:20]=1[C:22]([OH:24])=[O:23].[NH4+:13]
Reactant: O=C(O)C(=O)/C=C/C=C/O
Reactant: O=[N+]([O-])[O-]
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccn1

Procedure:
A culture of strain CEL 2052 (ATCC 39636), growing continuously on 20 mM glucose and 8.5 mM nitrate, is induced with toluene in the absence of ammonium ions. 2-Hydroxymuconic semialdehyde is observed to accumulate rapidly at a rate which would produce 0.082 g/gdw/hr of picolinic acid if excess ammonium ions had been present. Instead, growth is inhibited immediately and the culture washes out at a dilution rate of 0.12 hr-1.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([O:10]C)=[O:9].C[O-].[Na+].CO.Cl>O>[NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1sc(Br)cc1N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1cc(Br)sc1C(=O)O
Temperature: 75 °C
Reaction time: 5 h
Yield: 69.4 %

Procedure:
A mixture of methyl 3-amino-5-bromothiophene-2-carboxylate (0.236 g, 1.00 mmol), sodium methoxide (0.162 g, 3.00 mmol), methanol (4.0 mL) and water (1.0 mL) was stirred at 75° C. for 5 h. The mixture was cooled in an ice-bath and conc. HCl (0.250 mL, 3.00 mmol) was added. The mixture was concentrated in vacuo to remove methanol. The residue was triturated with water, and the precipitate was collected by filtration and washed with water to afford the title compound (0.154 g, 69%) as a pale orange solid:
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:30].[C:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:42])[CH3:41]>>[C:40]([N:43]1[CH2:48][CH2:47][N:46]([C:16]2[N:17]=[C:18]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[C:9]3[C:8](=[O:30])[N:7]([CH2:6][C:5]4[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=[C:3]([C:2]([F:1])([F:39])[F:38])[CH:4]=4)[CH2:14][CH2:13][CH2:12][NH:11][C:10]=3[N:15]=2)[CH2:45][CH2:44]1)(=[O:42])[CH3:41]
Reactant: CS(=O)(=O)c1nc2c(c(-c3ccc(F)cc3)n1)C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(c2nc3c(c(-c4ccc(F)cc4)n2)C(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCN3)CC1
Yield: 81.5 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 17; 86.5 mg) was reacted with 1-acetylpiperazine (23.1 mg) to obtain 2-(4-acetylpiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro-5-oxopyrimido[4,5-b][1,5]diazocine (76.4 mg, 82%).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=2[Cl:29])=[CH:14][C:5]=1[O:6][CH2:7][P:8](=O)([O:11][CH3:12])[O:9][CH3:10])([O-:3])=[O:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:31]>>[N+:1]([C:4]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=2[Cl:29])=[CH:14][C:5]=1[O:6][CH2:7][P:8](=[S:31])([O:11][CH3:12])[O:9][CH3:10])([O-:3])=[O:2]
Reactant: COP(=O)(COc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])OC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: COP(=S)(COc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])OC

Procedure:
In the same way, dimethyl 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxymethylphosphonate and phosphorus pentasulfide are reacted together to yield O,O'-dimethyl 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxymethylphosphonothioate
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[N:6][CH:7]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]#[CH:26])=[N:23][CH:24]=2)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]#[C:26][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[N:6][CH:7]=3)=[N:23][CH:24]=2)=[CH:17][CH:18]=1
Reactant: OCCCc1ccc(I)cn1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: OCCCc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cn1

Procedure:
The product was obtained analogously to Example 7.1e starting from 3-(5-iodopyridin-2-yl)propan-1-ol and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 0.80 g (74% of theoretical); C21H17ClN2O (M=348.825); calc.: molpeak (M+H)+: 349/351 (Cl); found: molpeak (M+H)+: 349/351 (Cl); HPLC-MS: 8.24 minutes (method A).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH2:6][N:7]([CH3:9])[CH3:8].[CH2:13]([Li])[CH2:14]CC.ICC.C(OCC)C>C1COCC1>[CH2:13]([C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[CH:10][C:5]=1[CH2:6][N:7]([CH3:9])[CH3:8])[CH3:14]
Reactant: COc1cccc(CN(C)C)c1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCI
Product: CCc1c(CN(C)C)cccc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
(3-Methoxybenzyl)dimethylamine (2.03 mL, 2.00 g, 12.1 mmol) was dissolved in anhydrous THF (20 mL) under nitrogen and cooled to 0° C. with an ice-water bath. Butyllithium (2.5M in hexanes, 5.3 mL, 13.3 mmol) was added dropwise via syringe over 10 min (temperature kept below 5° C.). After stirring at 0° C. for 2 h, iodoethane (1.1 mL, 2.1 g, 13.8 mmol) was added dropwise via syringe over 25 min (temperature kept below 5° C.). The reaction mixture was allowed to reach ambient temperature. After 4 h, the reaction contents were transferred with diethyl ether and adsorbed onto silica gel (3.8 g) upon removal of the solvent in vacuo. Chromatography gave (2-ethyl-3-methoxybenzyl)dimethylamine (1.30 g, 56%) as a pale yellow solid.
Reaction SMILES: [CH:1]1([N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8](Cl)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][C:25]([NH2:27])=[O:26])[CH:18]=1>>[CH:1]1([N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]([NH:27][C:25]([NH:24][CH2:23][C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)=[O:26])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)N(C1CCCCC1)C1CCCCC1
Reactant: NC(=O)NCc1cccnc1
Product: O=C(NCc1cccnc1)NC(=O)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in General Procedure 1 using dicyclohexyl carbamoyl chloride and 1-(3-pyridylmethyl)urea.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][O:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:19][CH2:20][CH3:21])[C:13]=2[OH:22])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38](=[O:40])[CH3:39])[C:32]=1[O:41][C:42](=[O:44])[CH3:43]>CN(C)C=O>[C:3]1([CH2:9][O:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38](=[O:40])[CH3:39])[C:32]=3[O:41][C:42](=[O:44])[CH3:43])=[C:14]([CH2:19][CH2:20][CH3:21])[C:13]=2[OH:22])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCc1c(O)ccc(C(=O)OCc2ccccc2)c1O
Reactant: CC(=O)Oc1cccc(CCCCCCBr)c1OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCCCc2cccc(OC(C)=O)c2OC(C)=O)ccc(C(=O)OCc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.5 %

Procedure:
To a suspension of 0.14 g (3.5 mmol, 60% on oil) of sodium hydride in 10 mL of anhydrous dimethylformamide stirred at room temperature was added 0.88 g (3.1 mmol) of 2,4-dihydroxy-3-propylbenzoic acid phenylmethyl ester. The reaction mixture was stirred for 2 hours and then 1.09 g (3.1 mmol) of 1-(6-bromohexyl)-2,3-bis(acetyloxy)benzene in 10 mL of dimethylformamide was added dropwise. Stirring at 50° was continued for 16 hours and then the solvent was removed on the oil pump. The crude product was purified by HPLC using 25% ethyl acetate-hexane to give 0.55 g (28% yield) of 4-[6-[2,3-bis(acetyloxy)phenyl]hexyloxy]-2-hydroxy-3-propylbenzoic acid phenylmethyl ester as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[C:12]([C:13]3[C:14]([NH:19][CH2:20][CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:11][S:10][CH:9]=2)=[CH:6][CH:5]=[C:4]([Cl:22])[N:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+]>O1CCCC1>[CH3:21][CH2:20][N:19]1[C:2]2[N:3]=[C:4]([Cl:22])[CH:5]=[CH:6][C:7]=2[C:8]2[C:12](=[CH:11][S:10][CH:9]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]1=2
Reactant: CCNc1ncccc1-c1cscc1-c1ccc(Cl)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1c2ncccc2-c2cscc2-c2ccc(Cl)nc21
Reaction time: 0.33 h
Yield: 45.4 %

Procedure:
A mixture of 3-bromo-4-(2-ethylaminopyridin-3-yl)thiophene [synthesis described above] (0.757 g), 2, 6-dichloro-3-tributylstannylpyridine (1.331 g), triphenylarsine (0.261 g), and trisdibenzylideneacetone dipalladium (0.092 g) in N-methylpyrrolidinone (3 mL) was heated at 100° C. for 48 hours. Tetrabutylammonium fluoride (1M in tetrahydrofuran, 3 mL) was added . After 2 hours, the mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. The residue was fractionated by chromatography to give 3-(2,6-dichloropyridin-3-yl)-4-(2-ethylaminopyridin-3-yl)thiophene (0.059 g) which was used directly in the next step. To a solution of 3-(2,6-dichloropyridin-3-yl)-4-(2-ethylaminopyridin-3-yl)thiophene (0.059 g) in tetrahydrofuran (2 mL) was added sodium hexamethyldisilazide (1 molar in tetrahydrofuran, 1 mL). After 20 minutes, the reaction was quenched with methanol, diluted with ethyl acetate, washed with water, dried, filtered and evaporated. The residue was fractionated by chromatography to give 6-chloro-8-ethyl-thienyl[3',4':6,5]dipyrido[2,3-b:3',2'-f]azepine (0.024 g) mp 139-141° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].Cl[CH2:15][CH2:16][O:17][CH2:18][CH2:19]Cl.O>CS(C)=O>[C:10]([C:9]1([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)#[N:11]
Reactant: ClCCOCCCl
Reactant: N#CCc1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC1(c2cc(F)cc(F)c2)CCOCC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 74.6 %

Procedure:
To a solution of 3,5-difluorophenylacetonitrile (24.2 g, 0.158 mol) in DMSO (240 ml) was added sodium hydride (60% w/w dispersion in mineral oil, 13.3 g, 0.332 mol) portionwise over 10 min. The reaction mixture was stirred for 40 min at room temperature and then bis-(2-chloroethyl)ether (24.9 g, 0.174 mol) was added slowly and stirring continued for an additional 1 h. The reaction mixture was poured into water (500 ml) and the mixture was extracted with an ethyl acetate-toluene mixture (2:1 v/v, 400 ml×3). The combined extracts were washed with 2 N aqueous HCl (300 ml), water (300 ml) and brine (300 ml), dried (MgSO4) and concentrated to 100 ml. The precipitated solids were collected and washed with cold Et2O (50 ml) to afford 26.3 g (71%) of the titled compound as off white solids.
Reaction SMILES: [C:1]([O:7][CH2:8]Br)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[I-].[Na+].[NH2:12][C:13]1[S:14][CH:15]=[C:16](/[C:18](=[N:41]/[O:42][CH3:43])/[C:19]([NH:21][C@@H:22]2[C:39](=[O:40])[N:24]3[C:25]([C:36]([O-:38])=[O:37])=[C:26]([CH2:29][CH:30]4[O:34][C:33](=[O:35])[CH:32]=[CH:31]4)[CH2:27][S:28][C@H:23]23)=[O:20])[N:17]=1.[Na+]>CC(C)=O.CN(C=O)C>[NH2:12][C:13]1[S:14][CH:15]=[C:16](/[C:18](=[N:41]/[O:42][CH3:43])/[C:19]([NH:21][C@@H:22]2[C:39](=[O:40])[N:24]3[C:25]([C:36]([O:38][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:37])=[C:26]([CH2:29][CH:30]4[O:34][C:33](=[O:35])[CH:32]=[CH:31]4)[CH2:27][S:28][C@H:23]23)=[O:20])[N:17]=1
Reactant: CC(C)(C)C(=O)OCBr
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CC3C=CC(=O)O3)CS[C@H]12)c1csc(N)n1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(CC3C=CC(=O)O3)CS[C@H]12)c1csc(N)n1

Procedure:
The title compound was prepared as described in Example 3, using pivaloyloxymethyl bromide (0.051 g) in acetone (1ml), sodium iodide (0.039 g) and sodium 7β-[2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido]-3-[(5RS)-2,5-dihydro-2-oxofuran-5-ylmethyl]ceph-3-em-4-carboxylate (0.13 g) in DMF (2 mls).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[N:12]2[CH2:13][CH2:14][CH:15]([C:16]([OH:18])=[O:17])[C:11]2=[CH:10][CH:9]=1)=[O:7].[N+](=[CH2:21])=[N-]>ClCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[N:12]2[CH2:13][CH2:14][CH:15]([C:16]([O:18][CH3:21])=[O:17])[C:11]2=[CH:10][CH:9]=1)=[O:7]
Reactant: C=[N+]=[N-]
Reactant: O=C(c1ccco1)c1ccc2n1CCC2C(=O)O
Solvent: ClCCl
Product: COC(=O)C1CCn2c(C(=O)c3ccco3)ccc21
Temperature: 25 °C

Procedure:
A solution of 200 mg. of 5-(2-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in 5 ml. of dichloromethane is treated with an excess of ethereal diazomethane, and the reaction mixture is maintained at room temperature for 30 minutes. The solvents and excess reagent are eliminated under reduced pressure and the residue crystallized from ethyl acetate-methanol, to yield methyl 5-(2-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH2:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH3:26].C(N(CC)CC)C.Cl>C(O)C.C(OCC)C>[ClH:1].[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:5]1[N:6]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:7]2[C:3]([N:4]=1)=[C:2]([N:30]1[CH2:31][CH2:32][N:27]([CH2:25][CH3:26])[CH2:28][CH2:29]1)[N:10]=[C:9]([CH3:11])[N:8]=2
Reactant: CCN1CCNCC1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3Cl)n(C3CCOCC3)c2n1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCN1CCN(c2nc(C)nc3c2nc(-c2ccccc2Cl)n3C2CCOCC2)CC1
Yield: 83.8 %

Procedure:
Heat a solution of 6-chloro-8-(2-chlorophenyl)-2-methyl-9-(tetrahydro-2H-pyran-4-yl)-9H-purine (0.0005 mol, 0.2 g), N-ethyl piperazine (0.0006 mol, 0.069 g, 1.1 equiv.), and triethylamine (0.0006 mol, 0.061 g, 1.1 equiv.) in ethanol (5.0 mL) at reflux for 20 hours. Alternatively, heat the reaction with microwave irradiation. Upon reaction completion, concentrate the reaction mixture under reduced pressure. Dissolve the residue in dry dichloromethane and wash with saturated sodium bicarbonate solution, water, and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give the residue. Purify by silica gel chromatography eluting with hexanes:acetone 90:10 to give the freebase. Add HCl (2M solution in ethanol) (1.0 equiv.) to the freebase (0.23 g, 0.500 mmol) in diethyl ether (5 mL) at 0° C. and stir for 2 hours at room temperature. Filter and wash precipitate with diethyl ether. Dry the precipitate under vacuum to give the title compound (0.2 g). MS (m/z): 441.28 (M+1). Alternatively, prepare the HCl salt by dissolving the freebase in acetone, 1:1 acetonitrile:water, or another suitable organic solvent, then add with stirring a solution of aqueous or ethereal HCl. Then lyophilize to afford the hydrochloride salt.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH2:14][CH3:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:16]12[C:25](=[O:26])[O:24][C:22](=[O:23])[CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21]2>>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]([CH2:13][CH2:14][CH3:15])[C:22]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]3[C:25]([OH:24])=[O:26])=[O:23])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1OC(=O)C2CCCCC12
Reactant: CCCNc1ccc(-n2ccnc2)cc1
Product: CCCN(C(=O)C1CCCCC1C(=O)O)c1ccc(-n2ccnc2)cc1

Procedure:
In a manner similar to Preparation 6, react 4-(1H-imidazol-1-yl)-N-propylbenzenamine with 1,2-cyclohexanedicarboxylic acid anhydride to obtain the title compound.
Reaction SMILES: C[O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[C:14](=[O:32])[NH:15][C:16](=[O:31])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][C:23]([N+:27]([O-:29])=[O:28])=[CH:24][CH:25]=3)[N:20]([CH3:30])[CH:19]=2)=[CH:5]1.Cl>C1COCC1>[OH:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[C:14](=[O:32])[NH:15][C:16](=[O:31])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][C:23]([N+:27]([O-:29])=[O:28])=[CH:24][CH:25]=3)[N:20]([CH3:30])[CH:19]=2)=[CH:5]1
Reactant: COCn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccccc21
Agent: Cl
Solvent: C1CCOC1
Product: Cn1cc(C2=C(c3cn(CO)c4ccccc34)C(=O)NC2=O)c2ccc([N+](=O)[O-])cc21
Yield: 17.5 %

Procedure:
A solution of 727.5 mg of 3-[1-(methoxymethyl)-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indole-3-yl)-pyrrole-2,5-dione (11) from Step F above in 65 ml of THF was treated with approximately 40 ml of 2N-HCl. The reaction mixture was refluxed for 5 hours, cooled and the product was extracted with ethyl acetate. The organic phase was dried on MgSO4 and the solvent evaporated to give an orange solid. Chromatographic purification of this material yielded 123.3 mg of 3-(1-hydroxymethyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione (II) as a red solid, mp 210-213° C. MS: (M+), m/z 416.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][CH2:8][OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Mn]([O-])(=O)(=O)=O.[K+]>ClCCl>[CH:1]1([CH2:6][CH2:7][CH:8]=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCC1CCCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=CCCC1CCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.8 %

Procedure:
3-Cyclopentyl-1-propanol (15.0 g, 117 mmol) was dissolved in dichloromethane (600 mL) and treated with Celite (50 g) and pyridinium chlorochromate (50.0 g, 232 mmol). The reaction was stirred at room temperature for 24 hours. The reaction was found to be complete by thin layer chromatography (stain: potassium permanganate) and filtered through a pad of silica (dichloromethane) to afford 3-cyclopentyl-propionaldehyde as an oil (10.3 g, 70%). 1H NMR (CDCl3, 300 MHz) δ 11.1-10.8 (br s, 1 H), 2.36 (t, 7.73 Hz, 2 H), 1.8-1.5 (m, 9 H), 1.09 (m, 2 H).