Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[C:6]([CH3:9])[C:7]=1[CH3:8].O.[NH2:12][NH2:13]>O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:12][NH2:13])=[C:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)nnc(Cl)c1C
Reactant: NN
Solvent: O
Product: Cc1c(Cl)nnc(NN)c1C
Temperature: 90 °C
Reaction time: 4 h

Procedure:
3,6-Dichloro-4,5-dimethylpyridazine (W4.006; 29.0 g) was admixed with 160 ml of hydrazine monohydrate solution (160 ml) and heated to 90° C. while stirring for 4 h. The reaction mixture was admixed with water and the precipitate was filtered off with suction, washed with water and dried over phosphorus pentoxide. 27.2 g of the title compound were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.[OH-].[K+].Cl>CO.CN1CCCC1=O>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 20.8 %

Procedure:
To a mixture of 301 mg (purity: 100%; 1.82 mmol) of 4-hydroxy-3,6-dichloropyridazine and 827 mg (5.49 mmol) of 2-cyclopropyl-6-methylphenol were added N-methylpyrrolidone (2.76 g) and 322 mg (5.46 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 105 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 21%) and 4.2 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.8%) were obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:16][C:17]([CH:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([F:29])[CH:23]=1)=[O:18]>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:28][C:25]3[CH:26]=[CH:27][C:22]([CH:20]4[CH2:21][CH:19]4[C:17]([OH:18])=[O:16])=[CH:23][C:24]=3[F:29])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COC(=O)C1CC1c1ccc(O)c(F)c1
Reactant: ClCc1cccnc1SC1CCCC1
Product: O=C(O)C1CC1c1ccc(OCc2cccnc2SC2CCCC2)c(F)c1
Yield: 71 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.032 g, 0.14 mmol) obtained in Step C of Preparation Example 8 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (less polar) (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 64 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.033 g, 71%).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[C:17]([C:19]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:20]=2)[CH:16]=[CH:15][N:14]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1ccnc(Cl)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2ccnc(Cl)c2)sc2ccccc12
Yield: 7.9 %

Procedure:
Methyl thiosalicylate (3.6 g, 21.6 mmol) and 2-chloro-4-cyanopyridine (3.0 g, 21.7 mmol) were dissolved in toluene (5.0 ml), and triethylamine (4.5 ml, 32.3 mmol) was added thereto. The reaction mixture was refluxed for 22 hrs. The reaction mixture was subjected to a silica gel (120 g) column chromatography, eluted with hexane-ethyl acetate (1:2, v/v) and recrystallized from acetone-ethyl acetate to give 2-(2-chloro-4-pyridyl)-4H-1,3-benzothiazine-4-one (0.47 g, 8.0%) as white crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]2[C@H:8]3[C@H:13]([CH2:14][CH2:15][C:6]=2[CH:5]=1)[NH:12][CH2:11][CH2:10][CH2:9]3)([O-:3])=[O:2].[CH2:18](Br)[CH:19]=[CH2:20]>C1COCC1>[CH2:20]([N:12]1[C@@H:13]2[C@H:8]([C:7]3[CH:16]=[CH:17][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=3[CH2:15][CH2:14]2)[CH2:9][CH2:10][CH2:11]1)[CH:19]=[CH2:18]
Reactant: O=[N+]([O-])c1ccc2c(c1)CC[C@@H]1NCCC[C@@H]21
Reactant: C=CCBr
Solvent: C1CCOC1
Product: C=CCN1CCC[C@H]2c3ccc([N+](=O)[O-])cc3CC[C@@H]21
Temperature: 50 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
(4aS,10bS)-8-Nitro-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline (0.50 g, 1.51 mmol) was dissolved in THF (30 mL) and allyl bromide (0.40 g, 3.30 mmol) added. The solution was stirred at 50° C. for 8 h, room temperature for 18 h and then evaporated. The residue was partitioned between ethyl acetate and NaOH (2M), and the organic phase separated and dried over MgSO4. The filtered solution was concentrated and separated by column chromatography (dichloromethane: 0-3% MeOH) to give the product as a yellow oil (0.40 g, 97%).
Reaction SMILES: [I-].[Li+].C[O:4][C:5]([C:7]1[N:8]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)(=[O:19])=[O:18])[C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([OH:16])=[CH:11][CH:10]=2)=[O:6]>N1C=CC=CC=1>[Cl:27][C:22]1[CH:21]=[C:20]([S:17]([N:8]2[C:9]3[C:14](=[CH:13][C:12]([OH:16])=[CH:11][CH:10]=3)[CH:15]=[C:7]2[C:5]([OH:6])=[O:4])(=[O:18])=[O:19])[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: COC(=O)c1cc2cc(O)ccc2n1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=C(O)c1cc2cc(O)ccc2n1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Yield: 28.7 %

Procedure:
A solution of anhydrous lithium iodide (870 mg) and methyl_N-(3,4-dichlorophenylsulphonyl)-5-hydroxyindole-2-carboxylate (260 mg) in pyridine (15 ml) was stirred at reflux for 4 hours. The reaction was cooled and concentrated in vacuo. The residue was dissolved in water (20 ml) and acidified with acetic acid. The product was extracted with ethyl acetate and the combined extracts were dried, concentrated in vacuo and the residue purified by column chromatography using dichloromethane-50% ethyl acetate containing 1% acetic acid as eluent to give the desired product as a glass (72 mg, 29%). NMR: δ 6.9 (m, 2H), 7.25 (s, 1H), 7.85 (d, 1H), 7.9 (m, 2H), 8.15 (s, 1H), 9.5 (s, 1H); m/z 385.8 (M−H−). The starting material was prepared by
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:9]1[CH:13]=[C:12]([CH:14]=[O:15])[O:11][CH:10]=1.Cl.C(OCC)(=O)C>C1COCC1>[O:11]1[CH:10]=[CH:9][CH:13]=[C:12]1[CH:14]([OH:15])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=Cc1ccco1
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(O)c1ccco1
Yield: 91 %

Procedure:
Under nitrogen atmosphere, 30 mL of THF was added to 6.09 g (10 mmol, 1.0 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.96 g (10 mmol) of 2-furfural in 5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 0˜5° C. for 3 hours. 25 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 10 mL of 1N hydrochloric acid, 20 mL of an aqueous saturated sodium chloride solution, 20 mL (×3) of an aqueous saturated sodium bicarbonate solution, and 20 mL of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.77 g of the desired product (yield 91%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)[N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:28]([O:30][C:31](=[O:44])[C:32]#[C:33][C:34]1[CH:35]=[N:36][C:37]2[C:42]([CH:43]=1)=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:44])[CH:32]=[C:33]([N:23]1[C:24]2[C:20](=[CH:19][C:18]([O:17][CH2:16][CH2:15][C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:27])[CH3:8])[N:10]=3)=[CH:26][CH:25]=2)[CH:21]=[CH:22]1)[C:34]1[CH:35]=[N:36][C:37]2[C:42]([CH:43]=1)=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:29]
Reactant: CCOC(=O)C#Cc1cnc2ccccc2c1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(CCOc2ccc3[nH]ccc3c2)n1
Product: CCOC(=O)C=C(c1cnc2ccccc2c1)n1ccc2cc(OCCc3cccc(N(C)C(=O)OC(C)(C)C)n3)ccc21
Yield: 48 %

Procedure:
The title compound was synthesized from {6-[2-(1H-indol-5-yloxy)-ethyl]-pyridin-2-yl}-methyl-carbamic acid tert-butyl ester and quinolin-3-yl-propynoic acid ethyl ester, using the procedure described in Example 16, step (d1), in 48% yield, as an E/Z isomeric mixture. H1 NMR (Cl3CD), δ: 8.91 (d, 0.3H, J=2.1 Hz), 8.88 (d, 0.3H, J=2.3 Hz), 8.17 (d, 0.7H, J=8.8 Hz), 8.14–8.11 (m, 1H), 7.97 (d, 0.3H, J=2.0 Hz), 7.82–7.74 (m, 2H), 7.60 (m, 1H), 7.53 (m, 1H), 7.49 (m, 1H), 7.17 (m, 1H), 7.11 (m, 1H), 6.92–6.97 (m, 2H), 6.78 (dd, 0.7H, J=2.5, 9.0 Hz), 6.70 (dd, 0.3H, J=2.5, 9.0 Hz), 6.64 (d, 0.3H, J=3.2 Hz), 6.55 (d, 0.7H, J=3.5 Hz), 6.39 (s, 0.3H), 6.32 (s, 0.7H), 4.39 (m, 2H), 4.10 (q, 1.4H, J=7.2 Hz), 4.04 (q, 0.6H, J=7.2 Hz), 1.39 (s, 0.9H), 1.38 (s, 2.1H), 3.21 (m, 2H), 1.51 (s, 9H), 1.14 (t, 2.1H, J=7.2 Hz), 1.05 (t, 0.9H, J=7.2 Hz).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[CH:6][CH:5]=[N:4]1)[CH3:2].[Cl:9][C:10]1[C:18]([C:19]2[N:23]([CH3:24])[N:22]=[C:21]([C:25]([CH3:27])=[O:26])[CH:20]=2)=[C:17]([Cl:28])[CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(#N)C>[Cl:9][C:10]1[C:18]([C:19]2[N:23]([CH3:24])[N:22]=[C:21]([C:25]([CH3:27])=[O:26])[CH:20]=2)=[C:17]([Cl:28])[CH:16]=[CH:15][C:11]=1[C:12]([O:8][C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][CH:6]=1)=[O:13]
Reactant: CC(=O)c1cc(-c2c(Cl)ccc(C(=O)O)c2Cl)n(C)n1
Reactant: CCn1nccc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCn1nccc1OC(=O)c1ccc(Cl)c(-c2cc(C(C)=O)nn2C)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 27.1 %

Procedure:
0.21 g (1.9 mmol) of 1-ethyl-5-hydroxy-1H-pyrazole and 0.39 g (1.9 mmol) of N,N-dicyclohexylcarbodiimide were added to 0.59 g (1.9 mmol) of 2,4-dichloro-3-(1-methyl-3-methylcarbonyl-1H-pyrazol-5-yl)benzoic acid in 8 ml of acetonitrile. The mixture was stirred at room temperature for 12 hours and 25 ml of 5% strength sodium carbonate solution and 50 ml of ethyl acetate were added, insoluble components were filtered off and the organic phase was separated off, dried and concentrated. The residue was subsequently chromatographed over silica gel (eluent: ethyl acetate:cyclohexane=1:1). 0.21 g (27% of theory) of (1-ethylpyrazol-5-yl) 2,4-dichloro-3-(1-methyl-3-methylcarbonyl-1H-pyrazol-5-yl)benzoate was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[OH:26][CH2:27][CH2:28][NH:29][CH2:30][CH2:31][OH:32]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12](=[O:14])[N:29]([CH2:30][CH2:31][OH:32])[CH2:28][CH2:27][OH:26])=[CH:15][CH:16]=2)=[CH:4][C:3]=1[C:17]([NH:18][C:19]1[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=1)=[O:25]
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1C(=O)Nc1ccncc1
Reactant: OCCNCCO
Product: Nc1ncc(-c2ccc(C(=O)N(CCO)CCO)cc2)cc1C(=O)Nc1ccncc1

Procedure:
Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid with 2-(2-hydroxy-ethylamino)-ethanol gives “A93”; method 2: HPLC/MS: 1.62 min, [M+H]=422;
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:23]1[CH:27]2[CH2:28][CH:29](Br)[CH:25]([CH2:26]2)[CH2:24]1>O>[CH:25]12[CH2:26][CH:27]([CH2:28][CH2:29]1)[CH2:23][CH:24]2[O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1]
Reactant: COc1ccc(C=O)cc1O
Reactant: BrC1CC2CCC1C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C=O)cc1OC1CC2CCC1C2
Temperature: 80 °C
Yield: 87.2 %

Procedure:
Isovanillin (50 g, 0.328 mol) is placed in a 1 liter round bottom flask which is equipped with a stir bar and reflux condensor and is charged with 500 ml of dimethylformamide. Potassium carbonate (45.3 g, 0.328 mol) is added to the reaction mixture which is heated to 80° C. At this temperature exo-2-bromonorbornane (12.57 g, 0.072 mol, 0.219 equivalents) is added and the reaction mixture is heated to 120° C. for 48 hours. The reaction is then cooled to room temperature and poured into 300 ml of water. The aqueous layer is extracted with ethyl ether (3×100 ml). The ethereal layer is washed with 1N sodium hydroxide solution (4×100 ml), water (3×100 ml) and saturated sodium chloride solution (3×100 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield 15.47 g of a green/brown oil. The crude product is purified by flash chromatography using a gradient eluent system of ethyl acetate/hexane [10% ethyl acetate/hexane→20% ethyl acetate/hexane] to yield 7.76 g (14.4%) of the aldehyde as a white solid. MP: 75.5° C.-79.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[NH:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)=[O:21])=[O:10])=[N:6][CH:7]=1.Cl.[OH:31][NH2:32].CCN(CC)CC>CCO>[NH2:29][C:28](=[N:32][OH:31])[C:25]1[CH:24]=[CH:23][C:22]([C:20]([NH:19][C:12]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=2[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])=[O:21])=[CH:27][CH:26]=1
Reactant: NO
Reactant: COc1ccc(NC(=O)c2ccc(C#N)cc2)c(C(=O)Nc2ccc(Cl)cn2)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2ccc(C(N)=NO)cc2)c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a suspension of compound N-(5-chloro(2-pyridyl)){2-[(4-cyanophenyl)carbonylamino]-5-methoxyphenyl}carboxamide (150 mg) in EtOH (10 mL) was added hydroxyamine hydrochloride (80 mg) and Et3N (200 μL). The mixture was stirred at 60° C. overnight and the reaction was complete. The solvent was evaporated and the crude material was purified by RP-HPLC to give the title compound. MS found for C21H18ClN5O4 (M+H)+: 440.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[CH:10]([CH3:23])[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH3:23])=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=3)[N:8]=2)[N:7]=1
Reactant: Cc1ccc(C(=O)C(C)Br)cc1[N+](=O)[O-]
Reactant: Nc1ccc(Cl)nn1
Solvent: CC#N
Product: Cc1ccc(-c2nc3ccc(Cl)nn3c2C)cc1[N+](=O)[O-]
Yield: 57.8 %

Procedure:
A stirred solution of 6-chloropyridazin-3-amine (2.38 g, 18.3 mmol) and 2-bromo-1-(4-methyl-3-nitrophenyl)propan-1-one (5.0 g, 18.3 mmol) in acetonitrile (100 mL) is heated at 80° C. for 16 hours. The mixture is concentrated to dryness and then purified via silica chromatography (hexanes to EtOAc) to afford the title compound (3.2 g, 57%) as a light yellow solid: Rf 0.30 (CH2Cl2); LCMS (m/z)=303.3, 305.2 [M+H]+, tR=2.84 min.
Reaction SMILES: CO.[CH3:3][NH2:4].[Cl:5][C:6]1[S:7][C:8]([CH2:11][NH:12][C:13](=[N:16][N+:17]([O-:19])=[O:18])SC)=[CH:9][N:10]=1>C(#N)C>[Cl:5][C:6]1[S:7][C:8]([CH2:11][NH:12][C:13]([NH:4][CH3:3])=[N:16][N+:17]([O-:19])=[O:18])=[CH:9][N:10]=1
Reactant: CN
Reactant: CSC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Solvent: CO
Solvent: CC#N
Product: CNC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Reaction time: 1.5 h

Procedure:
349 mg of a 40% methylamine methanol solution was dropwise added to a mixture consisting of 1 g N-(2-chloro-5-thiazolylmethyl)-S-methyl-N'-nitroisothiourea and 30 ml acetonitrile, at room temperature, over 5 minutes. After stirring for 1.5 hours, the resultant white precipitate was collected by filtration and then dried to afford 410 mg of N-(2-chloro-5-thiazolylmethyl)-N'-methyl-N"-nitroguanidine (compound No.14) as a white powder. The mother liquor after the filtration was concentrated, then 20 ml of ethanol was added, followed by stirring thoroughly, and the crystals formed were collected by filtration to obtain additional 330 mg of compound No.14 (mp 172-173° C.). Upon recrystallization from acetonitrile, this product exhibited mp 173-174° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[F:11][C:12]([F:32])([F:31])[O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][NH2:30])[CH2:25][CH2:24]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1.N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:30][O:29][CH:26]2[CH2:25][CH2:24][N:23]([S:20]([C:17]3[CH:16]=[CH:15][C:14]([O:13][C:12]([F:32])([F:11])[F:31])=[CH:19][CH:18]=3)(=[O:21])=[O:22])[CH2:28][CH2:27]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 32.9 %

Procedure:
1-Fluoro-4-isocyanatobenzene (96 mg, 0.70 mmol) was added to a solution of O-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yl) hydroxylamine (238 mg, 0.70 mmol) and pyridine (111 mg, 2.1 mmol) in CH2Cl2 (6 ml), and the whole was stirred at room temperature for 17 hours. The resulting precipitation was collected, washed with aqueous 1 N HCl solution (10 ml×3), aqueous NaHCO3 solution (10 ml×3), diethyl ether (10 ml×2) to give 1-(4-fluorophenyl)-3-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yloxy)urea (110 mg, 33%) as a white solid: LCMS: 478 [M+1]+. 1H NMR (DMSO-d6) δ: 1.81 (m, 2H), 1.92 (m, 2H), 2.85 (m, 2H), 3.22 (m, 2H), 3.78 (m, 1H), 7.10 (m, 2H), 7.51 (m, 2H), 7.65 (m, 2H), 7.91 (m, 2H), 8.62 (s, 1H), 9.38 (s, 1H).
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:6]=1[CH:7]=O)#[N:2].[SH2:15].[Na].Cl>CN(C)C=O>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:5]2[O:4][C:3]([C:1](=[S:15])[NH2:2])=[CH:7][C:6]=2[CH:9]=1
Reactant: COc1ccc(OCC#N)c(C=O)c1
Reactant: S
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2oc(C(N)=S)cc2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89.7 %

Procedure:
To a solution of 2-cyanomethoxy-5-methoxybenzaldehyde (420.0 g) in N,N-dimethylformamide (2.1 l), sodium hydrogen sulfide (281.5 g) was added over 16 minutes and stirred for 3 hours and 20 minutes below 8° C. After being stirred for 1 hour at 40° to 47° C., the mixture was poured into ice-water (10.5 l) with stirring. The resulting mixture was neutralized with 6N-aqueous hydrochloric acid and further stirred for 30 minutes. The resulting precipitates were collected by filtration, washed with water (1 l×5 times) and dried at 50° C. under reduced pressure to give 5-methoxy-2-benzofurancarbothioamide (408.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[CH:8]=[CH:7]2.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:8]=[CH:7]2
Reactant: Clc1ccc2cccc(Br)c2n1
Reactant: C1CNCCN1
Product: Brc1cccc2ccc(N3CCNCC3)nc12

Procedure:
Prepared analogously to Example 3 from 8-bromo-2-chloro-quinoline and piperazine.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([C:12]2[CH:13]=[N:14][C:15]3[N:16]([C:18]([C:21]4([C:24]5[CH:25]=[C:26]6[C:31](=[CH:32][CH:33]=5)[N:30]=[CH:29][CH:28]=[CH:27]6)[CH2:23][CH2:22]4)=[CH:19][N:20]=3)[CH:17]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN.F[P-](F)(F)(F)(F)F.[N:43]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:47]2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[C:10]([F:11])=[C:9]([C:12]2[CH:13]=[N:14][C:15]3[N:16]([C:18]([C:21]4([C:24]5[CH:25]=[C:26]6[C:31](=[CH:32][CH:33]=5)[N:30]=[CH:29][CH:28]=[CH:27]6)[CH2:23][CH2:22]4)=[CH:19][N:20]=3)[CH:17]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:43][CH3:47])=[O:6]
Reactant: O=C(O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c(F)c1F
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2,3-difluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoic acid (9.0 mg, 0.020 mmol), methylamine (2M in THF, 0.02 mL, 0.041 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (11 mg, 0.024 mmol) and N,N-diisopropylethylamine (11 μL, 0.061 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at RT for 4 h. The reaction mixture was purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=456.0.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[O:4].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14](O)=O>P(Cl)(Cl)(Cl)=O>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]1[O:4][C:3]([NH2:5])=[N:2][N:1]=1
Reactant: NNC(N)=O
Reactant: O=C(O)Cc1ccccc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nnc(Cc2ccccc2Cl)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Semicarbazide (9.0 g, 120 mmol) was slowly added to a solution of (2-chlorophenyl)acetic acid (10. g, 60 mmol) in phosphorus oxychloride (50 mL). The mixture was stirred at room temperature for 16 hours and then poured into crushed ice (500 g). A viscous solid was decanted from the aqueous layer and then the aqueous layer was adjusted to pH 4 to 5 with sodium hydroxide (50% aqueous solution). The resulting precipitate was filtered and then washed with sodium carbonate (10% aqueous solution, 100 mL) to give the product as a white solid. (5.9 g, 28 mmol, 47%). ESI-MS m/z calc. 209.0. found; 210.1 (M+1)+ 1H NMR (DMSO) δ 7.44-7.30 (m, 4H), 6.88 (s, 2H), 4.13 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])[C:4]([CH3:17])=[N:3]1.[F:18][C:19]1[CH:20]=[C:21]([N+:27]([O-:29])=[O:28])[CH:22]=[C:23]([F:26])[C:24]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:18][C:19]1[CH:20]=[C:21]([N+:27]([O-:29])=[O:28])[CH:22]=[C:23]([F:26])[C:24]=1[O:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:17])[C:5]=1[C:8]1[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=1[F:16]
Reactant: Cc1nn(C)c(O)c1-c1c(F)cc(F)cc1F
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(C)c(Oc2c(F)cc([N+](=O)[O-])cc2F)c1-c1c(F)cc(F)cc1F
Temperature: 80 °C

Procedure:
1,3-Dimethyl-4-(2,4,6-trifluorophenyl)-1H-pyrazol-5-ol (i.e. the product of Step C) (0.310 g, 1.28 mmol), was combined with 3,4,5-trifluoronitrobenzene (157 μL, 1.35 mmol) and potassium carbonate powder (0.27 g, 2 mmol) in dry N,N-dimethylformamide (4 mL). This mixture was stirred and heated at 80° C. for 45 minutes and then allowed to cool. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The organic phase was washed with water and with brine, dried over MgSO4, and concentrated to leave a viscous residue. This residue was purified by column chromatography through silica gel eluted with a gradient of ethyl acetate (30% to 100%) in hexane to give the title product, a compound of the present invention, as an off-white solid (209 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[CH2:16]([NH:23][C:24]([NH2:26])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]1[C:4](=[O:6])[C:3]2[C:2](=[CH:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=2)[NH:26][C:24]1=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC(=O)NCc1ccccc1
Reactant: COC(=O)c1ccc(C(=O)OC)c(Br)c1
Product: COC(=O)c1ccc2c(=O)n(Cc3ccccc3)c(=O)[nH]c2c1

Procedure:
The title compound was prepared from dimethyl 2-bromoterephthalate (2.4 g, 8.8 mmol) and benzylurea (1.7 g, 11.4 mmol) following the procedure outlined in Example 14, step 1 (1.8 g, 66%). LC-MS: (FA) ES+ 311.