Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:18]([F:19])=[C:17]([CH2:20][CH2:21][C:22](=[O:38])[C:23]2[S:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)[CH:16]=[CH:15][C:3]=1[O:4][C:5]([CH3:14])([CH3:13])[C:6]([O:8]C(C)(C)C)=[O:7].FC(F)(F)C(O)=O>>[F:1][C:2]1[C:18]([F:19])=[C:17]([CH2:20][CH2:21][C:22](=[O:38])[C:23]2[S:24][C:25]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:33]=3)=[CH:26][CH:27]=2)[CH:16]=[CH:15][C:3]=1[O:4][C:5]([CH3:13])([CH3:14])[C:6]([OH:8])=[O:7]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(F)c1F
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(F)c1F)C(=O)O

Procedure:
2-(2,3-Difluoro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-phenoxy)-2-methylpropanoic acid is prepared from tert-butyl 2-(2,3-difluoro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoate according to general procedure E using 15 equivalents of trifluoroacetic acid.
Reaction SMILES: C([O-])([O-])=[O:2].[K+].[K+].[CH2:7]([NH:14][CH:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][N:23]=2)[CH2:17][CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.OO>CS(C)=O>[CH2:7]([NH:14][C@H:15]1[CH2:16][CH2:17][C@H:18]([O:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]([NH2:27])=[O:2])=[CH:24][N:23]=2)[CH2:19][CH2:20]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(OC2CCC(NCc3ccccc3)CC2)nc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(O[C@H]2CC[C@H](NCc3ccccc3)CC2)nc1

Procedure:
Add K2CO3 (200 mg, 1.44 mmol) to a solution of 6-(4-benzylamino-cyclohexyloxy)-nicotinonitrile (890 mg, 2.89 mmol) in DMSO (25 mL). Cool the reaction to 0° C. and add hydrogen peroxide (0.87 mL). Stir the resulting reaction mixture at room temperature for 2 h. Then quench the reaction mixture with water (25 mL) and extract with EtOAc (30 mL). Dried over sodium sulfate, filter and concentrate. Further purify the residue by SCX chromatography to provide the title compound (700 mg, 74%). Mass spectrum (ion spray): m/z=326.0 (M+1); 1H NMR (CDCl3): 8.61 (s, 1H), 8.04 (m, 1H), 7.36 (m, 5H), 6.74 (d, J=8.8 Hz, 1H), 5.10 (m, 1H), 3.87 (s, 2H), 2.64 (m, 1H), 2.22–2.07 (m, 4H), 1.58–1.33 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([Br:7])[N:6]=1.F[P-](F)(F)(F)(F)F.[N:18]1(OC(N(C)C)=[N+](C)C)[C:22]2C=[CH:24][CH:25]=[CH:26][C:21]=2N=N1.N1CCCCC1.C(Cl)Cl.C(N(CC)CC)C>>[Br:1][C:2]1[S:3][C:4]([C:8]([N:18]2[CH2:24][CH2:25][CH2:26][CH2:21][CH2:22]2)=[O:10])=[C:5]([Br:7])[N:6]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1sc(Br)nc1Br
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1sc(Br)nc1Br)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a stirred solution of 2,4-dibromo-5-thiazole carboxylic acid (48, 400 mg, 1 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (790 mg, 2.1 mmol) and piperidine (180 uL, 1.8 mmol) in methylene chloride (5.0 mL, 78 mmol) was added triethylamine (580 μL, 4.2 mmol) at room temperature. The resulting turbid mixture was allowed to stir at rt overnight and quenched with water. The product was extracted using dichloromethane and washed with water, citric acid solution, water and brine. Removal of solvent gave the intermediate (49) (2,4-Dibromo-thiazol-5-yl)-piperidin-1-yl-methanone (300 mg, 30%) which was used as such for the next step.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[NH:4][N:3]=1.C([O-])(O)=O.[Na+].[F:17][C:18]1[C:19](Cl)=[N:20][C:21]([Cl:24])=[N:22][CH:23]=1>C1COCC1.CCO>[Cl:24][C:21]1[N:22]=[C:23]([NH:11][C:7]2[CH:6]=[C:5]3[C:10]([C:2]([CH3:1])=[N:3][NH:4]3)=[CH:9][CH:8]=2)[C:18]([F:17])=[CH:19][N:20]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1n[nH]c2cc(N)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1n[nH]c2cc(Nc3nc(Cl)ncc3F)ccc12
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a stirred solution of 3-methyl-6-aminoindazole (2.71 g, 0.015 mol) and NaHCO3 (1.26 g, 0.045 mol) in THF (15 mL) and EtOH (60 mL) was added 5-fluoro-2,4-dichloropyrimidine (3.2 g, 0.019 mol) at room temperature. After the reaction was stirred overnight, the brown suspension was filtered and washed thoroughly with EtOH. The filtrate was concentrated under reduced pressure, and the resulting solid was washed with ether to remove excess pyrimidine to yield 3.7 g of the desired product (89%). HNMR: δ 12.57 (s, 1H), 10.01 (s, 1H), 8.28 (d, 1H), 7.93 (s, 1H), 7.60 (d, 1H), 7.27 (dd, 1H) 3.11 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[Cl:21][CH:22]([CH3:27])[C:23](=O)[CH2:24][OH:25]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:23]([CH2:24][OH:25])[CH:22]([Cl:21])[CH3:27])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(F)cc2C(c2ccccc2)=NC1
Reactant: CC(Cl)C(=O)CO
Solvent: C1CCOC1
Product: CC(Cl)C(CO)=NNC1=Nc2ccc(F)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 1, 7-fluoro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 3-chloro-1-hydroxy-2-butanone under nitrogen to give 7-fluoro-2-[[2-chloro-1-(hydroxymethyl)propylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([NH:26][C:27](=[O:29])[CH3:28])[CH:16]=[C:17]([C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:18]=1.[F-].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:12][C:13]2[CH:14]=[C:15]([NH:26][C:27](=[O:29])[CH3:28])[CH:16]=[C:17]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:18]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CC(=O)Nc1cc(N)cc(-c2ncccc2F)c1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(Nc2ccc(Br)cc2[N+](=O)[O-])cc(-c2ncccc2F)c1
Yield: 50 %

Procedure:
Solution of 4-bromo-1-fluoro-2-nitrobenzene (3.0 g, 13.63 mmol), N-(3-amino-5-(3-fluoropyridin-2-yl)phenyl)acetamide (4.0 g, 16.36 mmol), and potassium fluoride (0.95 g, 16.36 mmol) in DMF was heated at 130° C. for 16 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to afford the crude residue which was purified by column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to yield the title product in 50% yield (3.4 g). 1H NMR (300 MHz, DMSO-d6): δ 8.55 (brs, 1H), 8.23 (brs, 1H), 7.96 (m, 2H), 7.85 (m, 2H), 7.67 (d, 1H), 7.51 (m, 2H), 7.21 (d, 1H), 2.07 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([Cl:28])[CH:22]=1.Br[CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:23]([Cl:28])[CH:22]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: O=C(N1CCc2ccc(Cl)c(NCc3ccc(O)c(Cl)c3)c2CC1)C(F)(F)F
Product: CC(C)(C)C(=O)COc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1Cl
Yield: 82.2 %

Procedure:
Use a method similar to the General Procedure 4-1 to react 7-chloro-6-(3-chloro-4-hydroxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (438 mg, 1.01 mmol) and 1-bromopinacolone (217 mg, 1.21 mmol). Purify by chromatography on silica gel eluting with EtOAc/hexane (1:4) to give 7-chloro-6-[3-chloro-4-(3,3-dimethyl-2-oxo-butoxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil (441 mg, 82%). MS (ES+) m/z: 531 (M+H)+.
Reaction SMILES: [F:1][CH2:2][O:3][N:4]=[C:5]([C:10]1[N:14]=[C:13]([NH2:15])[S:12][N:11]=1)[C:6]([O:8][CH3:9])=[O:7].[CH:16](O)=[O:17]>>[F:1][CH2:2][O:3][N:4]=[C:5]([C:10]1[N:14]=[C:13]([NH:15][CH:16]=[O:17])[S:12][N:11]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=CO
Reactant: COC(=O)C(=NOCF)c1nsc(N)n1
Product: COC(=O)C(=NOCF)c1nsc(NC=O)n1
Yield: 33.1 %

Procedure:
A solution of methyl 2-fluoromethoxyimino-2-(5-amino-1,2,4-thiadiazole-3-yl)-acetate (anti-isomer) (1.17 g, 5 mmol) in 99% formic acid (2.34 g, 51 mmol) was reacted at 35° C. for 90 hrs. The reaction mixture was cooled to below 10° C. to separate crystals, which were collected by filtration, washed with methanol and dried to give methyl 2-fluoromethoxyimino-2-(5-formamido-1,2,4-thiadiazole-3-yl)-acetate (syn-isomer) (434 mg). The crystals thereof (100 mg) were further obtained from the mother liquor. (Yield: 39.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]2[CH:6]=[CH:7][N:8]3[CH:19]=[CH:18][CH:17]=[C:9]3[C:10](=[CH:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[C:4]=2[CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([NH:1][C:2]1[CH:21]=[CH:20][C:5]2[CH:6]=[CH:7][N:8]3[CH:19]=[CH:18][CH:17]=[C:9]3[C:10](=[CH:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[C:4]=2[CH:3]=1)(=[O:24])[CH3:23]
Reactant: CN(C)CCC=C1c2cc(N)ccc2C=Cn2cccc21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)C(=CCCN(C)C)c1cccn1C=C2

Procedure:
9-Amino-11-(3-dimethylaminopropylidene)-11H-pyrrolo[2,1-b][3]benzazepine (11.4 mmoles) dissolved in 15 ml. pyridine is treated with acetic anhydride (2 ml.) at room temperature for 19 hours. The volatiles are removed under vacuum and the residue is dissolved in chloroform, and chromatographed on silica gel. Elution with chloroform-methanol yields 9-acetamido-11-(3-dimethylaminopropylidene)-11H-pyrrolo[2,1-b][3]benzazepine.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:8][OH:9].O=[C:11]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[CH:19][CH:18]=1)[CH2:12][CH2:13][C:14]([OH:16])=[O:15]>O.C(O)C>[OH:9]/[N:8]=[C:11](\[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[CH:19][CH:18]=1)/[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)CCC(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)CC/C(=N/O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Reaction time: 0.25 h
Yield: 37.5 %

Procedure:
Sodium carbonate (0.80 g, 5.76 mmol) was added to hydroxylamine hydrochloride (0.80 g, 11.5 mmol) in water (3 mL), and the mixture stirred for 15 minutes with ice cooling. The resulting mixture was added to 4-oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid (2.99 g, 8.86 mmol) (Example 1) in ethanol (50 mL) and the resulting mixture refluxed for 6 hours, concentrated to one-third volume, and allowed to cool. The resulting precipitate was dissolved in hot sodium bicarbonate solution, filtered, and the filtrate acidified with 1M HCl to yield a slurry which was filtered, washed with water, and dried in vacuo to give the title compound as a white solid (1.17 g, %C,H,N found: 71.77, 6.79, 7.88).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].Br[CH2:11][CH2:12][CH2:13][CH2:14][Cl:15]>>[Cl:15][CH2:14][CH2:13][CH2:12][CH2:11][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: ClCCCCBr
Reactant: COc1ccccc1O
Product: COc1ccccc1OCCCCCl

Procedure:
Prepared by Procedure U and Scheme AK using 2-methoxyphenol and 1-bromo-4-chlorobutane.
Reaction SMILES: Cl.[C:2]1(=[O:12])[NH:6][C:5](=[O:7])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]12.C(O)(=O)C1C(=CC=CC=1)C(O)=[O:17]>N1C=CC=CC=1>[OH:17][N:6]1[C:2](=[O:12])[C:3]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:4]2[C:5]1=[O:7]
Reactant: O=C(O)c1ccccc1C(=O)O
Reactant: O=C1NC(=O)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)N1O
Yield: 71 %

Procedure:
To a flask was added 50 mL of 1N hydrochloric acid, and powdery phthalimide (2.9 g, 20 mmol) was slowly added thereto with stirring. Then, the mixture was stirred at 97° C. for 3 hours to obtain an aqueous solution containing phthalic acid. Phthalic acid was recovered by condensing and filtering the aqueous solution. Then, after hydroxylamine hydrochloride NH2OH.HCl (1.39 g 40 mmol) was dissolved in 100 mL of pyridine, the recovered phthalic acid was added thereto, and stirred at 97° C. for 4 hour to form N-hydroxyphthalimide (2.3 g yield 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH:12]([C:15]1[NH:16][CH:17]=[CH:18][N:19]=1)([CH3:14])[CH3:13].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:16]2[CH:17]=[CH:18][N:19]=[C:15]2[CH:12]([CH3:14])[CH3:13])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Reactant: CC(C)c1ncc[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)c1nccn1-c1ccc(Cl)cc1[N+](=O)[O-]
Yield: 64.1 %

Procedure:
A mixture of 4-chloro-1-fluoro-2-nitrobenzene 1.01 g, 2-isopropylimidazole 634 mg, N,N-diisopropylethylamine, 1.46 mL and acetonitrile 12 mL was heated under reflux for 15 hours. The solvent was distilled off and water was added to the residue which was then rendred acidic with diluted hydrochloric acid. After washing the same with diethyl ether, the aqueous layer was rendered alkaline with aqueous sodium hydroxide solution and extracted twice with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and removed of the solvent by distillation to provide 0.98 g of the title compound.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:6]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:9][CH:10]=1.[CH2:15]([N:22]1[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCOCC>[CH2:15]([N:22]1[CH2:27][CH2:26][CH2:25][C:24]([OH:28])([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=2)[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: OC1(c2cccc(C(F)(F)F)c2)CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under anhydrous conditions, to a mixture of 11 g. of magnesium in 15 ml. of ethyl ether an iodine crystal is added followed by the addition of a solution of 100 g. of m-bromotrifluoromethylbenzene in 300 ml. of ether over a two hour period. The resulting mixture is stirred for two hours at ambient temperature then cooled to 5° C. A solution of 70 g. of N-benzyl-3-piperidone in 300 ml. of ether is added at this temperature over one hour. After stirring for 15 minutes at 5° C. and one hour at 20°-25° C., the reaction mixture was poured onto 800 ml. of ice-water with stirring. The mixture is filtered, the organic layer extracted with 4×100 ml. of 1 N hydrochloric acid and once with brine. The aqueous phase is made alkaline by addition of triethylamine in the cold and the resulting mixture extracted with ethyl acetate. The combined extracts are washed with brine, dried (MgSO4) and evaporated to dryness. The crude product is purified by silica gel chromatography, eluting with cyclohexane/chloroform/triethylamine (85:10:5 by volume) to obtain the desired product as an orange colored solid.
Reaction SMILES: C([C:5]1N=C(N2CCC(F)(F)C2)[C:8]2[C:9](=[N:11][N:12](CC)[N:13]=2)[N:10]=1)(C)(C)C.[F:23][C:24]1([F:44])[CH2:28][CH2:27][N:26]([C:29]2[C:30]3[N:43]=[N:42][NH:41][C:31]=3[N:32]=[C:33]([O:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[N:34]=2)[CH2:25]1.ClCC1N(C)N=NN=1>>[F:44][C:24]1([F:23])[CH2:28][CH2:27][N:26]([C:29]2[C:30]3[C:31](=[N:41][N:42]([CH2:8][C:9]4[N:10]([CH3:5])[N:13]=[N:12][N:11]=4)[N:43]=3)[N:32]=[C:33]([O:35][CH2:36][C:37]([CH3:38])([CH3:39])[CH3:40])[N:34]=2)[CH2:25]1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: CC(C)(C)COc1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: Cn1nnnc1CCl
Product: Cn1nnnc1Cn1nc2nc(OCC(C)(C)C)nc(N3CCC(F)(F)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 7-(3,3-Difluoro-pyrrolidin-1-yl)-5-(2,2-dimethyl-propoxy)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-methyl-1H-tetrazole. MS (m/e): 409.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH:12][CH3:13])[C:9]([N+:14]([O-])=O)=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]>C1COCC1.CO.[Pd]>[NH2:14][C:9]1[C:10]([NH:12][CH3:13])=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: CNc1cc(OC)c(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CNc1cc(OC)c(C(=O)O)cc1N

Procedure:
Prepared analogously to example 1b by hydrogenation of 2-methoxy-4-methylamino-5-nitro-benzoic acid using palladium/charcoal 10% in THF and methanol.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][NH2:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:23]O>C(OCC)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:15]([O:17][CH3:23])=[O:16])[CH2:13][NH2:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
Dissolve Nα -(benzyloxycarbonyl)-β-(amino)-L-alanine (47.6 g, 0.2 mol) in methanol (500 mL) and treat with concentrated sulfuric acid (0.5 mL). Heat to 60° C. for 16 hours, cool and reduce the solvent by 50% in vacuo. Dilute with ethyl ether (500 mL), wash with saturated sodium hydrogen carbonate, then brine. Dry (MgSO4) and evaporate the solvent in vacuo to give Nα -(benzyloxycarbonyl)-β-(amino)-L-alanine, methyl ester.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([N:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:30])[CH:26]=3)[N:21]=[CH:20]2)[C:9]([NH:11][C:12]2[S:13][C:14]([CH:17]=O)=[CH:15][N:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:31]([CH2:34][CH3:35])[CH2:32][CH3:33].CC([O-])=O.[Na+].[BH3-]C#N.[Na+]>C(Cl)Cl.CO>[CH:1]1([CH2:7][CH:8]([N:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:30])[CH:26]=3)[N:21]=[CH:20]2)[C:9]([NH:11][C:12]2[S:13][C:14]([CH2:17][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:15][N:16]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=Cc1cnc(NC(=O)C(CC2CCCCC2)n2cnc3ccc(F)cc3c2=O)s1
Reactant: CCNCC
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)Cc1cnc(NC(=O)C(CC2CCCCC2)n2cnc3ccc(F)cc3c2=O)s1
Reaction time: 0.5 h

Procedure:
A mixture of Compound 150 (0.2 g, 0.4675 mmol), Et2NH (0.037 mL, 0.360 mmol), and NaOAc (46 mg, 0.561 mmol) was dissolved in DCM:MeOH (20:1, 1 mL) and stirred for 30 min. To this solution was added NaBH3CN (0.056 mg, 0.891 mmol) and the mixture was stirred at RT overnight. The reaction was quenched with aqueous NaHCO3 and extracted into DCM. The organic layer was washed with water and dried over MgSO4. The crude product was purified via preparative HPLC. 1H NMR (400 MHz, MeOD) δ ppm 0.99-1.27 (m, 6H) 1.35 (s, 6H) 1.59-1.89 (m, 5H) 2.06-2.16 (m, 1H) 2.17-2.28 (m, 1H) 3.21 (q, J=7.07 Hz, 4H) 4.59 (s, 2 H) 5.91 (dd, J=11.12, 5.56 Hz, 1H) 7.62-7.70 (m, 2H) 7.80 (dd, J=9.09, 4.80 Hz, 1H) 7.88 (dd, J=8.46, 2.91 Hz, 1H) 8.46 (s, 1H). [M+H] calc'd for C25H32FN5O2S, 486; found, 486.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([CH2:12][C:13]1([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[N:26][N:25]4[C:28]([C:31]5[CH:32]=[C:33]([NH:37][C:38]([NH:40][CH2:41][C:42]([F:45])([F:44])[F:43])=[O:39])[CH:34]=[CH:35][CH:36]=5)=[CH:29][N:30]=[C:24]4[CH:23]=3)[CH:19]=[N:18]2)[CH2:16][NH:15][CH2:14]1)#[N:11].C(N(CC)CC)C>CN(C)C=O.CO>[C:10]([CH2:12][C:13]1([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[N:26][N:25]4[C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38]([NH:40][CH2:41][C:42]([F:44])([F:45])[F:43])=[O:39])[CH:32]=5)=[CH:29][N:30]=[C:24]4[CH:23]=3)[CH:19]=[N:18]2)[CH2:14][N:15]([C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[CH2:16]1)#[N:11]
Reactant: O=C=Nc1ccccc1
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CN(C(=O)Nc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Phenyl isocyanate (5.4 mg, 0.045 mmol) was added to a mixture of N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (15.0 mg, 0.0303 mmol) and triethylamine (13 μL, 0.093 mmol) in N,N-dimethylformamide (0.5 mL) and methanol (0.1 mL). The reaction mixture was stirred at r.t. for 2 h. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=615.2.
Reaction SMILES: [CH3:1]C1C=C(C=CC=1[N+]([O-])=O)N.[CH3:12][C:13]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15](=[O:26])[C:16](=[O:25])[NH:17]2.[CH:27]1[C:32]([NH:33][NH2:34])=[CH:31][CH:30]=[C:29]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:28]=1.Cl>>[CH3:12][C:13]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15](=[O:26])[C:16](=[O:25])[NH:17]2.[CH3:1][NH:38][S:35]([C:29]1[CH:28]=[CH:27][C:32]([NH:33][N:34]=[C:15]2[C:14]3[C:18](=[CH:19][CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[C:13]=3[CH3:12])[NH:17][C:16]2=[O:25])=[CH:31][CH:30]=1)(=[O:36])=[O:37]
Reactant: Cc1cc(N)ccc1[N+](=O)[O-]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cc1c([N+](=O)[O-])ccc2c1C(=O)C(=O)N2
Agent: Cl
Product: CNS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc([N+](=O)[O-])c(C)c32)cc1

Procedure:
4-Methyl-5-nitro-1H-indole-2,3-dione was prepared from 3-methyl-4-nitroaniline according to Procedure A: 1H NMR (DMSO-d6): δ 11.5 (s, 1H), 8.2 (d, 1H), 6.8 (d, 1H), 2.7 (s, 3H); APCI-MS m/z 205 (M−H)−. The title compound was prepared in 84% yield from 4-methyl-5-nitro-1H-indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G: 1H NMR (DMSO-d6): δ 13.0 (s, 1H), 11.6 (s, 1H), 7.9 (d, 1H), 7.7 (d, 2H), 7.6 (d, 2H), 7.3 (q, 1H), 6.9 (d, 1H), 2.8 (s, 3H), 2.4 (d, 3H); APCI-MS m/z 388 (M−H)−.
Reaction SMILES: [CH2:1]([N:3]([CH2:34][CH3:35])[CH2:4][CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([CH2:16][C:17]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([O:27][CH3:28])[C:20]([C:29]2[CH:33]=[CH:32][O:31][CH:30]=2)=[CH:19][CH:18]=1)(=[O:15])=[O:14])[CH3:2].[H][H]>[Pd].CO>[CH2:34]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([CH2:16][C:17]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([O:27][CH3:28])[C:20]([C:29]2[CH:33]=[CH:32][O:31][CH:30]=2)=[CH:19][CH:18]=1)(=[O:15])=[O:14])[CH3:35]
Reactant: [H][H]
Reactant: CCN(CC)CC=Cc1ccccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(OC)c1C(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCN(CC)CCCc1ccccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(OC)c1C(=O)OC
Yield: 93 %

Procedure:
A mixture of methyl 6-[2-(3-diethylaminoprop-1-en-1-yl)benzenesulphonyl-methyl]-3-(furan-3-yl)-2-methoxybenzoate (mixture of E and Z isomers, Intermediate 5, 0.03 g) and palladium on carbon (10%, 0.006 g) in methanol (1.2 ml) was stirred in an atmosphere of hydrogen (balloon) for 1 hour. The mixture was filtered through Celite and the filtrate was evaporated to dryness to give methyl 6-[2-(3-diethylaminopropyl)benzenesulphonylmethyl]-3-(furan-3-yl)-2-methoxybenzoate (0.028 g) as a colourless oil.