Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][C:9]1[NH:10][C:11]([CH3:27])=[C:12]([C:23]([O:25][CH3:26])=[O:24])[CH:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl.C1CCCCC1.CCOC(C)=O>[CH2:1]([S:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[C:12]([C:23]([O:25][CH3:26])=[O:24])=[C:11]([CH3:27])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1=C(C)NC(SCc2ccccc2)=NC1c1ccc(Cl)cc1Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)nc(SCc2ccccc2)nc1-c1ccc(Cl)cc1Cl
Reaction time: 1 h

Procedure:
The crude methyl 2-(benzylthio)-4-(2,4-dichlorophenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate (0.22 mmol) from Step 1 was dissolved in CH2Cl2 (2 mL) and DDQ (50 mg, 0.22 mmol) was added. After 1 hr, The reaction was diluted with cyclohexane/EtOAc solution (4:1, 10 mL) and the organic layer was extracted with saturated NaHCO3 solution (2×6 mL), brine (5 mL). The organic layer dried (MgSO4), filtered and concentrated under reduced pressure to give methyl 2-(benzylthio)-4-(2,4-dichlorophenyl)-6-methylpyrimidine-5-carboxylate. The crude reaction product (>95% purity) was moved onto next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([OH:27])=O)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=[CH:31][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:36](=[N:39]O)([NH2:38])[CH3:37].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>C(Cl)Cl.CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[O:27][N:39]=[C:36]([CH3:37])[N:38]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:28]=[C:29]([C:32]([F:34])([F:33])[F:35])[CH:30]=[CH:31][C:16]=3[CH2:15]2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(=O)O)cc32)cc1
Reactant: CC(N)=NO
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(-c2ccc3c(c2)N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)Cc2ccc(C(F)(F)F)nc2N3)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carboxylic acid (intermediate 58, 60 mg, 0.119 mmol), acetamide oxime (10 mg, 0.141 mmol), DIPEA (18 mg, 0.141 mmol), HOBt (19 mg, 0.14 mmol), DIC (23 mg, 0.18 mmol) in DCM (0.4 mL) and DMF (0.1 mL) was stirred at rt for 3 h. The reaction was quenched with water and the product was extracted with EtOAc. The combined extracts were washed with 5% NaHCO3, brine, dried (MgSO4) and concentrated. The residue was dissolved in NMP and was heated in a microwave reactor at 120° C. for 1 h. The reaction was quenched with water and the product was extracted with EtOAc. The extracts were washed with water and brine, dried (MgSO4) and concentrated. Flash column purification of the residue on SiO2 afforded the title compound. LC/MS: m/e 544.1 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 8.38 (1H, d, J=1.6 Hz), 8.00 (1H, dd, J=8.4, 1.8 Hz), 7.63 (1H, d, J=7.4 Hz), 7.16 (1H, d, J=7.4 Hz), 7.13 (1H, d, J=8.4 Hz), 7.05 (1H, br s), 6.97 (2H, J=8.5 Hz), 6.90 (1H, d, J=8.4 Hz), 4.65-4.95 (2H, br), 2.51 (3H, s), 1.26 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:21](O)[CH2:22][CH2:23][OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:19][CH2:18][C:17]4([O:24][CH2:23][CH2:22][CH2:21][O:20]4)[CH2:16][CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCCCO
Reactant: O=C1CCC2(CC1)CC(C#Cc1cccc(Cl)c1)=NO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: Clc1cccc(C#CC2=NOC3(CCC4(CC3)OCCCO4)C2)c1
Yield: 75.3 %

Procedure:
A solution of the compound of Example 32 (0.41 g, 1.42 mmol), 1,3-propandiol (0.15 g, 1.95 mmol) and p-toluensulfonic acid. H2O (7.5 mg, 0.04 mmol) in 30 mL of benzene was stirred at reflux for 10.5 h, removing water with a Dean-Stark Apparatus. Dilution with water, washing with aq. 5% NaHCO3, drying the organic layer over Na2SO4 afforded the title compound as dense yellow oil. This was further purified by means of automated flash chromatography (SP01®TM-Biotage; gradient Petroleum Ether-EtOAc from 9:1 to 7:3) giving a white solid. Yield: 75.3%.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39]([NH2:42])(=[O:41])=[O:40]>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[F:32])(=[O:41])=[O:40])=[O:24])=[CH:16][CH:15]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: NS(=O)(=O)c1ccccc1F
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccccc3F)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 2-fluorobenzenesulfonamide: 1H-NMR (CDCl3) δ 7.89 (1H, t, J=6.9 Hz), 7.45-7.06 (12H, m), 6.48 (1H, br.s), 3.46-3.36 (2H, m),2.77-2.71 (2H, m), 2.28 (3H, s), 2.21 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[C:13]([CH2:14][NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][C:5]([C:6]([O:8][CH2:9][CH2:10]Cl)=[O:7])=[CH:4][C:3]=1[Br:20].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([O-:39])=[O:38].[Na+]>>[NH2:1][C:2]1[C:13]([CH2:14][NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][C:5]([C:6]([O:8][CH2:9][CH2:10][O:39][C:37](=[O:38])[CH2:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[NH:29][C:23]2[C:22]([Cl:21])=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:28])=[O:7])=[CH:4][C:3]=1[Br:20]
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: CC(C)(C)NCc1cc(C(=O)OCCCl)cc(Br)c1N
Agent: [Na+]
Product: CC(C)(C)NCc1cc(C(=O)OCCOC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc(Br)c1N

Procedure:
This compound was prepared from 2-(4-amino-3-bromo-5-tert.butylaminomethyl-benzoyloxy)-ethyl chloride and sodium 2-[(2,6-dichlorophenyl)-amino]-phenylacetate analogous to Example 8.
Reaction SMILES: [C:1]([CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:12]=1)[C:5](OCC)=[O:6])(=O)[CH3:2].O.[NH2:26][NH2:27]>C(O)C>[CH:20]1([O:19][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=2[O:17][CH3:18])[CH2:10][C:4]2[C:5](=[O:6])[N:26]=[N:27][C:1]=2[CH3:2])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NN
Reactant: CCOC(=O)C(Cc1ccc(OC)c(OC2CCCC2)c1)C(C)=O
Solvent: O
Solvent: CCO
Product: COc1ccc(CC2=C(C)N=NC2=O)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 65.6 %

Procedure:
To a stirred solution of ethyl 2-acetyl-3-(3-cyclopentyloxy-4-methoxyphenyl)-propanoate (585 mg, 1.74 mmol) in absolute ethanol (10 ml) at 0° C. was added hydrazine monohydrate (87 mg, 1.74 mmol) in one portion. The resulting solution was stirred at 0° C. for 45 minutes and then refluxed at 80° C. for 3 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo and purified by flash chromatography (SiO2;methylene chloride/ethanol/ammonia (4:1:0.1)) to-afford the title compound as a white solid (343 mg). m.p. 186-187° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](C=O)=[CH:7][N:6]=1)=[O:4].[CH2:13]([OH:16])[CH2:14][OH:15].O.[C:18]1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH:18]2[O:16][CH2:13][CH2:14][O:15]2)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: OCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)c1cnc(C=O)cn1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1nccnc1C1OCCO1
Yield: 757.6 %

Procedure:
A mixture of 5-formyl-pyrazine-2-carboxylic acid methyl ester (325 mg, 1.56 mmol), ethylene glycol (100 μL, 1.79 mmol), and p-toluenesulfonic acid monohydrate (30 mg, 0.157 mmol) in benzene (10 mL) was heated under reflux with a Dean-Stark condenser for 17 h. The mixture was cooled and diluted with benzene (25 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (25 mL) and a saturated aqueous sodium chloride solution (25 mL). Each aqueous wash was back-extracted with a small portion of benzene. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 5-[1,3dioxolan-2-yl-pyrazine-2-carboxylic acid methyl ester as an orange-red oil (250 mg).
Reaction SMILES: C[O-].[Na+].[CH2:4]([OH:7])[CH2:5][OH:6].[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:10]=1[CH2:11]Br>O>[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:10]=1[CH2:11][O:6][CH2:5][CH2:4][OH:7]
Reactant: OCCO
Reactant: Clc1cccc(Cl)c1CBr
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: OCCOCc1c(Cl)cccc1Cl

Procedure:
Sodium methoxide (104.4 g, 1.93 mol) was added portionwise to ethylene glycol (3.74 L) under N2, keeping the temperature below 35° C. After 1–2 h, 2,6-dichlorobenzylbromide (400 g, 1.67 mol) was added and the mixture heated to 55–60° C. for 1 h. On cooling to 20° C. water (2.14 L) was added and the mixture extracted with ethyl acetate (2.14 L). The aqueous layer was separated and extracted twice with ethyl acetate (2.14 L, 1.28 L). The combined organic extracts were washed with water (2.14 L) then evaporated to dryness to afford a colourless oil (371.8 g)—LC RT=4 min. This may be chromatographed on silica (Biotage) eluting with 10% ethyl acetate in 60/80 petrol to afford the title compound.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[CH3:8]CCCCC.[Cl:14][C:15]1[CH:16]=[C:17]([C@@H:21]([OH:25])[C:22]([OH:24])=[O:23])[CH:18]=[CH:19][CH:20]=1.CO>C1C=CC=CC=1>[CH3:8][O:23][C:22](=[O:24])[C@@H:21]([C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([Cl:14])[CH:16]=1)[OH:25]
Reactant: O=C(O)[C@H](O)c1cccc(Cl)c1
Reactant: CCCCCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)[C@H](O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.9 %

Procedure:
A solution of trimethylsilyldiazomethane in hexane (2 M, 1.5 mL, 3.0 mmol) was added to a solution of (R)-(3-chloro-phenyl)hydroxy-acetic acid (497 mg, 2.66 mmol) in benzene (2.6 mL)-methanol (1.3 mL) under cooling with ice. Then, the ice bath was removed and the mixture was stirred at room temperature for five minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (533 mg, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>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.C1(C)C=CC=CC=1.C(O)C>[CH:12]([N:11]1[C:5]2[CH:4]=[CH:3][C:2]([C:21]3[CH:22]=[CH:23][C:24]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)=[CH:25][CH:26]=3)=[CH:18][C:6]=2[CH:7]=[C:8]([C:14]([O:16][CH3:17])=[O:15])[CH2:9][CH2:10]1)=[O:13]
Reactant: [O-]B([O-])Oc1ccc(N2CCOCC2)cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C=O)CC1
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: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2N(C=O)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 82 %

Procedure:
To a mixture of methyl 7-bromo-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (3.51 g), 4-morpholinophenyl borate (3.51 g) and potassium carbonate (3.75 g) was added a mixture of water (20 ml), ethanol (20 ml) and toluene (100 ml), and the mixture was stirred under argon atmosphere at room temperature for 40 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.52 g), and the mixture was refluxed under argon atmosphere for 12 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-formyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (3.64 g) as pale yellow crystals.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=[O:8])=CC=1.[O:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=NO)[CH2:14][CH2:13]1>N1C=CC=CC=1>[O:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:8])[CH2:14][CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: ON=C1CCOc2ccccc21
Solvent: c1ccncc1
Product: O=C1CCOc2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.5 %

Procedure:
p-Toluenesulfonyl chloride (52.5 g, 275 mmol) was added to a solution of chroman-4-one oxime (44.9 g, 275 mmol) in pyridine (275 ml) and the mixture was stirred for 12 hours at room temperature. Solvent was evaporated under reduced pressure and the residue was partitioned between water and chloroform. The organic layer was washed with 1N aqueous hydrochloric acid and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropylether, and dried to afford chroman-4-one O-p-toluenesulfoxime (85.1 g, 268 mmol, 97%) as white crystals.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH3:19])[CH:10]=1)[C:7]#[N:8].C([O-])(=O)C.[Na+].[N+:25]([C:28]1[CH:38]=[CH:37][CH:36]=[C:30]2[C:31]([O:33][C:34](=O)[C:29]=12)=[O:32])([O-:27])=[O:26]>C(O)(=O)C.C(Cl)Cl>[N+:25]([C:28]1[CH:38]=[CH:37][CH:36]=[C:30]2[C:29]=1[C:34](=[O:33])[N:5]([CH:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH3:19])[CH:10]=1)[C:7]#[N:8])[C:31]2=[O:32])([O-:27])=[O:26]
Reactant: CCOc1cc(C(N)C#N)ccc1OC
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOc1cc(C(C#N)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Yield: 87.4 %

Procedure:
A mixture of 2-amino-2-(3-ethoxy-4-methoxyphenyl)ethanenitrile acetate (8.0 g, 28.5 mmol), sodium acetate (2.6 g, 31 mmol) and 3-nitrophthalic anhydride (5.5 g, 28.5 mmol) in glacial acetic acid (60 mL) was heated to reflux for 5 hours. The mixture was concentrated in vacuo to give an oil. The oil was dissolved in CH2Cl2, and washed with water and brine, and dried over MgSO4. Solvent was removed and the residue was purified by chromatography (SiO2, Hexane: EtOAc 6:4) to give 9.5 g (84%) of 2-(4-nitro-1,3-dioxoisoindolin-2-yl)-2-(3-ethoxy-4-methoxyphenyl)ethanenitrile; mp 155-157° C.; 1H NMR(DMSO-d6) δ 8.31 (d, J=7.8 Hz, 1H), 8.20 (d, =7.2 Hz, 1H), 8.09 (t, J=7.8 Hz, 1H), 7.06-6.91 (m, 3H), 5.59 (t, J=8.0 Hz, 1H), 4.04-3.96 (q, J=7 Hz, 2H), 3.74 (s, 3H), 3.66 (d, J=8 Hz, 2H), 1.31 (t, J=7 Hz, 3H); 13C NMR (DMSO-d6) δ 165.46, 162.69, 149.07, 147.78, 144.45, 136.63, 132.81, 128.81, 128.52, 127.24, 122.39, 119.77, 118.08, 112.46, 111.68, 63.80, 55.48, 50.36, 20.30, 14.60. Analy. Calculated For C20H17N3O6: C 60.75; H 4.34; N 10.63. Found: C 60.95; H 4.37; N 10.50.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:24][C:25]1[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[CH:29][C:30]=1[CH2:31]Cl>O>[CH3:36][O:35][C:27]1[CH:26]=[C:25]2[C:30](=[CH:29][C:28]=1[O:33][CH3:34])[CH2:31][N:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[CH2:24]2
Reactant: COc1cc(CCl)c(CCl)cc1OC
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1OC)CN(S(=O)(=O)c1ccc(C)cc1)C2
Temperature: 25 °C
Yield: 95.2 %

Procedure:
1.89 g (11 mmol) of p-toluenesulfonamide was added to 20 ml of N,N-dimethylformamide, and 3.3 g (24 mmol) of pulverised potassium carbonate and 2.0 g (8.5 mmol) of 4,5-bischloromethyl veratrol were added thereto at room temperature under stirring. The mixture was stirred at room temperature for 20 hours, and after an addition of 40 ml of water, extracted with methylene chloride. The extract was washed with water, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the crystalline residue was washed with diisopropyl ether to obtain 2.7 g (yield: 95.2%) of the above identified compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[C:12](=[O:15])([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)CBr>CC#N>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][C:12](=[O:15])[C:25]1[CH:24]=[CH:21][CH:20]=[C:19]([F:18])[CH:26]=1
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: O=C([O-])[O-]
Reactant: Fc1cccc(CBr)c1
Agent: [K+]
Solvent: CC#N
Product: O=C(Oc1ccc([N+](=O)[O-])cc1Cl)c1cccc(F)c1
Temperature: 70 °C
Yield: 90 %

Procedure:
To 90 mL CH3CN was added 2-chloro-4-nitrophenol (15 g, 86.4 mmol) followed by potassium carbonate (17.9 g, 129.6 mmol). To the stirring suspension was added via dropping funnel a 10 mL CH3CN solution of 3-fluoro-benzylbromide (16.3 g, 86.4 mmol). The contents were stirred and heated at 70° C. for 18 h, after which time the bright yellow mixture was allowed to cool to it The yellow contents were poured onto H2O (200 mL) and stirred, upon which solid formation occurs. The solid was filtered and filter cake washed with additional H2O (50 mL). The collected solid was dried in vacuo, yielding 2-chloro-1-(3-fluoro-benzoyloxy)-4-nitro-benzene (23 g, 94%) as a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][C:14]([OH:16])=O)=[CH:10][CH:9]=1)=[O:6])[CH:2]=[CH2:3].ClC(N(C)C)=C(C)C.[CH2:27]([O:30][C:31](=[O:67])[C:32]([N:52]1[C@H:55]([SH:56])[C@@H:54]([C@H:57]([O:59][C:60]([O:62][CH2:63][CH:64]=[CH2:65])=[O:61])[CH3:58])[C:53]1=[O:66])=[P:33]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:28]=[CH2:29].CN(C1C=CC=CN=1)C>C(Cl)Cl.[Ag].N1C=CC=CC=1>[CH2:27]([O:30][C:31](=[O:67])[C:32]([N:52]1[C@H:55]([S:56][C:14](=[O:16])[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:8]([NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])=[CH:18][CH:17]=2)[C@@H:54]([C@H:57]([O:59][C:60]([O:62][CH2:63][CH:64]=[CH2:65])=[O:61])[CH3:58])[C:53]1=[O:66])=[P:33]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:28]=[CH2:29]
Reactant: C=CCOC(=O)Nc1ccc(OCC(=O)O)cc1
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1S
Agent: [Ag]
Agent: CC(C)=C(Cl)N(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCOC(=O)Nc1ccc(OCC(=O)S[C@@H]2[C@@H]([C@@H](C)OC(=O)OCC=C)C(=O)N2C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 1.25 h

Procedure:
1 g of 4-(allyloxycarbonylamino)-phenoxyacetic acid is suspended in 2 ml of CH2Cl2 and 0.6 ml of 1-chloro-1-dimethylamino-2-methylprop-1-ene is added thereto. The mixture is stirred for 75 minutes and is then added dropwise, over a period of 5 minutes, to a solution of 1.74 g of the silver salt of 2-[(3S,4R)-3-[(1R)-1-allyloxycarbonyloxyethyl]-4-mercapto-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester, 50 mg of dimethylaminopyridine and 0.41 ml of pyridine in 30 ml of absolute methylene chloride. The title compound is obtained after working up analogously to Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:14])([F:13])[F:12])[C:5]#[N:6].Cl.[NH2:16][OH:17].C(N(C(C)C)C(C)C)C>C(O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:12])([F:13])[F:14])/[C:5](=[N:16]/[OH:17])/[NH2:6]
Reactant: N#Cc1ccc(OC(F)(F)F)c(Cl)c1
Reactant: NO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: N/C(=N\O)c1ccc(OC(F)(F)F)c(Cl)c1
Temperature: 80 °C
Yield: 61.8 %

Procedure:
To a solution of 3-chloro-4-(trifluoromethoxy)benzonitrile (1.0 g, 4.51 mmol) and hydroxylamine hydrochloride (1.5 eq, 0.47 g, 6.77 mmol) in ethanol (10 ml) was added N-ethyl-N-isopropylpropan-2-amine (1.6 eq, 1.26 ml, 7.22 mmol) and refluxed at 80° C. for 12 hours under N2. Allow to cool to rt. Dilute with EtOAc (25 ml), wash with water (25 ml), brine (25 ml), dry, concentrate in vacuo afforded (Z)-3-chloro-N′-hydroxy-4-(trifluoromethoxy)benzimidamide (0.71 g, 62.1%, white solid). Used crude in the next step. HRMS(B) m/z 254.0070
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([Cl:10])[C:3]=1[OH:11].C(O)(=O)C.[N+:16]([O-])([OH:18])=[O:17]>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([N+:16]([O-:18])=[O:17])[C:5]([F:9])=[C:4]([Cl:10])[C:3]=1[OH:11]
Reactant: Oc1c(Cl)c(F)cc(F)c1Cl
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(F)c(Cl)c(O)c(Cl)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
20 g of 2,6-dichloro-3,5-difluorophenol are introduced into 70 ml of acetic acid, and 8 g of 98% strength nitric acid are added dropwise. The mixture is subsequently stirred for a further 2 hours at room temperature and taken up in 150 ml of dichloromethane, and the solution is washed twice with water. After removing the dichloromethane by distillation, 18 g of product remain. 94% purity according to GC analysis. EXAMPLE A6: 2-Chloro-3,5,6-trifluoro-4-nitrophenol
Reaction SMILES: CC1C=CC(S(O[C:12]2[C:13]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]([CH3:25])([CH3:24])[C:14]=3[N:15]=[C:16]([NH2:18])[N:17]=2)(=O)=O)=CC=1.[N:26]1(C(OC(C)(C)C)=O)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.N1C[CH2:42][C@@H:41](NC(=O)OC(C)(C)C)[CH2:40]1>>[C:19]1([CH:20]2[C:12]3[N:17]=[C:16]([NH2:18])[N:15]=[C:14]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[C:13]=3[CH2:23][CH2:22][CH2:21]2)[CH:24]=[CH:42][CH:41]=[CH:40][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCCC3(C)C)cc1
Product: Nc1nc2c(c(N3CCNCC3)n1)CCCC2c1ccccc1

Procedure:
The title compound was prepared according to the procedures of Examples 1E and 1F, substituting the product from Example 9C for the product from Example 1D and substituting tert-butyl piperazine-1-carboxylate for (R)-tert-butyl pyrrolidin-3-ylcarbamate. 1H NMR (300 MHz, CDCl3) δ 7.24 (m, 2H), 7.18 (m, J=7.54 Hz, 1H), 7.06 (d, J=8.33 Hz, 1H), 4.55 (s, 2H), 3.99 (t, J=6.94 Hz, 1H), 3.31 (m, 4H), 2.98 (m, 4H), 2.55 (m, 2H), 2.20 (m, 1H), 1.79 (m, 3H); MS (ESI+) m/z 310 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9](O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S([O-])(=O)=[O:25])=CC=1.[NH+]1C=CC=CC=1.CCOCC>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:25][CH:17]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1=COCCC1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CC(O)NC(=O)OC(C)(C)C
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCCOC1CCCCO1

Procedure:
A solution of N-t-butoxycarbonylaminoethanol (2.0 g), dihydropyran (1.7 ml) and pyridinium p-toluenesulphonate (310 mg) in anhydrous dichloromethane (90 ml) was stirred at room temperature for 2 1/2 hours. Ether (150 ml) was added, the solution was washed with water (2×50 ml), dried, and the solvent removed under reduced pressure to give 2-(2-(2-(N-t-butoxycarbonylamino)ethoxy)tetrahydropyran (3.0 g) as a yellow oil.