Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[CH2:9]([SH:13])[CH:10]([SH:12])[CH3:11]>>[CH3:11][CH:10]1[S:12][C:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=2[S:13][CH2:9]1
Reactant: O=C1CCCCC1Cl
Reactant: CC(S)CS
Product: CC1CSC2=C(CCCC2)S1
Yield: 66 %

Procedure:
The procedure of Example 1(a) is followed using 2-chloro-cyclohexanone and 1,2-propanedithiol to give 5,6,7,8-tetrahydro-2-methyl-1,4-benzodithian as a greenish oil, bp 127°-130°/2.3 mm, Yield 66%. NMR, 1.36 (3d), 1.4-1.88 (4m), 1.88-2.3 (4m), 2.6-3.7 (3m). IR, 2920, 1615, 1410, 1325, 1250, 1120, 855, 715.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[OH:1][C:2]1[C:7]([N+:12]([O-:14])=[O:13])=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: Oc1ccc(C(F)(F)F)cn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cnc1O
Temperature: 80 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
To a mixture of 9.84 g of 2-hydroxy-5-(trifluoromethyl)pyridine and 40 ml of concentrated sulfuric acid, 10.9 g of 70% nitric acid was dropped at 80° C. This mixture was stirred at 80° C. for 1 hour. The reaction mixture was cooled down to room temperature, then, the reaction mixture was poured into ice water. The deposited solid was collected by filtration. This solid was washed with ice water, then, dissolved in ethyl acetate, and washed with saturated saline. The organic layer was dried over magnesium sulfate, then, concentrated under reduced pressure, to obtain 5.22 g of 2-hydroxy-3-nitro-5-(trifluoromethyl)pyridine.
Reaction SMILES: O=[C:2]([CH3:17])[CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[N+:14]([O-])=O>C(O)(=O)C>[CH3:11][O:10][C:8]([C:7]1[CH:6]=[C:5]2[C:4]([CH:3]=[C:2]([CH3:17])[NH:14]2)=[CH:13][CH:12]=1)=[O:9]
Reactant: COC(=O)c1ccc(CC(C)=O)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2cc(C)[nH]c2c1
Yield: 28.9 %

Procedure:
A mixed solution of methyl 4-(2-oxopropyl)-3-nitrobenzoate (3.86 g), reduced iron (9.0 g) and acetic acid (40 ml) is stirred at 90° C. for 24 hours. The solid is taken out through filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified through silica gel column chromatography (eluent: hexane/ethyl acetate=3/1) to obtain 6-methoxycarbonyl-2-methylindole (0.890 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.Cl[C:11](Cl)([O:13]C(=O)OC(Cl)(Cl)Cl)Cl>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:11](=[O:13])[NH:9][N:8]=2)[CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NNc1ccc(Br)cn1
Solvent: CC(Cl)Cl
Product: O=c1[nH]nc2ccc(Br)cn12
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.5 %

Procedure:
To a solution of 3-2 (2.0 g, 10.6 mmol) in dichloroethane (106 mL) was added triphosgene (3.16 g, 10.64 mmol). The reaction mixture was stirred at room temperature for 3 days. An off-white precipitate formed, which was washed with dichloroethane (100 mL) and dried in vacuo to give 2.03 g (89%) of 3-3 as a tan solid. LC/MS: m/z (M+H)=213.9.
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:15]=[CH:14][C:13]3[C:12]([C:16]([NH:18][CH2:19]C4CCCCC4)=[O:17])=[C:11]([Cl:26])[CH:10]=[CH:9][C:8]=3[N:7]=2)[CH2:3]1.[C:27]([O:31]CC)(=[O:30])[CH:28]=[CH2:29].[OH-].[Na+].Cl>CO>[Cl:26][C:11]1[C:12]([C:16]([NH:18][CH2:19][CH2:16][CH:12]2[CH2:13][CH2:8][CH2:9][CH2:10][CH2:11]2)=[O:17])=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([N:4]1[CH2:5][CH:2]([NH:1][CH2:29][CH2:28][C:27]([OH:31])=[O:30])[CH2:3]1)[CH:15]=[CH:14]2
Reactant: C=CC(=O)OCC
Reactant: NC1CN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCNC1CN(c2ccc3c(C(=O)NCCC4CCCCC4)c(Cl)ccc3n2)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 2-(3-amino-1-azetidinyl)-6-chloro-N-(cyclohexylmethyl)-5-quinolinecarboxamide (Example 97(a)) (0.1 g) in methanol (1 mL) was added ethyl acrylate (0.032 mL). The mixture was stirred at room temperature for 20 hours. Sodium hydroxide (1 mL, 1M) was added and the reaction mixture was stirred for 72 hours. Hydrochloric acid (0.5 mL, 2M) was added and the reaction mixture was concentrated under vacuum. Purification (HPLC—Symmetry, 0.1% aqueous ammonium acetate:acetonitrile as eluant) gave the title compound as a solid (0.026 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][OH:22])=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:15][CH:14]=1
Reactant: OCCOc1ccc(-c2ccccc2F)nc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1ccc(-c2ccccc2F)nc1
Reaction time: 7 h

Procedure:
217.1 mg (1.89 mmol) of methanesulfonyl chloride were added dropwise with cooling to 340 mg (1.46 mmol) of 2-(6-(2-fluorophenyl)pyridin-3-yloxy)ethanol and 442.5 mg (4.37 mmol) of triethylamine in 25 ml of methylene chloride. After 7 h at room temperature, the mixture was extracted with water, and the organic phase was separated and concentrated. Yield: 394 mg (87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:11]=1[C:12]([NH:14][C:15](Cl)=[O:16])=[O:13]>>[Cl:9][C:10]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:11]=1[C:12]([NH:14][C:15]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:16])=[O:13]
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(Cl)NC(=O)c1c(F)cccc1Cl
Product: O=C(NC(=O)c1c(F)cccc1Cl)Nc1ccc(Cl)cn1

Procedure:
A portion of 5-chloro-2-aminopyridine is reacted with 2-chloro-6-fluorobenzamidocarboxylic acid chloride in the presence of a hydrogen halide acceptor as described in Example 12. The product, named in the heading above, is isolated as described in Example 12 to obtain the desired compound, identical to the product of Example 3.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[C:15]([O:17]C)=[O:16])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CO.C1COCC1>[C:1]1([S:7]([N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[C:15]([OH:17])=[O:16])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccn1S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccn1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of methyl 1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate (Intermediate 1) (500 mg, 1.885 mmol) in MeOH (7 ml) and THF (7 ml) cooled to 0° C., aqueous 1N KOH (2.827 ml, 2.83 mmol) was added drop-wise and the resulting mixture was stirred at RT for 24 hours. UPLC-MS analysis showed the presence of desired compound in admixture with methyl 1H-pyrrole-2-carboxylate as the main product. The mixture was poured into ice-water and washed with DCM. The aqueous phase was acidified with 37% HCl (pH=2) and extracted with DCM. The organic layer was dried over sodium sulfate, filtered and evaporated to afford a mixture of 1-(phenylsulfonyl)-1H-pyrrole-2-carboxylic acid (Intermediate 2) (MS/ESI+252.0 [MH]+) and methyl 1H-pyrrole-2-carboxylate (MS/ESI+126.0 [MH]+) (234 mg, ratio about 3/7). This mixture was used as such in the next step.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:11]([O-])(=O)[CH3:12].[Na+].C(=O)C>O.C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[CH:11][CH3:12])=[CH:5][CH:4]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CC(=O)[O-]
Agent: CC=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC=NNc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Chlorophenylhydrazine hydrochloride (5.0 g) and 3.4 g of sodium acetate were dissolved in a mixture of 50 ml of water and 25 ml of ethanol, to which 1.69 g of 80% acetaldhyde aqueous solution were added dropwise at room temperature, and the resulting mixture was stirred for 30 minutes at room temperature. After adding 50 ml of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried and distilled off to give acetaldehyde 4-chlorophenylhydrazone as an oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:29])[CH2:27][CH3:28]>C1COCC1>[C:13]1([CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10][NH:11][C:26](=[O:29])[CH2:27][CH3:28])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCC(=O)Cl
Reactant: NCCN(Cc1ccccc1)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(=O)NCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a chilled solution of 5.0 g (21 mmol) N,N-dibenzylethylenediamine and 30mL (21 mmol) triethylamine in 20 mL THF is added 1.8 mL (21 mmol) propionylchloride, dropwise. The temperature of the reaction mixture is maintained below 0° C. during addition. The reaction mixture is stirred for 30minutes at 0° C. After this time, the reaction mixture is filtered and the solvents are evaporated to give the product which can be purified via column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[H-].[Na+].Cl[CH2:24][O:25][CH2:26][CH3:27].ClCCl>CO>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:24][O:25][CH2:26][CH3:27])=[CH:13][CH:14]=2)=[O:7])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: CCOCCl
Reactant: O=C(Nc1ccc(O)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCOCOc1ccc(NC(=O)c2ccc(Cl)c([N+](=O)[O-])c2)cc1
Temperature: 0 °C
Yield: 81 %

Procedure:
4-Chloro-N-(4-hydroxy-phenyl)-3-nitro-benzamide (14.6 g, 0.05 mol) was placed in an oven dried 2-necked 500 ml round-bottomed flask and flushed with N2. Enough Dimethoxyethane (DME, 100 ml) was added to dissolve the amide. The mixture was cooled in ice bath and sodium hydride (NaH, 50% in oil, 3.6 g total, 0.075 mol) added in small portions with vigorous stirring. An hour after addition was complete, chloromethoxy-ethane (7.13 g, 0.075 mol, commercially available) was added drop wise via a pressure-equalising dropping funnel. The reaction was followed by TLC (dichloromethane, DCM:methanol, MeOH, 95:5). The reaction mixture was poured into ice water and extracted with EtOAc (3×50 ml). The organic phase was dried (MgSO4) and evaporated under reduced pressure. The crude product was recrystallised form Hexane/ethyl acetate, 1:4. to give 81% of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1ccc(C)cc1
Yield: 77 %

Procedure:
Prepared according to the procedure described for Example 121 using 4-methylbenzenesulfonyl chloride (2.06 g, 10 mmol) and 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g, 10.0 mmol) to afford the product (3.053 g); m.p. 200-202° C.
Reaction SMILES: C(OC([N:7]1[C@@H:12]([CH3:13])[CH:11]=[C:10]([C:14]2[N:15]=[C:16]([S:19][C:20]3[C@H:26]([CH3:27])[C@H:25]4[N:22]([C:23](=[O:31])[C@@H:24]4[C@H:28]([OH:30])[CH3:29])[C:21]=3[C:32]([O:34]CC=C)=[O:33])[S:17][CH:18]=2)[CH2:9][CH2:8]1)=O)C=C.C(O)(=O)C.C([SnH](CCCC)CCCC)CCC.P([O-])([O-])([O-])=O>ClCCl>[OH:30][C@@H:28]([C@H:24]1[C:23](=[O:31])[N:22]2[C@@H:25]1[C@@H:26]([CH3:27])[C:20]([S:19][C:16]1[S:17][CH:18]=[C:14]([C:10]3[CH2:9][CH2:8][NH:7][C@@H:12]([CH3:13])[CH:11]=3)[N:15]=1)=[C:21]2[C:32]([OH:34])=[O:33])[CH3:29]
Reactant: C=CCOC(=O)C1=C(Sc2nc(C3=C[C@H](C)N(C(=O)OCC=C)CC3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: CCCC[SnH](CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@H]1C=C(c2csc(SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)n2)CCN1
Yield: 73.3 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(4-{(6S)-1-[(allyloxy)carbonyl]-6-methyl-1,2,3,6-tetrahydro-4-pyridinyl}-1,3-thiazol-2-yl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (270 mg, 0.49 mmol) in dichloromethane (10 ml) were added acetic acid (73 μl) and tributyltin hydride (1.23 ml, 4.6 mmol) and added at room temperature bis(triphenylphosphine)palladium chloride(II) (36 mg, 0.051 mmol). Ten minutes later the reaction mixture was poured into a mixture of ice (log) and phosphate buffer (pH7.0, 10 ml). After separation of the mixture with a separating funnel, the organic layer was extracted twice with water and the aqueous layer was washed twice with dichloromethane (3 ml). The organic solvent in the aqueous layer was evaporated under reduced pressure, and the residue was purified by polymer chromatography (CHP-20P). The fractions eluted with 3–5% aqueous THF solution were combined and lyophilized to give (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-({4-[(6S)-6-methyl-1,2,3,6-tetrahydro-4-pyridinyl]-1,3-thiazol-2-yl}sulfanyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (151.5 mg) as a white amorphous.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10](Cl)[CH:11]=2)[CH:6]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([O:16][C:17]2[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:21][CH:22]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(Oc2ccc(S(C)(=O)=O)cc2)c1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1cc2ccccc2c(Oc2ccc(S(C)(=O)=O)cc2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of [6-chloro-4-(4-methanesulfonyl-phenoxy)-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (110 mg, 0.26 mmol) in methanol (3 mL) was added 10% palladium on carbon (10 mg). The resulting mixture was vigorously stirred at room temperature overnight under a hydrogen atmosphere (balloon) and then filtered. The filtrate was concentrated in vacuo to give [4-(4-methanesulfonyl-phenoxy)-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (68 mg, 67%) as a colorless oil which was directly used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([Mg]Br)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:14]([C:9]2[C:10]([CH3:13])=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[OH:15])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Br[Mg]c1ccc(OCc2ccccc2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1ccc(OCc2ccccc2)cc1

Procedure:
Prepared according to the procedure described in Example 25, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 4-(benzyloxy)phenyl magnesium bromide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])=[O:4].S(Cl)(Cl)=O.O.[NH2:22][NH2:23]>>[N+:14]([C:6]1[CH:7]=[C:8]([C:9]([NH:22][NH2:23])=[O:10])[CH:12]=[CH:13][C:5]=1[C:3]([O:2][CH3:1])=[O:4])([O-:16])=[O:15]
Reactant: COC(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: NN
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(C(=O)NN)cc1[N+](=O)[O-]

Procedure:
From 4-methoxycarbonyl-3-nitrobenzoic acid, thionyl chloride and hydrazine monohydrate, 758 mg of the desired product was obtained in the same manner as in Reference Synthetic Example 39 as a white solid (yield 79%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1([NH:19]C(=O)OC(C)(C)C)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:19][C:13]1([CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1(CNC(=O)OCc2ccccc2)CCOCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(CNC(=O)OCc2ccccc2)CCOCC1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (4-(((benzyloxycarbonyl)amino)methyl)tetrahydro-2H-pyran-4-yl)carbamate (G16, 141 mg) in methylene chloride (2 mL), trifluoroacetic acid (2 mL) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The solvent was evaporated under reduced pressure, and then ethyl acetate and saturated aqueous sodium hydrogencarbonate were added to the residue. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain benzyl ((4-aminotetrahydro-2H-pyran-4-yl)methyl)carbamate (G17, 106 mg).
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3].Cl[C:11](=[CH2:14])[C:12]#[N:13]>O>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][N:1]1[CH:14]=[C:11]([C:12]#[N:13])[N:3]=[N:2]1)[CH3:9]
Reactant: C=C(Cl)C#N
Reactant: CCOC(=O)CN=[N+]=[N-]
Solvent: O
Product: CCOC(=O)Cn1cc(C#N)nn1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of ethyl 2-azidoacetate (1.29 g) and 2-chloroacrylonitrile (1.75 g) in water (10 ml) is stirred at about 80° C. for 16 hours. After cooling, the product is extracted with dichloromethane and the concentrated extract is purified by means of column chromatography on silica gel 60 (6 g; eluent toluenelethyl acetate=4:1). The purified product (yield 1.21 g; 67% of theory) of m.p. 47-48° C. (recrystallization from toluene/hexane) is obtained after concentrating the eluate and drying.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[CH:6][CH:7]=1.[CH:15]([NH:17][NH2:18])=O>C(O)CCC>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:15]=[N:17][N:18]=2)[N:4]=1
Reactant: Clc1ccc(-c2ccccc2Cl)nn1
Reactant: NNC=O
Solvent: CCCCO
Product: Clc1ccccc1-c1ccc2nncn2n1

Procedure:
A mixture of 5.67 g. of 3-chloro-6-(o-chlorophenyl)pyridazine, 3.03 g. of formylhydrazine in 50 ml. of butanol is refluxed 48 hrs. to give 2.3 g. of product as pale yellow crystals, m.p. 156°-158° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:26]1([CH2:32][CH2:33][OH:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H-].[Na+].O>C1(C)C=CC=CC=1>[CH2:33]([O:34][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)[CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OCCc1ccccc1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(Cl)nn2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(OCCc3ccccc3)nn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
A mixture of [4-(6-chloropyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone (0.075 g, 0.202 mmol), 2-phenylethanol (0.025 g, 0.202 mmol) and sodium hydride (0.010 g) in 5 mL of toluene was stirred at room temperature for 1 hour, and then refluxed overnight. The reaction mixture was cooled to room temperature, added 20 mL of water, and then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate, concentrated in vacuo. The residue was purified by column chromatography to yield the title compound as a white solid (58 mg, 62.9%). 1H NMR (400 MHz, CDCl3) δ 7.73, 7.61-7.64, 7.53-7.56, 7.36, 7.22-7.30, 7.20-7.24, 7.02, 6.86, 4.64, 3.91-3.98, 3.57, 3.48-3.52, 3.32, 3.11.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:9]1([NH:8][C:4](=[O:5])[CH:3]=[C:2]([CH3:7])[CH3:1])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)=CC(=O)Cl
Reactant: Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)=CC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3,3-dimethylacryloyl chloride (4.8 mL, 43.2 mmol) in dry DCM (100 mL), was added aniline (4.02 g, 43.2 mmol) followed by diisopropylethylamine (14.28 mL, 86.4 mmol). The mixture was stirred at ambient temperature for 2 hrs. Saturated sodium bicarbonate was added to quench the reaction. The organic layer was separated and washed with sat NaHCO3 (50 mL) and water (50 mL×2). The resulting solution was dried over MgSO4 and the filtrate evaporated to afford 3-methyl-but-2-enoic acid phenylamide as a brown solid in quantitative yield (7.6 g). MS: 176.0 (M+H)+; tR=2.40 min (method 1).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([SH:8])=[N:5][N:4]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH:26][CH:27]([CH2:32][CH:33]3[O:35][CH2:34]3)[C:28]([O:30]C)=[O:29])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH:26][CH:27]([CH2:32][CH:33]([OH:35])[CH2:34][S:8][C:6]3[S:7][C:3]([S:2][CH3:1])=[N:4][N:5]=3)[C:28]([OH:30])=[O:29])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: CSc1nnc(S)s1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nnc(SC)s3)C(=O)O)cc2)cc1

Procedure:
Example 33 is prepared from 5-(methylthio)-1,3,4-thiadiazole-2-thiol and 1d using the procedure described for compound 20.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:40])[CH2:18][CH:19]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[C:33](=[N:37][O:38]C)[CH2:32][CH2:31]3)[C:20](=O)[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:55][S:56](O)(=[O:58])=[O:57]>>[CH3:55][S:56]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[O:40][C:20]([C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)=[C:19]([C:28]3[CH:29]=[C:30]4[C:34](=[CH:35][CH:36]=3)[C:33](=[N:37][OH:38])[CH2:32][CH2:31]4)[CH:18]=2)[CH2:15][CH2:16]1)(=[O:58])=[O:57]
Reactant: CS(=O)(=O)O
Reactant: CON=C1CCc2cc(C(CC(=O)C3CCN(C(=O)OCc4ccccc4)CC3)C(=O)c3ccncc3)ccc21
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CS(=O)(=O)N1CCC(c2cc(-c3ccc4c(c3)CCC4=NO)c(-c3ccncc3)o2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
The product of Example 31, Step 3 (3.0 g, 5.5 mmol) was added to a stirred suspension of phosphorus pentoxide (8 g) in dry methane sulphonic acid (50 ml). After stirring at room temperature for 4 hours the reaction mixture was cautiously poured into a stirred solution of ice cold 50% aqueous sodium hydroxide (final pH 10). The mixture was extracted with chloroform, washed with water and brine, dried and concentrated in vacuo and the residue purified by silica gel chromatography to give the title compound (1.04 g, 50%); MS(ES+) m/e 466 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]O>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: COc1cccc(CO)c1
Product: COc1cccc(COc2ccnn2-c2cc(C#N)ccn2)c1
Yield: 13 %

Procedure:
The title compound was prepared in 13% yield from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 3-methoxybenzyl alcohol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C17H14N4O2, 307; Found, 307.