Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.S(=O)(=O)(O)O.[NH2:8][C:9]1[C:13]([NH2:14])=[N:12][O:11][N:10]=1.[N:15]([C:17]1[C:18]([NH2:22])=[N:19][O:20][N:21]=1)=[O:16]>>[NH2:22][C:18]1[C:17]([N+:15](=[N:14][C:13]2[C:9]([NH2:8])=[N:10][O:11][N:12]=2)[O-:16])=[N:21][O:20][N:19]=1
Reactant: Nc1nonc1N
Reactant: Nc1nonc1N=O
Agent: O=S(=O)(O)O
Agent: OO
Product: Nc1nonc1N=[N+]([O-])c1nonc1N
Temperature: 18 °C
Yield: 88 %

Procedure:
This procedure was modeled from the original Russian preparation. To 30% hydrogen peroxide (100.0 g, 0.88 mol) in a 500 ml jacketed flask maintained at 18° C. was added 98% sulfuric acid (55.0 g, 0.56 mol) over 10 minutes with stirring. Then, 3,4-diaminofurazan (10.0 g, 0.10 mole) was added. The suspension was stirred for 24 hours in which time the soluble green nitroso-aminofurazan was converted to the insoluble orange DAAF. The product was filtered on a glass frit, washed with water and air dried to yield 9.29 g (88%) of crude material. For recrystallization the crude compound was dissolved in the minimum amount of room temperature DMSO (approximately 22 ml) and then water (45 ml) was added over 5 minutes with stirring. The pure DAAF was filtered, washed with water and air-dried. This material had the same properties as previously reported by the Russians. 1H NMR (deuteriomethylsulfoxide) δ 6.65 (s, 2H), 6.93 (s, 2H); 13C NMR (deuteriomethylsulfoxide) δ 148.3, 151.2, 152.6, 153.9.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH:15]=O)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2].[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22]2.N1CCCC1>C(O)C>[CH2:1]([NH:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12](/[CH:15]=[C:22]2\[C:23](=[O:28])[NH:24][C:25]3[C:21]\2=[CH:20][C:19]([F:18])=[CH:27][CH:26]=3)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2]
Reactant: CCNCCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: CCO
Solvent: C1CCNC1
Product: CCNCCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Temperature: 25 °C
Yield: 95.6 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-ethylamino-ethyl)-amide (99 g), ethanol (400 mL), 5-fluoro-2-oxindole (32 g) and pyrrolidine (1.5 g) were refluxed for 3 hours with stirring. The mixture was cooled to room temperature and the solids collected by vacuum filtration. The solids were stirred in ethanol at 60° C., cooled to room temperature and collected by vacuum filtration. The product was dried under vacuum to give 5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-ethylamino-ethyl)-amide (75 g, 95% yield). 1H-NMR (dimethylsulfoxide-d6) δ 1.03 (t, 3H, CH3), 2.42, 2.44 (2×s, 6H, 2×CH3), 2.56 (q, 2H, CH2), 2.70, 3.30 (2×t, 4H, 2×CH2), 6.85, 6.92, 7.58, 7.72, 7.76 (5×m, 5H, aromatic, vinyl and CONH), 10.90 (br s, 1H, CONH), 13.65 (br s, 1H, pyrrole NH).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[CH2:33][CH2:32][O:31][CH:30]([C:34]([OH:36])=O)[CH2:29]1)(=[O:27])[CH3:26].CCN(C(C)C)C(C)C.[NH:46]1[C:54]2[C:49](=[C:50]([C:55]3[CH:56]=[C:57]([NH2:64])[C:58]4[CH:59]=[N:60][NH:61][C:62]=4[CH:63]=3)[CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47]1>CN(C=O)C>[C:25]([N:28]1[CH2:33][CH2:32][O:31][CH:30]([C:34]([NH:64][C:57]2[CH:56]=[C:55]([C:50]3[CH:51]=[CH:52][CH:53]=[C:54]4[C:49]=3[CH:48]=[CH:47][NH:46]4)[CH:63]=[C:62]3[C:58]=2[CH:59]=[N:60][NH:61]3)=[O:36])[CH2:29]1)(=[O:27])[CH3:26]
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: CC(=O)N1CCOC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCOC(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)C1
Reaction time: 0.17 h
Yield: 30.1 %

Procedure:
To a solution of HATU (0.107 g, 0.28 mmol) in dry DMF (3 ml) was added 4-acetyl-2-morpholinecarboxylic acid (0.05 g, 0.282 mmol). DIPEA (0.098 ml, 0.56 mmol) was added and the mixture was left to stand for 10 min. 6-(1H-indol-4-yl)-1H-indazol-4-amine (0.04 g, 0.14 mmol), dissolved in dry DMF (3 ml) was added and the solution was left to stand at room temperature for 20 hr. DMF was removed by blow down under a stream of nitrogen, then the residue was dissolved and purified by Mass Directed AutoPrep Method B. The solvent was removed in vacuo and product dried in a vacuum oven at 50° C. overnight to give the title compound as a brown oil (17 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH3:19])([CH3:18])[CH2:7][CH:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:31]=2[C:32]([NH:34][CH3:35])=[O:33])[C:26]([Cl:41])=[CH:25][N:24]=1>>[Cl:41][C:26]1[C:27]([NH:29][C:30]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[N:28][C:23]([NH:1][C:2]2[CH:21]=[CH:20][C:5]3[C:6]([CH3:18])([CH3:19])[CH2:7][CH:8]([N:12]4[CH2:13][CH2:14][O:15][CH2:16][CH2:17]4)[C:9](=[O:11])[NH:10][C:4]=3[CH:3]=2)=[N:24][CH:25]=1
Reactant: CC1(C)CC(N2CCOCC2)C(=O)Nc2cc(N)ccc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)C(N2CCOCC2)CC3(C)C)ncc1Cl

Procedure:
2-[5-Chloro-2-(5,5-dimethyl-3-morpholin-4-yl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide was prepared from 8-Amino-5,5-dimethyl-3-morpholin-4-yl-1,3,4,5-tetrahydro-1-benzazepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1221d. Title compound was isolated as a yellow (5 mg, 10%), HPLC purity=99%, LCMS 570 (M+H), 1H-NMR (DMSO-d6, 400 MHz) δ 9.32 (s, 1H), 9.06 (bs, 1H), 8.53 (bs, 1H), 8.13 (s, 1H), 7.58-7.52 (m, 1H), 7.47 (d, J=7.9 Hz, 1H), 7.38-7.36 (m, 1H), 6.90 (d, 1H), 6.80 (bs, 1H) 6.73-6.71 (m, 1H), 4.33-4.30 (m, 1H), 3.63-3.50 (m, 8H), 2.72 (d, J=4.0 Hz, 3H), 1.77-1.73 (m, 1H), 1.49-1.46 (m, 1H), 1.24 (s, 3H), 1.19 (s, 3H).
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][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:35][C:36](=O)[O:37]C2C=CC=CC=2)[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=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][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:36]([NH:35][C:27]2[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:25]([O:24][CH3:23])[CH:26]=2)=[O:37])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: COc1cc(NC(=O)Oc2ccccc2)cc(C(F)(F)F)c1
Product: COc1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(OC)c(OC)cc34)c2)cc(C(F)(F)F)c1
Yield: 46.7 %

Procedure:
3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 g, 0.3 mmol) and phenyl 3-methoxy-5-(trifluoromethyl)phenylcarbamate from Example 115A (140 mg, 0.45 mmol) were reacted using the procedure in Example 115C to give 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-methoxy-5-(trifluoromethyl)phenyl)urea (71 mg, 0.14 mmol, 46%). 1H NMR (300 MHz, DMSO-d6) δ 9.19 (s, 1H), 9.08 (s, 1H), 8.56 (s, 1H), 7.62-7.55 (m, 2H), 7.48 (s, 1H), 7.45-7.37 (m, 2H), 7.31-7.24 (m, 2H), 6.95 (d, 1H), 6.84 (s, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 3.80 (s, 3H); LC-MS (ESI) m/z 515 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].S(O[CH2:28][CH:29]1[CH2:32][CH2:31][CH2:30]1)(C1C=CC(C)=CC=1)(=O)=O.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:28][CH:29]2[CH2:32][CH2:31][CH2:30]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC2)cc1
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Cl)ccc1OCC1CCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 117.1 %

Procedure:
5-Chlorosalicylaldehyde (7.7 g, 49.4 mmol) was dissolved in DMF (20 ml) with potassium carbonate (7.5 g, 54.1 mmol) and the cyclobutanemethanol tosylate (13 g, 54.1 mmol). The mixture was stirred at 50 ° C. under argon for 16 hours. Poured into water (500 ml), extracted with ethyl acetate (4×100 ml)and the combined organic fractions washed with 1M sodium hydroxide solution (100 ml), water (100 ml), saturated brine (100 ml) dried (MgSO4) and concentrated in vacuo to give 5-chloro-2-(cyclobutylmethoxy)benzaldehyde as a brown oil (13 g) which was used without further purification.
Reaction SMILES: [OH-].[Na+].[S].[NH2:4][NH2:5].[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O>>[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)/[CH:10]=[N:4]/[N:5]=[CH:10]/[C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([Br:6])[CH:8]=1
Reactant: NN
Reactant: O=Cc1cccc(Br)c1
Agent: [Na+]
Agent: [OH-]
Agent: [S]
Product: Brc1cccc(/C=N/N=C/c2cccc(Br)c2)c1
Temperature: 85 °C
Yield: 80.6 %

Procedure:
To a 250 mL 3-neck round-bottom flask equipped with condenser was added sodium hydroxide (6.2 g, 156 mmol), sulfur (5.0 g, 156 mmol), and hydrazine (5.0 g, 156 mmol). The mixture was stirred at reflux 85° C. for 2 hours. The solution was cooled to room temperature and treated dropwise via syringe with 3-bromobenzaldehyde (18 mL, 156 mmol). The precipitate was recovered by filtration, washed with water and dried in an oven to provide (1E,2E)-1,2-bis(3-bromobenzylidene)hydrazine (23 g, 40%). LCMS (M+H) 367.1 calc. for C14H, Br2N2 366.9. 1H NMR (400 MHz, CDCl3): δ ppm 7.30-7.35 (m, 2H) 7.59 (d, J=7.82 Hz, 2H) 7.70-7.73 (d, 2H) 8.03 (s, 2H) 8.56 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[C:13]([O:22]C)[CH:12]=2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.B(Br)(Br)[Br:26].BrBr>ClCCl>[NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[C:13]([OH:22])[CH:12]=2)=[O:9])=[C:6]([Br:26])[N:5]=[CH:4][N:3]=1
Reactant: COc1cc(NC(=O)c2c(N)ncnc2Cl)ccc1-c1cnco1
Reactant: BrB(Br)Br
Agent: BrBr
Solvent: ClCCl
Product: Nc1ncnc(Br)c1C(=O)Nc1ccc(-c2cnco2)c(O)c1
Yield: 33.6 %

Procedure:
4-Amino-6-chloro-N-(3-methoxy-4-(oxazol-5-yl)phenyl)pyrimidine-5-carboxamide (788 mg, 1.74 mmol) was treated with boron tribromide (1 M in dichloromethane, 11.8 ml, 11.8 mmol) with dichloromethane (10 ml) as a solvent according to the method described in Example 23. In this reaction conditions the chlorine atom was transformed into bromine. The solid residue (220 mg, 33% yield) was used in the next synthetic step without further purification. Purity 99%.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40].C(=O)([O-])O.[Na+]>C1COCC1>[C:39]([N:23]1[CH2:24][CH2:25][CH:20]([C:18]([N:17]([CH2:16][CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:19])[CH2:21][CH2:22]1)(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: O=C(C1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccccc2)CC1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
The compound obtained in Example 2 (252 mg, 0.60 mmol), triethylamine (0.201 ml) were dissolved in THF (5 ml), and under ice cooling, to the solution was added acetyl chloride (0.085 ml). The mixture was stirred at the same temperature for 30 minutes. To the mixture was added a saturated aqueous solution of sodium hydrogencarbonate (15 ml) under ice cooling, and the mixture was extracted with ethyl acetate (15 ml×3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel log, ethyl acetate/methanol=1/0 to 9/1 to 4/1), and the desired fraction was concentrated under reduced pressure. To the concentrate was added ethyl acetate and the insolubles were filtered off. The filtrate was concentrated under reduced pressure to give the titled compound (237 mg, 0.51 mmol, Yield 85%) as colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:7][CH2:8][C:9](=[O:12])[NH:10][CH2:11][C:4]=2[CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([NH:38][CH3:39])(=[O:37])=[O:36])[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([NH:38][CH3:39])(=[O:37])=[O:36])=[N:27][C:22]([NH:1][C:2]2[CH:20]=[CH:19][C:5]3[N:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:7][CH2:8][C:9](=[O:12])[NH:10][CH2:11][C:4]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: Nc1ccc2c(c1)CNC(=O)CCN2C(=O)C(F)(F)F
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CNC(=O)CCN3C(=O)C(F)(F)F)ncc1Cl

Procedure:
Title compound was prepared from 8-Amino-1-(2,2,2-trifluoro-acetyl)-2,3,5,6-tetrahydro-1H-benzo[b][1,5]diazocin-4-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide in an analogous manner to Example 1221d. Title compound isolated as a yellow solid (66 mg, 23%). mp 181-183° C.; LCMS: m/z=583.83 (M+H+), HPLC (90% purity); 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.77 (s, 1H), 7.57 (m, 2H), 7.42 (m, 2H), 7.29 (m, 2H), 7.10 (m, 1H), 6.87 (m, 1H), 6.72 (m, 1H), 4.67 (m, 1H), 4.06 (m, 2H), 3.48 (m, 1H), 3.02 (s, 3H), 2.92 (m, 1H), 2.75 (m, 1H), 2.55 (m, 1H).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH:12]([CH3:34])[CH2:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[N:35]1[CH:40]=[CH:39][C:38]([CH:41]=O)=[CH:37][CH:36]=1.[H-].[Na+]>CS(C)=O.O1CCCC1>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH:12]([CH3:34])[CH2:13][CH:14]=[CH:41][C:38]1[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=1
Reactant: O=Cc1ccncc1
Reactant: COc1ccc(OC)c(C(C)CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1ccc(OC)c(C(C)CC=Cc2ccncc2)c1
Reaction time: 1 h

Procedure:
A mixture of 3-(2,5-dimethoxyphenyl)butyl triphenylphosphonium bromide (19.0 g., 35.4 mmoles) in dimethylsulfoxide (50 ml.) is added to 4-pyridinecarboxaldehyde (3.79 g., 35.4 mmoles) in tetrahydrofuran (40 ml.). The resulting mixture is then added dropwise to a slurry of 50% sodium hydride (1.87 g., 39 mmoles) in tetrahydrofuran (20 ml.) under a nitrogen atmosphere at 0°-5° C. Following completion of addition, the mixture is stirred for one hour at 0°-5° and then concentrated under reduced pressure. The concentrate is diluted with water (200 ml.) and then acidified with 6 N HCl. The aqueous acid solution is extracted with benzene (4×50 ml.). It is then made basic and extracted with ethyl acetate (3×50 ml.). Evaporation of the combined extracts after drying (MgSO4) affords 4-(2,5-dimethoxyphenyl)-1-(4-pyridyl)-1-pentene.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.C1(C)C=CC=CC=1>C(OCC)C>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:7]2[C:2]([NH:1][C:26]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=3)=[S:27])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(COc2cccnc2N)cc1
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 2-amino-3-(4-methoxybenzyloxy)pyridine (1.80 g, 0.0078 mol), 4chlorophenyl isothiocyanate (1.58 g, 0.0094 mol) and toluene (10 ml) was refluxed for 3.5 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 2.2 g (70.5%), m.p. 136°-138 ° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH3:29])[C:16](=[O:28])[C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])C=C(F)[CH:18]=2)=[C:4]([O:30][CH3:31])[CH:3]=1.[F:32][C:33]([F:48])([F:47])[C:34]1C=C(C=C(C(F)(F)F)[N:42]=1)C(O)=O>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH3:29])[C:16](=[O:28])[C:17]2[CH:18]=[C:34]([C:33]([F:48])([F:47])[F:32])[N:42]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=2)=[C:4]([O:30][CH3:31])[CH:3]=1
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: COc1cc(F)c(F)cc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4,5-difluoro-2-methoxy-phenyl)-pyridin-3-yl]-methyl-amine (example 130, intermediate) and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 23 hours. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown solid (38%). MS (ESI): m/z=492.10 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH2:9]([S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[CH3:10].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1>[NH2:1][C:2]1[N:3]=[N:4][C:5]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: CCSc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: Nc1ccc(Cl)nn1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCSc1ccccc1-c1ccc(N)nn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
A mixture of 700 mg of 3-amino-6-chloropyridazine, 1.42 g of 2-ethylsulfanylphenylboronic acid pinacol ester, 148 mg of tris(dibenzylideneacetone)dipalladiuim(0), 603 mg of tricyclohexylphosphine (18% toluene solution), 3.43 g of tripotassium phosphate, 4.5 ml of 1,4-dioxane and 1.5 ml of water was stirred at 100° C. for 3 hours. Water was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 927 mg of 3-amino-6-(2-ethylsulfanylphenyl)pyridazine.
Reaction SMILES: O1CCC[CH2:2]1.[CH3:6][O:7][N:8]=[C:9]1[CH2:15][C:14]([CH3:17])([CH3:16])[CH:13]([OH:18])[CH:12]([N:19]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20](=[O:22])[CH3:21])[CH:11]=[C:10]1[CH3:30].[H-].[Na+].CI>C(O)(=O)C>[CH3:6][O:7][N:8]=[C:9]1[CH2:15][C:14]([CH3:16])([CH3:17])[CH:13]([O:18][CH3:2])[CH:12]([N:19]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20](=[O:22])[CH3:21])[CH:11]=[C:10]1[CH3:30]
Reactant: C1CCOC1
Reactant: CON=C1CC(C)(C)C(O)C(N(Cc2ccccc2)C(C)=O)C=C1C
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CI
Product: CON=C1CC(C)(C)C(OC)C(N(Cc2ccccc2)C(C)=O)C=C1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of tetrahydrofuran (40 ml) containing the 4-(N-acetylbenzylamino)-5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one methyloxime obtained in step 2 (9.5 g, 27.6 millimoles) there was gradually added 55% sodium hydride (3.6 g) while cooling on ice. After then adding methyl iodide (7.8 g, 55.2 millimoles) and stirring for 30 minutes, the mixture was returned to room temperature and stirring was continued for one hour. The reaction solution was poured into ice water (100 ml) containing acetic acid (1 ml), and subjected to extraction with benzene. After washing the benzene solution with water, it was dried over anhydrous magnesium sulfate. The benzene was distilled off, and the resulting residue was subjected to silica gel column chromatography with benzene-ethyl acetate (9:1) as the eluent, to obtain 8.51 g (86%) of 4-(N-acetylbenzylamino)-5-methoxy-2,6,6-trimethyl-2-cyclohepten-1-one methyloxime as a colorless oil.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[N+:10]([O-:12])=[O:11].[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([F:21])[CH:20]=1)[NH2:17].CC(C)([O-])C.[K+].O>C1COCC1>[F:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=2[N+:10]([O-:12])=[O:11])[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1c(F)cc(F)cc1Nc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2,4,6-trifluoronitrobenzene (1.37 g, 7.74 mmol) and 3,5 difluoroaniline (1 g, 7.74 mmol) in THF (23 mL) was added potassium tert-butoxide (1.3 g, 11.6 mmol) and reaction mixture was stirred at rt for 4 h. After completion of the reaction, water (50 mL) was added and the organic phase extracted with EtOAc (200 mL), dried over sodium sulfate and purified by column chromatography using 100-200 mesh silica gel and 0-10% EtOAc in hexane to provide N-(3,5-difluorophenyl)-3,5-difluoro-2-nitroaniline: LC-MS (ESI) m/z 284.9 [M+H]+.
Reaction SMILES: [ClH:1].NC[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:17][CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1.C1(C(CC)C(OCC)=O)C=CC=CC=1>>[Cl:1][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:17][CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1
Reactant: Cl
Reactant: CCOC(=O)C(CC)c1ccc(CCN)cc1
Agent: CCOC(=O)C(CC)c1ccccc1
Product: CCOC(=O)C(CC)c1ccc(CCl)cc1

Procedure:
For the preparation of ethyl 2-[4-(2-aminoethyl)-phenyl]-butyrate hydrochloride, ethyl 2-phenylbutyrate is chloromethylated and the ethyl 2-(p-chloromethylphenyl)-butyrate obtained (b.p. 117°-123° C./0.2 mm Hg) is reacted with potassium cyanide in acetone to give ethyl 2-(p-cyanomethylphenyl)-butyrate (b.p. 156°-160° C./0.3 mm Hg). By the catalytic hydrogenation of the nitrile group in the presence of a palladium/charcoal catalyst in alcoholic hydrochloric acid solution, there is obtained ethyl 2-[4-(2-aminoethyl)-phenyl]-butyrate hydrochloride, which does not crystallize.
Reaction SMILES: [Cl:1][CH2:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.CO.C1C(=O)N(Br)C(=[O:16])C1>O>[Cl:1][CH2:2][S:3]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(SCCl)cc1
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)CCl)cc1
Yield: 89.5 %

Procedure:
(Choromethyl)(p-tolyl)sulfane (10 g, 57.91 mmol) was added to a mixture of methanol (50 mL) and water (10 mL). The resulting mixture was cooled to a temperature between 0° C. and 5° C. NBS (12.37 g, 1.2 eq) was added in small portions, maintaining the same temperature range. The reaction mixture was stirred within the same temperature range until the reaction was complete. Thereafter, the reaction mixture was quenched by the addition of Na2SO3 (10%, 30 mL). The pH of the reaction mixture was adjusted to a value between 7 and 8, with saturated NaHCO3 solution. The mixture was concentrated under vacuum at a temperature between 20° C. and 25° C. and then extracted with dichloromethane (40 mL, 30 mL). The combined organic layer was washed with water (2×60 ml) and concentrated to ⅓ of the volume. Heptane (10 mL) was added and then removed by distillation. The crude product was purified by flash chromatography (Ethyl Acetate/Hexane 30:70) to give 9.78 g (89.51%) of the desired product as a white solid.