Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[N:6][CH:5]=[C:4]([CH3:11])[N:3]=1.[CH2:12](O)[CH3:13]>>[OH:1][C:2]1[C:7]([C:8]([O:10][CH2:12][CH3:13])=[O:9])=[N:6][CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: CCO
Reactant: Cc1cnc(C(=O)O)c(O)n1
Product: CCOC(=O)c1ncc(C)nc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Hydroxy-6-methylpyrazine-3-carboxylic acid (32.5 g), prepared as described in J. Chem. Soc. 1955, 1379, was suspended in 500 mL of ethanol. The solution was cooled in an ice bath and hydrogen chloride gas was bubbled into the solution for 15 minutes. The mixture was stirred overnight at ambient temperature and then refluxed for 2 hours. The ethanol was removed under reduced pressure and the residue obtained crystallized from ethanol/ether to give 21.48 g of the title compound. m.p. 153° C.
Reaction SMILES: [OH-].[K+].C(N(CC)C(=O)[S:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=1[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C>CO.C1COCC1>[SH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=1[C:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:25]
Reactant: CCN(CC)C(=O)Sc1cc(OC)c(OC)cc1C(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(S)c(C(=O)c2ccccc2)cc1OC
Temperature: 25 °C
Yield: 87.8 %

Procedure:
Potassium hydroxide pellets (58.6 g) was slowly added to a solution of the product (85.0 g) from step (j) dissolved in 1 L of methanol/THF (1:1). After refluxing for 3 hours, the reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was triturated with 1N HCl then extracted with EtOAc. The organic layer was separated, washed with 2×250 ml of 1N HCl then washed with 3×400 ml of 1N NaOH. The aqueous basic layers were combined and acidified with conc. HCl to afford the title product (54.8 g) as a gold solid. 1H NMR was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([O:23][C:24]([F:27])([F:26])[F:25])[CH:3]=1.[N:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[N:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=4[C:13]=3[CH3:22])(=[O:10])=[O:11])=[C:4]([O:23][C:24]([F:27])([F:26])[F:25])[CH:3]=2)=[CH:30][CH:29]=1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2OC(F)(F)F)sc2ccc(F)cc12
Reactant: OB(O)c1ccncc1
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: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3ccncc3)cc2OC(F)(F)F)sc2ccc(F)cc12
Yield: 73.6 %

Procedure:
This compound was prepared in analogy to example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethoxy-phenyl)-amide (0.075 g) and 4-pyridineboronic acid (0.029 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.25 ml) and 2 M aqueous sodium carbonate solution (0.6 ml) with tetrakis(triphenylphosphine)palladium (0.009 g) to obtain the title compound (0.055 g) as a colorless solid. MS (ISP): 483.0 (M+H)+
Reaction SMILES: [CH:1]1([C:7]2[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=2[CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:20][C:21](=[CH2:23])[CH3:22].OS(O)(=O)=O>O1CCOCC1>[CH:1]1([C:7]2[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=2[CH2:9][C@@H:10]([C:12]([O:14][C:21]([CH3:23])([CH3:22])[CH3:20])=[O:13])[NH2:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C(C)C
Reactant: N[C@@H](Cc1ccccc1C1CCCCC1)C(=O)O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1C1CCCCC1
Yield: 80 %

Procedure:
According to example 54, 0.73 g of 2-cyclohexyl-L-phenylalanine.HCl was treated with 25 mL of isobutylene in 25 mL of 1,4-dioxane in the presence of 0.4 mL of conc. H2SO4. Work-up followed by acidification of the free amine with ethereal HCl afforded 0.70 g (80%) of tert-butyl 2-cyclohexyl-L-phenylalaninate.HCl as a yellow foam.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[CH:4]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH3:6])[CH3:5].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([Cl:31])[CH:30]=1)[C:25](Cl)=[O:26]>ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([Cl:31])[CH:30]=1)[C:25]([N:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]([CH3:6])[CH3:5])=[O:26]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)CNC(C)C
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C(=O)c1cc(Cl)cc(Cl)c1)C(C)C
Temperature: 25 °C

Procedure:
A 250 milliliter round-bottom, 3-neck flask was equipped with a condenser, a thermometer, a dropping funnel, and a Teflon® spin-bar magnet for stirring. The outlets were protected from moisture by calcium chloride drying tubes, and the flask was immersed in an ice-water cooling mixture. The flask was charged with an 80 milliliter dichloromethane solution containing 0.015 mole (2.2 grams) of the ethyl N-isopropylaminoacetate (described above) and 0.015 mole (1.5 grams) of triethylamine. The solution was stirred while cooling in an ice-water bath. A 20 milliliter solution of dichloromethane containing 0.015 mole (3.14 grams) of 3,5-dichlorobenzoylchloride was added dropwise over a period of 1.0 hour with stirring and the stirring was continued for several hours followed by allowing the mixture to warm to room temperature. The reaction solution was washed four times with water (25 milliliters) to remove the triethylamine hydrochloride. The washed organic solution was filtered to remove the phase water and concentrated first by rotary evaporation (house vacuum, water bath to 65° C.) to 4.9 grams of a dull yellow syrup (nD20 1.5257) and then, using a vacuum pump (<1 mm, oil bath to 50° to 60° C.) for 1.0 hour, to 4.5 grams (94 percent crude yield) nD20 (1.5280) ethyl N-3,5-dichlorobenzoyl-N-isopropylaminoacetate. It had a mass spectra (m/e) of molecular weight of 317, an infrared spectra (neat) mull technique with ester C=O band at 1745 centimeters-1 and amide (C=O) band at 1635 centimeters-1. It had the following nuclear magnetic resonance values δ (CDCl3) of 1.1 (doublet, 6H, (CH3)2C--), 1.3 (triplet, 3H, CH3--), 3.7-4.5 (4.0 broad singlet, 4.2 quartet, (overlap), 5H, CH2N, CH2, CH (heptet obscured)), and 7.3-7.5 (multiplets, 3H, aromatic).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:23])=[CH:8][CH:7]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33]([NH:35][C:36]1[CH:41]=[C:40]([Cl:42])[C:39]([O:43][CH3:44])=[CH:38][C:37]=1[O:45][CH3:46])=[O:34].CN(C=O)C>O>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:32][C:33](=[O:34])[NH:35][C:36]3[CH:41]=[C:40]([Cl:42])[C:39]([O:43][CH3:44])=[CH:38][C:37]=3[O:45][CH3:46])[C:13]2=[O:23])=[CH:8][CH:7]=1)[CH3:2]
Reactant: COc1cc(OC)c(NC(=O)CBr)cc1Cl
Reactant: CCOC(=O)Cc1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(-n2c(=O)c3ccccc3n(CC(=O)Nc3cc(Cl)c(OC)cc3OC)c2=O)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A round bottomed flask charged with [4-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-acetic acid ethyl ester (Intermediate H) (2.0 g, 6.17 mmol), K2CO3 (2.5 eq, 2.14 g, 15.52 mmol), and 2-bromo-N-(5-chloro-2,4-dimethoxy-phenyl)-acetamide (Intermediate C) (1.02 eq, 1.99 g, 6.49 mmol) is treated with dry DMF (20 ml). The reaction is stirred at RT for 72 hours. The reaction mixture is diluted with distilled water and stirred for 15 minutes. The precipitate formed was filtered, washed with water and dried under vacuum to give the title compound; [M+H]+ 552
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=[O:17])[C:8](=[O:23])[CH:7]=1.[Br:29]N1C(=O)CCC1=O>ClCCl>[Br:29][C:7]1[C:8](=[O:23])[N:9]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=[O:17])[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:2]=1[F:1]
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)cc1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Reaction time: 14 h
Yield: 74 %

Procedure:
3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid (5.9 g, 15.2 mmol) (from step 3 above) was taken up in dichloromethane (25 ml). N-Bromosuccinimide was added and the reaction stirred for 14 hours. The dichloromethane was removed in vacuo and the residue was taken up in acetonitrile. The precipitate was collected on a filter pad and rinsed with acetonitrile to yield the desired product as a white solid (5.2 g, 74%). 1H NMR (300 MHz, CD3OD) δ 7.87 (dd, J=7.85, 1.61,Hz, 1H), 7.82 (d, J=1.81 Hz, 1H), 7.69 (app q, J=8.06 Hz 1H), 7.57 (d, J=8.06 Hz, 1H), 7.09 (dt, J=8.66, 2.22 Hz, 1H), 6.70 (s, 1H), 5.40 (s, 2H), 2.14 (s, 3H), 2.02 (s, 3H); ES-MS m/z 464 (M+H). ES-HRMS m/z 464.0275 (M+H calcd for C21H17BrF2NO4 requires 464.0304).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6](O)[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:46])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38]S(C)(=O)=O)[C:24]=1[CH2:43][CH2:44][CH3:45])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:15]([O:17][C:18](=[O:46])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:24]=1[CH2:43][CH2:44][CH3:45])[CH3:16]
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOS(C)(=O)=O
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCOCCOc2c(C(C)=O)ccc(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 17.7 %

Procedure:
A mixture of 1 g (0.0052 mol) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.45 g (0.0052 mol) of 4-[4-acetyl-3-[2-[2-[(methylsulfonyl)oxy]ethoxy]-ethoxy]-2-propylphenoxy]butanoic acid ethyl ester and 2.6 g (0.019 mol) of anhydrous potassium carbonate in 100 ml of anhydrous acetone and 50 ml of anhydrous dimethylformamide was stirred at reflux for 19 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil which was treated with ethyl acetate and sodium chloride solution. The organic phase was washed with 1N sodium hydroxide solution and sodium chloride solution. The yellow oil obtained on concentration of the ethyl acetate was purified by column chromatography, eluting with 5% ethyl acetate-toluene to yield 0.526 g (18% yield) of 4-[4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester as a pale yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[C:9](F)=[N:10][CH:11]=[C:12]([F:14])[CH:13]=1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]([CH3:29])[C:27](=[O:30])[N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:25](=[O:39])[C:24]=2[CH3:40])=[C:19]([CH3:41])[CH:18]=1.O>CS(C)=O>[Cl:7][C:8]1[C:9]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:28]([CH3:29])[C:27](=[O:30])[N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:25](=[O:39])[C:24]=3[CH3:40])=[C:19]([CH3:41])[CH:18]=2)=[N:10][CH:11]=[C:12]([F:14])[CH:13]=1
Reactant: Cc1cc(O)ccc1-c1c(C)c(=O)n(COCC[Si](C)(C)C)c(=O)n1C
Reactant: Fc1cnc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Oc2ncc(F)cc2Cl)ccc1-c1c(C)c(=O)n(COCC[Si](C)(C)C)c(=O)n1C
Temperature: 80 °C
Reaction time: 6 h

Procedure:
Cesium carbonate (476 mg, 1.46 mmol) was added to a mixture of 3-chloro-2,5-difluoropyridine (97%, 150 mg, 0.97 mmol) and C5 (366 mg, 0.972 mmol) in dimethyl sulfoxide (5 mL), and the reaction mixture was stirred at 80° C. for 6 hours. Water was added, and the mixture was extracted three times with ethyl acetate; the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 10% to 40% ethyl acetate in heptane) provided the product as a sticky solid. Yield: 414 mg, 0.818 mmol, 84%. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=2.7 Hz, 1H), 7.64 (dd, J=7.1, 2.7 Hz, 1H), 7.09-7.15 (m, 3H), 5.51 (AB quartet, JAB=9.3 Hz, ΔνAB=3.4 Hz, 2H), 3.74-3.80 (m, 2H), 3.07 (5, 3H), 2.19 (5, 3H), 1.69 (5, 3H), 1.00-1.06 (m, 2H), 0.03 (5, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH2:31]([N:33]=[C:34]=[S:35])[CH3:32].O.[Cl-].[Na+]>CN(C)C=O>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH3:30])[N:20]=[CH:19][N:18]=[C:17]2[N:14]1[CH2:13][CH2:12][N:11]([C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:34]([NH:33][CH2:31][CH3:32])=[S:35])=[CH:3][CH:4]=2)=[O:10])[CH2:16][CH2:15]1
Reactant: CCN=C=S
Reactant: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc(N)cc4)CC3)c2cc1OC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=S)Nc1ccc(NC(=O)N2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
To a solution of 514.0 mg (1.26 mmol) of N-(4-aminophenyl)-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamide obtained in Example 221 in 10 ml of dimethylformamide was added 0.13 ml (1.51 mmol) of ethyl isothiocyanate, followed by overnight stirring at room temperature. To the resulting mixture was added 0.13 ml (1.51 mmol) of ethyl isothiocyanate, followed by overnight stirring. The reaction mixture was poured into water, and sodium chloride was added thereto. The precipitated crystals were collected by filtration, washed with water, and dried, followed by purification by silica gel chromatography to give the desired compound as colorless crystals.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH3:8])[CH2:6][NH2:7])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH:16]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[C:20]=2[CH:19]=[CH:18][N:17]=1>C(Cl)(Cl)Cl>[C:1]([NH:4][CH:5]([CH3:8])[CH2:6][NH:7][S:26]([C:21]1[C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:25]=2[CH:24]=[CH:23][CH:22]=1)(=[O:27])=[O:28])(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CC(=O)NC(C)CN
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)NC(C)CNS(=O)(=O)c1cccc2cnccc12
Reaction time: 2 h
Yield: 82.9 %

Procedure:
In 50 ml of a chloroform solution containing 2.0 g of 2-acetylaminopropylamine and 2.6 g of triethylamine was added dropwise 50 ml of a chloroform solution containing 3.28 g of 5-isoquinolinesulfonyl chloride under cooling with ice. The mixed solution was stirred at a temperature of 15° C. to 25° C. for two hours, and then the reaction solution was washed with water and dried with anhydrous sodium sulfate. The chloroform was distilled therefrom under reduced pressure. The crystalline residue thus obtained was recrystallized from methanol to give 3.67 g of N-(2-acetylaminopropyl)-5-isoquinolinesulfonamide in a yield of 83%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[N:18]=[C:17]2[CH:19]=[CH:20][CH:21]=[C:22]([N+:23]([O-:25])=[O:24])[C:16]2=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[N:18]=[C:17]3[CH:19]=[CH:20][CH:21]=[C:22]([N+:23]([O-:25])=[O:24])[C:16]3=[N:15]2)[CH:7]=[CH:6][CH:5]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCn1nc2cccc([N+](=O)[O-])c2n1
Product: O=[N+]([O-])c1cccc2nn(CCC#Cc3cccc(CF)n3)nc12
Yield: 40909.1 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (92 mg, 0.48 mmol) and 2-but-3-ynyl-4-nitro-2H-benzo[d][1,2,3]triazole (95 mg, 0.44 mmol, Example, 160(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 59 mg (0.18 mol, 42%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-4-nitro-2H-benzo[d][1,2,3]triazole as an orange oil.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([C:22]3[CH:23]=[N:24][NH:25][CH:26]=3)=[N:8][C:7]=2[N:6]=[CH:5]1)[CH2:2][CH3:3].Br[CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:21])[CH3:19])[C:9]([C:22]3[CH:23]=[N:24][N:25]([CH2:28][C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)[CH:26]=3)=[N:8][C:7]=2[N:6]=[CH:5]1)[CH2:2][CH3:3]
Reactant: BrCc1cccnc1
Reactant: CCCn1cnc2nc(-c3cn[nH]c3)n(COCC[Si](C)(C)C)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1cnc2nc(-c3cnn(Cc4cccnc4)c3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 8.6 %

Procedure:
A mixture of 1-Propyl-8-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (100 mg, 0.2 mmol), 3-Bromomethylpyridine (55 mg, 0.3 mmol), K2CO3 (50 mg, 0.3 mmol) and DMF were stirred at 60° C. for 2 hours. Organic volatiles were evaporated and purified to obtain pure 1-Propyl-8-(1-pyridin-3-ylmethyl-1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (8 mg, 6%) as an colourless oil.
Reaction SMILES: [NH2:1][CH:2]1[C:28](=[O:29])[N:4]2[C:5]([C:12]([O:14]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:13])=[C:6](/[CH:9]=[CH:10]\[CH3:11])[CH2:7][S:8][C@H:3]12.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:1][CH:2]1[C:28](=[O:29])[N:4]2[C:5]([C:12]([OH:14])=[O:13])=[C:6](/[CH:9]=[CH:10]\[CH3:11])[CH2:7][S:8][C@H:3]12
Reactant: C/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C/C=C\C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
54.5 g (0.123 mol of benzhydryl 7-amino-3-[(Z)-1-propen-1-yl]-3-cephem-4-carboxylate (Example 10) are added to a stirred solution of 500 ml of trifluoroacetic acid (TFA) and 31 ml of anisole, which is cooled to 0° C. The mixture is stirred at room temperature for 1 hour and is then concentrated in vacuo at 30° C. and the oily residue is stirred with 600 ml of ether for 1 hour. The precipitate is filtered off with suction and washed with 300 to 400 ml of ether and the residue on the filter is dried in vacuo for 3 hours. The trifluoroacetate is suspended in 300 ml of water, the suspension is cooled to +5° C. and the pH is brought to 0.2-0.4 with 12N HCl. The resulting clear solution is cooled to +5° C. and stirred with 4 g of active charcoal for 10 minutes. The active charcoal is filtered off with suction over kieselguhr and rinsed with about 50 ml of 0.1N HCl. The filtrate is brought to pH 2.1 at +5° C. with 20% strength NaOH and the product which has precipitated out is left to stand in a refrigerator for 1 hour in order to bring the crystallization to completion. The crystal sludge is filtered off with suction, washed with 100 ml of water and 300 ml of acetone and dried in vacuo.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.O.O.[Sn](Cl)Cl>CO>[NH2:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]([F:11])=[N:4][CH:5]=1
Reactant: O=[N+]([O-])c1cnc(F)c(Br)c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: Nc1cnc(F)c(Br)c1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution of 3-bromo-2-fluoro-5-nitropyridine from step 131a above (5.0 g, 23 mmol) in MeOH (100 mL) was added tin(II) chloride dihydrate. The mixture was heated at reflux for 3 hours, then cooled to ambient temperature and concentrated in vacuo. The residue was diluted with saturated aqueous NaHCO3 and EtOAc resulting in formation of an emulsion which was filtered. The filtrate was poured into a separatory funnel and the layers were separated. The aqueous phase was extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. Purification by chromatography (silica gel; hexane/EtOAc, 70:30) afforded 3.61 g (83%) of the title compound as a yellow solid: mp 91-92° C.; 1H NMR (CDCl3, 300 MHz) δ 7.15 (dd, J=2.5, 7.5 Hz, 1H), (dd, J=2.0, 2.5 Hz, 1H); MS (CI/NH3) m/z 191, 193 (M+H)+ 208, 210 (M+NH4)+.
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[C:8]([NH2:14])[CH:7]=1)[CH2:2][CH3:3].C1(N(CCC(OCC)=O)C(=O)C2C=CC(NCC)=C(N)C=2)C=CC=CC=1.[Cl:49][CH2:50][C:51](O)=[O:52]>O1CCCC1>[CH2:1]([N:4]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[C:8]([NH:14][C:51](=[O:52])[CH2:50][Cl:49])[CH:7]=1)[CH2:2][CH3:3]
Reactant: O=C(O)CCl
Reactant: CCCN(CCC(=O)OCC)C(=O)c1ccc(NC)c(N)c1
Agent: CCNc1ccc(C(=O)N(CCC(=O)OCC)c2ccccc2)cc1N
Solvent: C1CCOC1
Product: CCCN(CCC(=O)OCC)C(=O)c1ccc(NC)c(NC(=O)CCl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.8 g (5.9 mMol) of 3-amino-4-methylamino-benzoic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide [prepared analogously to 3-amino-4-ethylamino-benzoic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide], 1.1 g (6.8 mMol) of N,N'-carbonyldiimidazole and 0.65 g (6.9 mMol) of chloroacetic acid in 75 ml tetrahydrofuran was stirred for 1 hour at room temperature. Then the solvent was distilled off in vacuo, and the crude product was purified by flash chromatography (silica gel; methylene chloride/ethanol=49:1). Yield: 1.7 g (77% of theory) yellow oil, Rf value: 0.58 (silica gel; ethyl acetate/ethanol/ammonia=90:10:1)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:24])[N:5]([CH:12]1[CH2:17][CH:16]([O:18][C:19](=[O:21])[CH3:20])[C:15](=[O:22])[NH:14][C:13]1=[O:23])[C:6]2=[O:11].[CH3:25][O:26][CH2:27][C:28](Cl)=[O:29]>O1CCCC1>[CH3:25][O:26][CH2:27][C:28]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:24])[N:5]([CH:12]1[CH2:17][CH:16]([O:18][C:19](=[O:21])[CH3:20])[C:15](=[O:22])[NH:14][C:13]1=[O:23])[C:6]2=[O:11])=[O:29]
Reactant: CC(=O)OC1CC(N2C(=O)c3cccc(N)c3C2=O)C(=O)NC1=O
Reactant: COCC(=O)Cl
Solvent: C1CCOC1
Product: COCC(=O)Nc1cccc2c1C(=O)N(C1CC(OC(C)=O)C(=O)NC1=O)C2=O

Procedure:
A solution of 3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxo-5-acetoxypiperidine (1 g, 3.5 mmol) and methoxyacetyl chloride (0.38 g, 3.5 mmol) in tetrahydrofuran (20 mL) is heated at reflux for 1 hour. The solvent is removed in vacuo to give 3-[4- (2-methoxyacetylamino)-1,3-dioxoisoindolin-2-yl]-2,6-dioxo-5-acetoxypiperidine which is further purified by column chromatography.
Reaction SMILES: N(OC(C)(C)C)=O.[F:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[CH3:16])N.[CH3:17][S:18]SC>C(Cl)(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]([S:18][CH3:17])[CH:13]=[CH:14][C:15]=1[CH3:16]
Reactant: Cc1ccc(N)cc1F
Reactant: CSSC
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)Cl
Product: CSc1ccc(C)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
t-Butyl nitrite (4 ml) was added to a mixture of 3-fluoro-4-methylaniline (5 g) and dimethyldisulphide (36 ml) in chloroform. After the reaction had initiated t-butyl nitrite (22 ml) and a solution of 3-fluoro-4-methylaniline (20.0 g) in chloroform were added simultaneously. The mixture was then stirred at room temperature for 2 hours. The mixture was washed with water, hydrochloric acid (2M), water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 2-fluoro-4-(methylsulphenyl)toluene (25.37 g) as a red oil which was not further purified.