Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[H-].[Na+].[N+:18]([C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([N+]([O-])=O)[C:22]=1[C:23]#[N:24])([O-:20])=[O:19]>C1COCC1.CN(C=O)C.O>[C:23]([C:22]1[C:21]([N+:18]([O-:20])=[O:19])=[CH:28][CH:27]=[CH:26][C:25]=1[O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])#[N:24]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCCC1COc1cccc([N+](=O)[O-])c1C#N
Temperature: -20 °C
Reaction time: 18 h
Yield: 70.6 %

Procedure:
To a solution of tert-butyl 2-(hydroxymethyl)piperidine-1-carboxylate (0.86 g, 4 mmol) in dry THF (30 mL) was added at −20° C. NaH (0.32 g, 8 mmol) and the mixture was stirred 10 min at −20° C. and then 20 min at room temperature. The reaction mixture was then cooled to −20° C. and 2,6-dinitrobenzonitrile (0.772 g, 4 mmol) in dry THF (10 mL) and DMF (1 mL) was added dropwise over 15 min period. The solution was stirred under nitrogen at room temperature for 18 hours, diluted with water and extracted with EtOAc, the combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by Biotage purification system (120 g Silicycle column, Hexane:EtOAc=3:2 as eluent) to give tert-butyl 2-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate (1.02 g, 70.6%). MS 262 [M+H-Boc]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)c1cccc(Cl)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CCC(=O)c1cccc(Cl)c1OC
Temperature: 25 °C
Yield: 98 %

Procedure:
3′-Chloro-2′-hydroxypropiophenone (10 g, 54.3 mmol) and potassium carbonate (17.5 g) in 70 ml of acetone are admixed with 7 ml of dimethyl sulphate. The reaction mixture is boiled at reflux for three hours. After it has cooled to room temperature, the batch is subjected to suction filtration through Celite and the filter cake is washed with diethyl ether. After the solvent has been removed on a rotary evaporator, the yellow oil which remains is diluted with 200 ml of diethyl ether and the organic phase is washed with 0.2 M aqueous sodium hydroxide solution (100 ml) and brine (100 ml). The organic phase is dried over sodium sulphate and the solvent is removed on a rotary evaporator. This leaves the desired title compound as a colourless oil (98% yield).
Reaction SMILES: [CH2:1](N(CC)CC)C.CCl.[NH:10]1[CH2:17][CH2:16][CH2:15][C@@H:11]1[C:12]([OH:14])=[O:13].[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](F)[N:20]=1.O>O1CCOCC1>[Br:18][C:19]1[N:20]=[C:21]([N:10]2[CH2:17][CH2:16][CH2:15][C@@H:11]2[C:12]([O:14][CH3:1])=[O:13])[CH:22]=[CH:23][CH:24]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)[C@H]1CCCN1
Reactant: Fc1cccc(Br)n1
Agent: CCl
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)[C@H]1CCCN1c1cccc(Br)n1
Reaction time: 0.5 h
Yield: 16.4 %

Procedure:
Triethylamine (1.91 mL, 13.7 mmol) and D-proline methyl hydrochloride (1.13 g, 6.84 mmol) were added to a solution of 2-bromo-6-fluoropyridine (802 mg, 4.55 mmol) in 1,4-dioxane (9 mL) at room temperature. The mixture thus obtained was stirred at the same temperature as above for 30 minutes, and then at 80° C. for 3 hours. Thereafter, triethylamine (951 uL, 6.84 mmol) was further added to the resulting solution at room temperature, and the mixture thus obtained was then stirred at 80° C. for 2 hours. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate three times. The organic layer thus obtained was dried over anhydrous magnesium sulfate, and the solvent was then distilled away under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 1:1, v/v) to obtain the title compound (213 mg, yield: 16%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.[OH-].[Na+].ClCCl.[CH3:16][C:17]([CH3:19])=[O:18]>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:16]/[C:17](=[O:18])[CH3:19])=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1F
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)/C=C/c1ccc(Cl)cc1F
Yield: 76 %

Procedure:
To a mechanically stirred solution of 4-chloro-2-fluorobenzaldehyde (23.8 grams (g), 0.15 mole (mol)) in acetone (100 milliliters (mL)) at room temperature was added over 20 minutes (min) a solution of sodium hydroxide (NaOH, 6.6 g, 0.165 mol) in water (H2O, 400 mL). After stirring the reaction mixture overnight, dichloromethane (CH2Cl2, 100 mL) was added. The aqueous layer was separated and extracted with CH2Cl2 (100 mL), and the combined organic extracts were washed with brine and dried over magnesium sulfate (MgSO4). Solvent removal followed by Kugelrohr distillation gave 4-(4-chloro-2-fluorophenyl)-3-buten-2-one (1; 22.5 g, 76%) as a colorless liquid, which solidified upon standing: by 70-80° C., 0.1 mmHg (13.33 pascals (Pa)); 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J=16.5 Hz, 1H), 7.50 (t, J=8.1 Hz, 1H), 7.22-7.12 (m, 2H), 6.76 (d, J=16.5 Hz, 1H), 2.39 (s, 3H); HRMS-ESI (m/z): calcd for C10H8ClFO, 198.024. found 198.025.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]2=[O:14])[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.[Cl:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[CH:32]=[C:31]([S:36]([CH2:39][C@@H:40]([OH:44])[C:41](O)=[O:42])(=[O:38])=[O:37])[CH:30]=[CH:29]2.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[CH:32]=[C:31]([S:36]([CH2:39][C@@H:40]([OH:44])[C:41]([N:1]1[CH2:2][CH2:3][CH:4]([N:7]3[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]3=[O:14])[CH2:5][CH2:6]1)=[O:42])(=[O:37])=[O:38])[CH:30]=[CH:29]2
Reactant: O=C1CCN(C2CCNCC2)C(=O)N1
Reactant: O=C(O)[C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C1CCN(C2CCN(C(=O)[C@H](O)CS(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)C(=O)N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 9.1 %

Procedure:
To a solution of 1-piperidin-4-yl-dihydropyrimidin-2,4(1H,3H)-dione (105 mg) obtained in Example 4 5e), HOBt (83 mg) and (2S)-3-[(6-chloro-2-naphthyl)sulfonyl]-2-hydroxypropionic acid (170 mg) in DMF (10 mL) was added WSC (105 mg) at room temperature. The mixture was stirred at room temperature for 3 days, and DMF was distilled off under reduced pressure. The residue was diluted with chloroform, washed with an aqueous saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=10/1), and recrystallized from ethanol to obtain the title compound (24 mg, 9%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])[O:28][C:29](Cl)(Cl)Cl)Cl.[Cl:35][C:36]1[CH:37]=[C:38](CO)[CH:39]=[CH:40][CH:41]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:28][CH2:29][C:40]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:35])[CH:41]=2)=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: OCc1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCc4cccc(Cl)c4)cc3)c2cc1OC
Yield: 100.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (151 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (3-chlorophenyl)methanol (73 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (158 mg, yield 93%).
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][NH:8][C@H:9]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[F:26])=[C:14]([CH3:27])[N:13]([CH2:28][C:29]2[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:30]=2[F:39])[C:12]1=[O:40])C.[OH-].[Na+:49].O>>[Na+:49].[F:26][C:19]1[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:18]=1[C:15]1[C:16](=[O:17])[N:11]([CH2:10][C@H:9]([NH:8][CH2:7][CH2:6][CH2:5][C:4]([O-:47])=[O:3])[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:12](=[O:40])[N:13]([CH2:28][C:29]2[C:34]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:32]=[CH:31][C:30]=2[F:39])[C:14]=1[CH3:27]
Reactant: CCOC(=O)CCCN[C@@H](Cn1c(=O)c(-c2cccc(OC)c2F)c(C)n(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](NCCCC(=O)[O-])c3ccccc3)c2=O)c1F
Temperature: 22.5 °C
Reaction time: 5 h
Yield: 53.3 %

Procedure:
To a reactor was charged a stock solution of 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid ethyl ester 4a (81.8 kg solution, containing ˜17.1 kg of 4a). A solution of NaOH/water (2.2 kg/70 L) was added and the reactor contents were stirred at 20-25° C. for five hours until reaction completion. The reactor contents were concentrated using vacuum distillation. Water (124 L) was added and the solution was passed through a 5 μm line filter. Methyl isobutyl ketone (120 L) was charged and the mixture heated to 55° C. Separate the layers and add methyl isobutyl ketone (120 L) to the aqueous layer at ambient temperature. Agitate the mixture and add 48% aqueous sodium hydroxide (33 kg). Separate the layers and wash the aqueous layer with methyl isobutyl ketone (51 L). Separate the layers and wash the combined methyl isobutyl ketone layers with an aqueous brine solution (15.4 kg NaCl/44 L water). Separate the layers and concentrate the organic layer to ˜2-3 volumes methyl isobutyl ketone. Filter the concentrated solution through a 0.2 μm filter. Charge the methyl isobutyl ketone solution to a well-agitated reactor containing heptane (171 L) cooled to 20° C. The mixture is stirred for two hours, filtered, and the cake is washed with heptane (10 L) to provide 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid sodium salt 5-1 as an off-white solid (13.2 kg, 78% yield). LCMS (ESI) m/z 632.2 (MH+)
Reaction SMILES: CN(C)[C:3](=[S:5])[SH:4].[N+:7]([C:10]1[C:11](Cl)=[C:12]([C:24]([F:27])([F:26])[F:25])[CH:13]=[C:14]([N+]([O-])=O)[C:15]=1[NH:16][CH2:17][CH2:18][O:19][CH3:20])([O-:9])=[O:8].CS(C)=[O:31]>>[CH3:20][O:19][CH2:18][CH2:17][NH:16][C:15]1[C:14]2[S:5][C:3](=[O:31])[S:4][C:13]=2[C:12]([C:24]([F:27])([F:26])[F:25])=[CH:11][C:10]=1[N+:7]([O-:9])=[O:8]
Reactant: COCCNc1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Reactant: CN(C)C(=S)S
Reactant: CS(C)=O
Product: COCCNc1c([N+](=O)[O-])cc(C(F)(F)F)c2sc(=O)sc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 9.5 g (0.053 mole) of N,N-dimethyldithiocarbamic acid (sodium salt dihydrate) in 25 ml of dimethyl sulfoxide is added dropwise at 20° C. in the course of 1 hour to a solution of 18 g (0.052 mole) of 3,5-dinitro-4-[2-methoxyethylamino]-2-chlorobenzotrifluoride in 160 ml of dimethyl sulfoxide, and the batch is stirred for 11/2 hours at room temperature. Stirring is then continued for 3 hours at 80° C. (internal temperature). For working up, the reaction mixture is poured on ice-water and extracted three times with ether. The combined ethereal phases are washed four times with water and three times with sodium chloride solution, died over sodium sulfate, filtered, and concentrated. The residue is recrystallised from ether, affording 7-[2-methoxyethylamino]-6-nitro-4-trifluoromethyl-1,3-benzodithiol-2-one with a melting point of 96°-98° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:18]2[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]([CH3:22])[C:13]=2[N:12]=[C:11](Cl)[C:10]=1[C:24]#[N:25].[CH3:26][CH2:27][CH:28]([NH2:31])[CH2:29][CH3:30].[C:32]([O-])(O)=[O:33].[Na+]>C(O)(C)C>[NH2:25][CH2:24][C:10]1[C:11]([NH:31][CH:28]([CH2:29][CH3:30])[CH2:27][CH3:26])=[N:12][C:13]2[N:14]([CH3:22])[C:15](=[O:21])[N:16]([CH3:20])[C:17](=[O:19])[C:18]=2[C:9]=1[C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[O:33][CH3:32]
Reactant: CCC(N)CC
Reactant: Cn1c(=O)c2c(-c3cc(F)ccc3Br)c(C#N)c(Cl)nc2n(C)c1=O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCC(CC)Nc1nc2c(c(-c3cc(F)ccc3OC)c1CN)c(=O)n(C)c(=O)n2C

Procedure:
The title compound was prepared from Compound 47a (Example 42, 1 equiv), pentan-3-amine (3 equiv) and NaHCO3 (5 equiv) in isopropanol under micro wave condition at 180° C. for 30 min, and purified by LC-MS. MS [m+H] calc'd C22H29FN5O3 430; found 430.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][C:13]([OH:15])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[CH:32][CH:31]=1.Cl[Si](C)(C)C.Cl>C(Cl)Cl.C(N(CC)CC)C>[C:36]([C:33]1[CH:34]=[CH:35][C:30]([CH2:29][NH:28][C:13](=[O:15])[CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:31][CH:32]=1)([OH:38])=[O:37]
Reactant: O=C(O)COc1ccc2ccccc2c1
Reactant: NCc1ccc(C(=O)O)cc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COc1ccc2ccccc2c1)NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2-Naphthoxy)acetic acid (8.5 g) is suspended in 160 mL methylene chloride and treated with 1,1'-carbonyldiimidazole (6.8 g) which is added in small portions. After stirring for 3 hrs at room temperature under a nitrogen atmosphere, the mixture is added dropwise to a previously prepared solution of alpha-amino-p-toluic acid (1.4 g), chlorotrimethylsilane (10 mL), and triethylamine (11 mL) in 250 mL methylene chloride at 0° C. The final mixture is stirred at room temperature under a nitrogen atmosphere overnight. The mixture is combined with 200 mL 1N HCl and shaken, after which the resultant precipitate is collected by suction filtration. The precipitate is recrystallized from methanol/2N HCl, m.p. 188°-189° C. as N-(4-carboxybenzyl)-(2-naphthoxy)acetamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.Cl.[CH2:26]([O:28][C:29](=[O:33])[CH2:30][CH2:31][NH2:32])[CH3:27].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:26]([O:28][C:29](=[O:33])[CH2:30][CH2:31][NH:32][C:16](=[O:17])[C:15]1[CH:14]=[CH:13][C:12]([S:9](=[O:11])(=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[C:21]([F:22])([F:23])[F:24])=[CH:20][CH:19]=1)[CH3:27]
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)cc1
Reactant: CCOC(=O)CCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)cc1

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 4-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.536 g (10 mmol) of β-alanine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel and the title compound eluted with ethyl acetate.
Reaction SMILES: [C:1]([C:9]1[N:13]([CH3:14])[C:12](=[O:15])[O:11][N:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][O:17][CH2:18][C:19]1[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(O)C>[NH2:25][C:23]1[N:24]=[C:19]([CH2:18][O:17]/[N:16]=[C:1](/[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)\[C:9]2[N:13]([CH3:14])[C:12](=[O:15])[O:11][N:10]=2)[CH:20]=[CH:21][CH:22]=1.[NH2:25][C:23]1[N:24]=[C:19]([CH2:18][O:17]/[N:16]=[C:1](\[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)/[C:9]2[N:13]([CH3:14])[C:12](=[O:15])[O:11][N:10]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: NOCc1cccc(N)n1
Reactant: Cn1c(C(=O)c2ccccc2)noc1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: Cn1c(/C(=N/OCc2cccc(N)n2)c2ccccc2)noc1=O
Product: Cn1c(/C(=N\OCc2cccc(N)n2)c2ccccc2)noc1=O
Yield: 25 %
Yield: 8 %

Procedure:
In a microwave tube, to a solution of 3-benzoyl-4-methyl-1,2,4-oxadiazol-5(4H)-one (500 mg, 2.44 mmol, 1 eq.) in iPrOH (10 ml) were added 6-[(aminooxy)methyl]pyridin-2-amine (340 mg, 2.44 mmol, 1 eq.) followed by pTSA.H2O (578 mg, 2.93 mmol, 1.2 eq.). The reaction was microwaved at 160° C. for 2 h then was quenched by addition of water and extracted with EtOAc (3×50 ml). The organics were combined, washed with aq. sat. NaHCO3, dried over MgSO4 and concentrated. The residue was purified by preparative HPLC to give 3-[(Z)-{[(6-aminopyridin-2-yl)methoxy]imino}(phenyl)methyl]-4-methyl-1,2,4-oxadiazol-5(4H)-one (200 mg, 25%) and 3-[(E)-{[(6-aminopyridin-2-yl)methoxy]imino}(phenyl)methyl]-4-methyl-1,2,4-oxadiazol-5(4H)-one (62 mg, 8%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][S:8][CH2:9][CH2:10][NH2:11])=[N:5][N:6]=1.[N+:12]([CH:15]=[C:16](SC)[S:17][CH3:18])([O-:14])=[O:13]>>[N+:12]([CH:15]=[C:16]([S:17][CH3:18])[NH:11][CH2:10][CH2:9][S:8][CH2:7][C:4]1[S:3][C:2]([NH2:1])=[N:6][N:5]=1)([O-:14])=[O:13]
Reactant: NCCSCc1nnc(N)s1
Reactant: CSC(=C[N+](=O)[O-])SC
Product: CSC(=C[N+](=O)[O-])NCCSCc1nnc(N)s1

Procedure:
By the procedure of Example 8(i), 2-amino-5-(2-aminoethyl)thiomethyl-1,3,4-thiadiazole (from the dihydrobromide) is reacted with 1-nitro-2,2-bis-methylthioethylene to give 1-nitro-2-methylthio-2-[2-((2-amino-5-(1,3,4)-thiadiazolyl)-methylthio)ethylamino]ethylene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=O)[NH:31][C:30]=2[CH3:37])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[NH:13][C:12]3=[O:18])[NH:31][C:30]=2[CH3:37])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)NCCn4ccnn4)c2C)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.8 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (54 mg, 45%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][SH:12])=[CH:9][C:4]=2[O:3][CH2:2]1.Br[CH2:14][CH2:15][S:16]([O-:19])(=[O:18])=[O:17].[Na+:20].[OH-].[Na+]>C(O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][S:12][CH2:14][CH2:15][S:16]([O-:19])(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1.[Na+:20]
Reactant: O=S(=O)([O-])CCBr
Reactant: SCCc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])CCSCCc1ccc2c(c1)OCO2
Yield: 73.9 %

Procedure:
15 g of 2-(1,3-benzodioxol-5-yl)ethanethiol and 17.4 g of sodium 2-bromoethanesulfonate were dissolved in a mixture of 280 ml of ethanol and 120 ml of water. 3.3 g of sodium hydroxide was added to the solution and the mixture was heated under reflux for 1 h. The reaction mixture was concentrated and 500 ml of ethyl acetate and 500 ml of water were added thereto. After separation of the layers, the aqueous layer was acidified with hydrochloric acid. After extraction with n-butanol, the extract was washed with a saturated aqueous common salt solution. The solvent was distilled off to obtain 19 g of a faint yellow residue. This product was dissolved in a solution of 2.94 g of sodium hydroxide in dilute methanol and recrystallized therefrom to obtain 14.7 g of the intended compound in the form of colorless crystals.
Reaction SMILES: CC([O-])(C)C.[K+].[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[CH:11]2.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>C1COCC1>[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:23][C:22]1[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=1)[N:12]=[CH:11]2
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: COc1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2ncc3cc(Br)ccc32)cc1
Reaction time: 0.5 h

Procedure:
To a suspension of KOtBu (8.13 g, 72.4 mmol) in THF (60 mL) was added 5-bromo-1H-indazole (12.98 g, 65.9 mmol) in THF (60 mL). After 30 min, 4-methoxybenzyl chloride (9.38 mL, 69.2 mmol) was added (neat) and the resulting pale yellow solution was stirred 48 h. The reaction was quenched by addition of saturated NH4Cl solution, and the mixture was extracted with EtOAc. Evaporation of the organic phase followed by column chromatography of the residue on silica gel, eluting with 1/9-EtOAc/heptane, afforded the title compound, which was recrystallized from toluene/heptane (1/5) to afford the title compound as colorless cubes (7.65 g, 37%). Also recovered from the chromatography was 5-bromo-2-(4-methoxybenzyl)-2H-indazole (8.0 g, 38%)
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([CH3:15])=[C:7]([Cl:16])[CH:6]=1)=[O:4].[CH3:17][NH:18][C:19]([NH:21][CH3:22])=[S:20]>>[BrH:1].[Cl:16][C:7]1[CH:6]=[C:5]([C:3]2([OH:4])[CH2:2][S:20][C:19](=[N:18][CH3:17])[N:21]2[CH3:22])[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]=1[CH3:15]
Reactant: Cc1c(Cl)cc(C(=O)CBr)cc1S(N)(=O)=O
Reactant: CNC(=S)NC
Product: Br
Product: CN=C1SCC(O)(c2cc(Cl)c(C)c(S(N)(=O)=O)c2)N1C

Procedure:
3.2 g of 2-bromo-3'-chloro-4'-methyl-5'-sulfamoyl-acetophenone were reacted according to the method described in Example 6 with 1.2 g of 1,3-dimethyl-thiourea to yield the 4-(3-chloro-4-methyl-5-sulfamoylpheny)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hyrobromide. M.p. 160° C (decomposition).