Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1.ClC(OCC)=O.[CH2:24]([NH2:27])[CH2:25][NH2:26].Cl>C(Cl)(Cl)Cl>[ClH:8].[NH2:26][CH2:25][CH2:24][NH:27][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([Cl:8])=[CH:17][CH:16]=1
Reactant: NCCN
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: NCCNC(=O)c1ccc(Cl)cc1
Yield: 85.6 %

Procedure:
23 ml (0.17 mol) of triethylamine are added dropwise at 0° to a suspension of 23.5 g (0.15 mol) of 4-chlorobenzoic acid and 15 ml (0.16 mol) of ethyl chloroformate in 200 ml of chloroform. After completion of the addition (0.5 hour), the solution obtained is added dropwise at 0° to a solution of 50 ml (0.75 mol) of ethylenediamine in 100 ml of chloroform. After completion of the reaction, 115 ml of concentrated hydrochloric acid are added dropwise at 0°. The acidic mixture is filtered and the neutral constituents remaining are removed by extraction with chloroform. The aqueous phase is then made alkaline with sodium hydroxide solution and extracted several times with chloroform. The chloroform extracts are dried and concentrated. The residue is converted into the hydrochloride which is recrystallized from ethanol/ether. There are obtained 15.1 g of N-(2-aminoethyl)-4-chlorobenzamide hydrochloride, m.p. 212°-214°. The free base melts at 43°-45°.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=O.Cl.[NH2:18][OH:19].N1C=CC=CC=1.ClCCl>CCCCCC>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=[N:18][OH:19]
Reactant: NO
Reactant: COc1cccc(C(=O)c2sccc2Br)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: c1ccncc1
Product: COc1cccc(C(=NO)c2sccc2Br)c1
Yield: 85.4 %

Procedure:
Stir a mixture of (3-bromothiophen-2-yl)-(3-methoxyphenyl)methanone (7 g, 0.024 mol), hydroxylamine hydrochloride (3.09 g, 0.048 mol) and pyridine (40 mL) overnight at room temperature, and then heat the mixture (100° C.-105° C.) for four hours. TLC (dichloromethane) shows that the reaction is complete. Quench the reaction mixture with water and extract with ether (three times). Wash the ether phase with HCl (3N) and water, dry (MgSO4), filter and concentrate to yield an oil that solidifies. Recrystallize the solid from ether:hexane to obtain the title compound (6.4 g, 87% Yield), m.p. 102-103° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(O)c(CO)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The compound obtained in (a) (1.80 g, 10 mmol) was mixed with 50 ml of methanol, and sodium borohydride (189 mg, 5 mmol) was added portionwise while maintaining the temperature below 20° C. After stirring for 5 minutes at room temperature, the methanol was evaporated off and the medium was then poured onto a 6N HCl/ice mixture, extracted with ethyl ether, washed with water to neutral pH, dried over magnesium sulfate and filtered, and the solvents were evaporated off. The properties of the final product were as follows:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[O:15][CH3:16].[N:17]([O-:19])=[O:18].[Na+].C(O)(=O)C.[N+]([O-])(O)=O>O>[CH3:16][O:15][C:6]1[C:5]([O:4][CH2:3][CH2:2][Cl:1])=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[C:8]([CH:7]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(OCCCl)c(OC)c1
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(OC)c(OCCCl)cc1[N+](=O)[O-]
Temperature: 40 °C
Yield: 966.6 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer and a dropping funnel were placed 1.02 g (4.08 mmol) of methyl 4-(2-chloroethoxy)-3-methoxybenzoate (purity: 98%) obtained in Reference Example III-1, 0.03 g (0.40 mmol) of sodium nitrite, and 1.25 mL of acetic acid. The resulting mixture was heated to 40° C. under stirring. To the reaction mixture was dropwise added slowly 1.72 g (16.5 mmol) of nitric acid (60 wt. %), and the mixture was heated to the same temperature for 5 hours. After the reaction was complete, 5 mL of water was added to the reaction mixture, and the aqueous mixture was cooled to 20° C., precipitating a crystalline product. The crystalline product was collected by filtration, washed with 5 mL of water, and dried under reduced pressure, to give 1.12 g (isolated yield: 93.0%, purity: 98% in terms of area percentage determined by high performance liquid chromatography) of methyl 5-methoxy-4-(2-chloroethoxy)-2-nitrobenzoate as a white crystalline product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[Cl:18][C:19]1[CH:20]=[C:21]([C:23]([CH3:26])=[CH:24][CH:25]=1)[NH2:22]>CN(C=O)C>[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:21]([NH:22][C:2]2[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=2)[CH:20]=1
Reactant: Cc1ccc(Cl)cc1N
Reactant: Clc1ncnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)cc1Nc1ncnc(Cl)n1
Temperature: 0 °C

Procedure:
2,4-Dichloro-1,3,5-triazine (3 g, 20 mmol) was dissolved in DMF (20 mL) under N2 and cooled to 0° C. DIEA (2.58 g, 20 mmol) was added, followed by 3-chloro-6-methylaniline (2.83 g, 20 mmol). The reaction solution was stirred with gradual warming to RT. The reaction was quenched after 3 h with water, then extracted 3 times with EtOAc. The EtOAc extracts were washed with brine, combined, dried over Na2SO4, filtered, and concentrated. The crude was purified by silica gel chromatography (25%, 40%, 60% EtOAc/Hexane step gradient) giving (5-chloro-2-methyl-phenyl)-(4-chloro-[1,3,5]triazin-2-yl)-amine as a white solid.
Reaction SMILES: [I:1][CH3:2].[CH2:3]([O:6][C:7]([N:9]1[C@H:13]([CH2:14][C:15]2[N:16]=[CH:17][N:18]3[CH:22]=[CH:21][S:20][C:19]=23)[CH2:12][C@H:11]([S:23][C:24]2[C@H:25]([CH3:41])[C@@H:26]3[C@@H:36]([C@H:37]([OH:39])[CH3:38])[C:35](=[O:40])[N:27]3[C:28]=2[C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30])[CH2:10]1)=[O:8])[CH:4]=[CH2:5]>>[I-:1].[CH2:3]([O:6][C:7]([N:9]1[C@H:13]([CH2:14][C:15]2[N:16]([CH3:2])[CH:17]=[N+:18]3[CH:22]=[CH:21][S:20][C:19]=23)[CH2:12][C@H:11]([S:23][C:24]2[C@H:25]([CH3:41])[C@@H:26]3[C@@H:36]([C@H:37]([OH:39])[CH3:38])[C:35](=[O:40])[N:27]3[C:28]=2[C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30])[CH2:10]1)=[O:8])[CH:4]=[CH2:5]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3ncn4ccsc34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: CI
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3c4scc[n+]4cn3C)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: [I-]
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Iodomethane (0.468 ml) is added to 43.0 mg of allyl (1R,5S,6S)-2-[(3S,5R)-1-allyloxycarbonyl-5-(imidazo[5,1-b]thiazol-7-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate described in Example 34-a), and the mixture is stirred in an argon atmosphere in a light-shielded state at room temperature for 19 hr. The excess reagent is removed by evaporation under reduced pressure to give a crude product of allyl(1R,5S,6S)-2-[(3S,5R)-1-allyloxycarbonyl-5-(6-methylimidazo[5,1-b]thiazolium-7-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate iodide. The procedure of Example 11-b) is repeated, except that the whole quantity of the crude product prepared just above is used. Thus, 3.2 mg of the title compound is obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3]#[C:4][CH2:5]Cl.C([O-])([O-])=O.[K+].[K+].[F:13][C:14]([F:44])([F:43])[C:15]1[CH:16]=[C:17]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C@H:21]1[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)=[O:19]>CN(C=O)C>[F:42][C:39]([F:40])([F:41])[C:37]1[CH:36]=[C:17]([CH:16]=[C:15]([C:14]([F:13])([F:43])[F:44])[CH:38]=1)[C:18]([N:20]1[CH2:25][CH2:24][N:23]([CH2:5][C:4]#[C:3][CH2:2][Cl:1])[CH2:22][C@H:21]1[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)=[O:19]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Reactant: ClCC#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CC#CCCl)C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 50 °C
Reaction time: 5 h

Procedure:
22 ml 1,4-dichloro-2-butine was added to a suspension of 43 g K2CO3 in 100 ml DMF at 20° C. under a protective gas atmosphere. The mixture was heated to 50° C. and then a solution of 50 g (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(1H-indol-3-ylmethyl)piperazine in 200 ml DMF was added dropwise to this receiving solution. The resulting mixture was stirred for 5 hours at 50° C. Stirring was continued overnight at room temperature, undissolved precipitate was filtered out, and the precipitate was washed twice with 200 ml portions of ethyl acetate. The combined filtrates were evaporated to dryness in a vacuum, and the resulting oil was purified by column chromatography (silica gel; mobile solvent: n-hexane/ethyl acetate 60/40 to 30/70). The combined product fractions were again evaporated to dryness. 40.4 g of (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]2-(1H-indol-3-ylmethyl]-4-(4-chloro-2-butin-1-yl)piperazine was obtained as an amorphous yellowish solid, which was used for the next synthesis stage without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([CH3:22])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH3:22][C:14]1[CH:13]=[C:12]([CH2:11][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1cc(CCl)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc(COc2ccc(C=O)cc2)c2ccccc2n1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
p-Hydroxybenzaldehyde (3.18 g, 26.1 mmol), 4-chloromethyl-2-methyl-quinoline (5.0 g, 26.1 mmol), and potassium carbonate (7.2 g, 52 mmol) were combined in acetonitrile (100 mL) and heated to reflux overnight. The reaction was allowed to cool to room temperature, diluted with ethyl acetate, filtered to remove the solids, and concentrated to give a semi-solid residue. The crude product was crystallized from ethyl ether to give 4-(2-methyl-quinolin-4-ylmethoxy)-benzaldehyde (6.5 g, 90%) as an off white precipitate. MS found: (M+H)+=278.
Reaction SMILES: [F:1][C:2]([CH3:9])([CH3:8])[C:3](=[O:7])[CH2:4][C:5]#[N:6].[CH3:10][Si](C=[N+]=[N-])(C)C>C(OCC)C>[F:1][C:2]([CH3:9])([CH3:8])[C:3]([O:7][CH3:10])=[CH:4][C:5]#[N:6]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(F)C(=O)CC#N
Solvent: CCOCC
Product: COC(=CC#N)C(C)(C)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 91 %

Procedure:
To a stirred solution of 4-fluoro-4-methyl-3-oxopentanenitrile (1 g, 7.75 mmol) in dry diethyl ether (150 mL) at 0° C., was added dropwise (trimethylsilyl)diazomethane (4.65 mL of a 2.0 M solution in diethyl ether, 9.30 mmol). After warming to room temperature the reaction mixture was stirred for a further 15 h. The reaction mixture was concentrated under reduced pressure to afford 4-fluoro-3-methoxy-4-methylpent-2-enenitrile as a yellow oil (1 g, 91%) which was taken on to the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 4.89 (s, 1H), 4.23 (s, 3H), 1.47 (d, J=21 Hz, 6H).
Reaction SMILES: [CH3:1][CH:2]([OH:5])[CH2:3][NH2:4].[O:6]=[C:7]1[NH:15][CH:14]=[N:13][C:12]2[N:11]([CH2:16][CH2:17][C:18](OCC)=[O:19])[CH:10]=[N:9][C:8]1=2>C(#N)C>[O:6]=[C:7]1[NH:15][CH:14]=[N:13][C:12]2[N:11]([CH2:16][CH2:17][C:18]([NH:4][CH2:3][CH:2]([OH:5])[CH3:1])=[O:19])[CH:10]=[N:9][C:8]1=2
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Reactant: CC(O)CN
Solvent: CC#N
Product: CC(O)CNC(=O)CCn1cnc2c(=O)[nH]cnc21
Temperature: 120 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
0.500 g (6.66 mmol) DL-1-amino-2-propanol and 0.250 (1.06 mmol) 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) were heated together in a 10 ml round bottom flask with stirring at 120° C. for one hour. The solution was allowed to cool to room temperature and 10 ml acetonitrile was added and the solution was stirred. The solution was triturated with a small amount of methanol (approximately 1 ml) and was stirred until the appearance of a fine white precipitate. The solution was filtered and the white solid was washed with acetonitrile and then with ether. Upon drying, 240 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-(2-hydroxypropyl)propanamide (AIT-0059) as a white solid was obtained. Yield: 85%. m.p. -212°-216° C.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]([CH2:27][CH3:28])=[C:14]2[CH2:29][C:30]([NH2:32])=[O:31])(=[O:6])[O:4]C.[OH-].[Na+]>CO.O>[CH3:1][O:2][P:3]([CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]([CH2:27][CH3:28])=[C:14]2[CH2:29][C:30]([NH2:32])=[O:31])(=[O:4])[OH:6]
Reactant: CCc1c(CC(N)=O)c2cc(OCCCP(=O)(OC)OC)ccc2n1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1c(CC(N)=O)c2cc(OCCCP(=O)(O)OC)ccc2n1Cc1ccccc1
Yield: 77.1 %

Procedure:
A mixture of 162 mg (0.35 mmol) of [3-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]propyl]phosphonic acid dimethyl ester and 5 mL of 1N NaOH in 10 mL of MeOH was heated to maintain reflux for 5 hours, diluted with water and extracted with ethyl acetate. The aqueous layer was made acidic to pH 2-3 with 1N HCl and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried (MgSO4) and concentrated at reduced pressure to give 120 mg (77% yield) of [3-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]propyl]phosphonic acid monomethyl ester.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:7]1
Reactant: C[C@H]1CNCCN1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: C[C@H]1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(S)-methylpiperazine (2.62 g, 26.2 mmol) in dichloromethane (100 mL) was trityl chloride (7.30 g, 26.2 mmol) added and the mixture was stirred at ambient temperature for 1.5 h. The organic phase was washed (x 1) with 1 M aqueous K2CO3, water, and brine. Drying (MgSO4) and solvent removal in vacuo furnished a quantitative yield of the title compound as a glassy oil which solidified upon standing. This material was used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=[O:6].[CH3:14][N:15](C=O)C>CCOCC.[C-]#N.[Zn+2].[C-]#N.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>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=1)[C:14]#[N:15])=[O:6]
Reactant: O=Cc1cc(Br)cc(C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Product: N#Cc1cc(C=O)cc(C(F)(F)F)c1
Temperature: 90 °C

Procedure:
To 3-bromo-5-(trifluoromethyl)benzaldehyde (1.0 gm, 3.95 mmol) in DMF (10 ml), zinc cyanide (278 mg, 2.37 mmol) was added followed by Pd(PPh3)4 (365 mg, 0.32 mmol) was added and heated at 90° C. for 5 h. Then the reaction mixture was cooled, diluted with ether and quenched with aqueous ammonium hydroxide solution. Then the reaction mixture was partitioned between water and ether. Organic layer was dried, evaporated and column purified (10% ethylacetate/90% hexanes) to yield 400 mg of 3-formyl-5-(trifluoromethyl)benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[CH:6]=[N:5]2.I[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7](=[O:13])[CH:6]=[N:5]2
Reactant: O=c1cnc2cc(Cl)c(Cl)cc2[nH]1
Reactant: CCOC(=O)CI
Solvent: CCO
Product: CCOC(=O)Cn1c(=O)cnc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Yield: 85 %

Procedure:
Under a nitrogen atmosphere Na (0.25 g, 11 mmol) was dissolved in 100 ml of abs. ethanol and 6,7-dichloroquinoxalin-2(1H)-one (2.15 g, 10 mmol) (Liebigs Ann. Chem., (1982), 754) was added. The mixture was refluxed for 30 min., cooled to room temperature, and ethyl iodoacetate (1.43 ml, 12 mmol) was added. The clear reaction mixture was refluxed for 2 h during which time a precipitate was formed. This was filtered off, washed with abs. ethanol and dried to afford 2.56 g (85%) of 6,7-dichloro-1-ethoxycarbonylmethylquinoxalin-2(1H)-one. 1H-NMR (DMSO-d6):δ1.23 (t, 3H), 4.20 (q, 2H), 5.08 (s, 2H), 8.05 (s, 1H), 8.17 (s, 1H), 8.38 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]([CH2:24][CH:25]=[CH:26][CH2:27]Br)[CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21].[CH2:30]([O:32][P:33]([O:37]CC)[O:34][CH2:35][CH3:36])[CH3:31]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:29])[CH:4]([CH2:24][CH:25]=[CH:26][CH2:27][P:33]([O:34][CH2:35][CH3:36])([O:32][CH2:30][CH3:31])=[O:37])[CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21]
Reactant: CCOP(OCC)OCC
Reactant: COC(=O)C(CC=CCBr)CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O
Solvent: Cc1ccccc1
Product: CCOP(=O)(CC=CCC(CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O)C(=O)OC)OCC
Yield: 44.5 %

Procedure:
A solution of 2-(4-bromo-but-2-enyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid methyl ester 159B (140 mg, 0.30 mmol) and triethylphosphite (600 mg, 3.6 mmol) in toluene (30 mL) was stirred at reflux for 20 hours. The mixture was concentrated and chromatographed on silica gel eluting with ethyl acetate (60% to 100%)/hexanes, affording 2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid methyl ester 159C as an oil (70 mg, 43%); 1H NMR (300 MHz, CDCl3) 1.27 (m, 6H), 1.79 (s, 3H), 2.0-2.7 (m, 8H), 3.37 (d, J=6.6 Hz), 3.52 (s, 3H), 3.75 (s, 3H), 4.08 (m, 4H), 5.20 m, 3H), 5.45 (m, 2H) ppm.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13].[F-].[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.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>[CH2:12]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:13]
Reactant: COC(=O)c1cccc(I)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1cccc(C(=O)OC)c1
Reaction time: 24 h

Procedure:
Methyl 3-iodobenzoate (13 g) and vinyl tributyltin (20 g) were dissolved in toluene (100 ml) and tetrakis(triphenylphosphine)palladium (0) (500 mg) added. The solution was heated at reflux with stirring under N2 for 1 day. Potassium fluoride (3 g) in water (50 ml) was added and the reaction mixture was allowed to stir under N2 for 15 minutes. The product was taken up in ethyl acetate and washed with water and then brine (×2). The organic extract was dried (MgSO4) and evaporated in vacuo.
Reaction SMILES: [C:1]([CH2:4][CH2:5][N:6]1[C:10]([SH:11])=[N:9][N:8]=[N:7]1)(O)=[O:2].C(C[N:16]1C(S)=NN=N1)(O)=O>>[C:1]([CH2:4][CH2:5][N:6]1[C:10]([SH:11])=[N:9][N:8]=[N:7]1)(=[O:2])[NH2:16]
Reactant: O=C(O)Cn1nnnc1S
Reactant: O=C(O)CCn1nnnc1S
Product: NC(=O)CCn1nnnc1S

Procedure:
When an equivalent amount of 1-(2-carboxyethyl)tetrazole-5-thiol was substituted in the procedure of Example 5 for 1-carboxymethyltetrazole-5-thiol, 1-(2-carbamoylethyl)tetrazole-5-thiol was obtained, m.p. 181°-182° (dec.).
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[O:8])=[CH:4][C:3]=1[C:34]1[N:38]([CH3:39])[N:37]=[CH:36][CH:35]=1.NN>O1CCCC1.CO>[NH2:12][CH2:11][C@@H:10]([NH:9][C:7]([C:5]1[O:6][C:2]([Cl:1])=[C:3]([C:34]2[N:38]([CH3:39])[N:37]=[CH:36][CH:35]=2)[CH:4]=1)=[O:8])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)oc1Cl
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nccc1-c1cc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)oc1Cl
Yield: 66.7 %

Procedure:
To a solution of 5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide (202 mg, 0.36 mmol) in tetrahydrofuran (1.8 ml) and methanol (1.8 ml) at 25° C. was added hydrazine (0.08 ml, 2.54 mmol) dropwise. After 12 h the solution was concentrated, dry loaded onto silica and purified by column chromatography (2% MeOH in DCM (1% NH4OH)). The free base was transferred to the HCl salt by addition of excess 2M HCl in diethyl ether (2 ml) to the residue in DCM (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide (120 mg, 0.24 mmol, 66% yield) as a yellow solid: LCMS (ES) m/z=427, 429 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.87 (d, J=9.09 Hz, 1H) 8.11 (br. s., 3H) 7.66-7.73 (m, 2H) 7.57 (t, J=7.45 Hz, 2H) 7.53 (d, J=1.52 Hz, 1H) 7.44 (d, J=6.82 Hz, 1H) 6.50 (d, J=1.52 Hz, 1H) 4.43-4.51 (m, 1H) 3.86 (s, 3H) 2.99-3.17 (m, 4H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[CH3:13])=[O:4].C(O)C.O.C(=O)=O.[N+:21]([O-])([OH:23])=[O:22]>S(=O)(=O)(O)O>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:11]([N+:21]([O-:23])=[O:22])=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[CH3:13])=[O:4]
Reactant: Cc1c(F)cccc1NC(=O)CCl
Reactant: O=[N+]([O-])O
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: Cc1c(F)ccc([N+](=O)[O-])c1NC(=O)CCl
Reaction time: 8 h
Yield: 94.6 %

Procedure:
A solution of 2-chloro-N-(3-fluoro-2-methylphenyl)acetamide (47.2 g, 234 mmol) in conc. sulphuric acid (220 ml) was treated at ca. −20° C. (ethanol/water/CO2(s) bath) with conc. nitric acid (69%, 15.25 ml, 19 g, 235 mmol) over 30 minutes, keeping internal temperature ≦9° C. The reaction was complete at the end of the addition. The mixture was added to ice with vigorous stirring then left to stand overnight. Filtration, washing of the solid with water and drying afforded the product (54.6 g, 95%) containing ˜9% impurity.