Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13](C(=O)C)[S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[CH:10][CH:11]=2)[C:6](=[C:26](OCC)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:5]1=[O:36])(=O)C.[C:37]([N:40]([C:50]1[CH:56]=[CH:55][C:53]([NH2:54])=[CH:52][CH:51]=1)[CH2:41][CH2:42][NH:43]C(=O)C(F)(F)F)(=[O:39])[CH3:38].CO.[OH-].[Na+]>CN(C=O)C.O>[C:37]([N:40]([C:50]1[CH:51]=[CH:52][C:53]([NH:54]/[C:26](=[C:6]2\[C:5](=[O:36])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:10][CH:11]=3)/[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:55][CH:56]=1)[CH2:41][CH2:42][NH2:43])(=[O:39])[CH3:38]
Reactant: CC(=O)N(CCNC(=O)C(F)(F)F)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc(N(C(C)=O)S(=O)(=O)c3ccccc3)cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CC(=O)N(CCN)c1ccc(N/C(=C2\C(=O)Nc3ccc(NS(=O)(=O)c4ccccc4)cc32)c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g (1 mmol) of 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-(N-acetyl-N-phenylsulphonyl-amino)-2-indolinone and 0.3 g (1.2 mmol) of 4-[N-acetyl-N-(2-trifluoroacetylamino-ethyl)-amino]-aniline are stirred in 5 ml of DMF for 6 hours at 120° C. After cooling to ambient temperature 5 ml of methanol and 3 ml (6 mmol) of 2 N sodium hydroxide solution are added, and the mixture is stirred for 30 minutes. The reaction mixture is diluted with 50 ml of water and the crystalline precipitate is suction filtered and dried. The residue is chromatographed on silica gel (dichloromethane/methanol/ammonia=9:1:0.1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13]CC)=[O:12])=[CH:7]2.CO.[OH-].[K+]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(C)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)O)[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.5 %

Procedure:
To a solution of ethyl 7-methyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (3.9 g), methanol (30 mL), and tetrahydrofuran (50 mL) was added aqueous solution (20 mL) of potassium hydroxide (2.0 g), and the mixture was stirred at room temperature for 15 hr. The reaction solution was concentrated, acidified with aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained pale-yellow crystals were washed with ethyl acetate-hexane to give the title compound (3.30 g, yield 92%) as pale-yellow crystals.
Reaction SMILES: [Cl:1]C1C=CC(SC(SC2C=CC(Cl)=CC=2)CN2C=CN=C2)=CC=1.Cl[C:25]1[CH:48]=[CH:47][C:28]([CH2:29][S:30][CH:31]([S:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)[CH2:32][N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)=C[CH:26]=1>>[ClH:1].[Cl:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][S:38][CH:31]([S:30][C:29]2[CH:26]=[CH:25][C:48]([Cl:1])=[CH:47][CH:28]=2)[CH2:32][N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)=[CH:45][CH:44]=1
Reactant: Clc1ccc(CSC(Cn2ccnc2)SCc2ccc(Cl)cc2)cc1
Reactant: Clc1ccc(SC(Cn2ccnc2)Sc2ccc(Cl)cc2)cc1
Product: Cl
Product: Clc1ccc(CSC(Cn2ccnc2)Sc2ccc(Cl)cc2)cc1
Yield: 55 %

Procedure:
The results of gas-liquid chromatography from a similar experiment showed the crude mixture of free bases to consist of: 3% of 1-[2,2-bis(4-chlorophenylthio)ethyl]-1H -imidazole, 55% of the title compound and 22% of 1-[2,2-bis(4-chlorobenzylthio)ethyl]-1H-imidazole.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[Al+3].[Cl-].[Cl-].[Cl-].Cl[CH2:15]Cl>>[CH2:15]1[C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2][CH2:3]1.[CH3:3][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:1]
Reactant: ClCCl
Agent: C=C(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: c1ccc2c(c1)CCC2

Procedure:
Alpha-methylstyrene (AMS) (2.0 L, 15.4 mole) was added slowly with stirring over 2 to 3 hrs to a mixture of AlCl3 (0.7 g, 5.2 mole) and dichloromethane (1.0 L, dried over 3 Å molecular sieves) in 4 L beaker, in a drybox at room temperature. After the addition of 1 L AMS, about 0.2 L dichloromethane was added to make up for the solvent evaporated due to the reaction exotherm. After the addition of all AMS, the reaction mixture was deactivated with 0.3 L methanol, washed three times with water, dried over calcium chloride, filtered and volatiles stripped first using a rotary evaporator and then high vacuum. Yield was 1,685 g (93%) of colorless, transparent oil. The material was analyzed to contain 60.5% dimer; 1,1,3-trimethyl-3-phenylindan (Registry No. 3910-35-8; GC/MS: Calc. 236.726, Found 236.157); and 39.5% trimer isomers; 1,3-dimethyl-1-(2-methyl-2-phenylpropyl)-3-phenylindan (Registry No. 41906-7-2; GC/MS: Calc. 354.905, Found 354.234). 1H NMR (CDCl3): ppm 0.8-2.7 (m, br, aliph. 13H), 7.0-7.3 (m, br, arom.11H) The viscosity of the mixture of compounds at 26° C. was 782 cp and was adjusted to 880 cp by distilling off 57 g dimer on a Kugelrohr. When the mixture was distilled, the composition of the distillate was 56.4% dimer and 41.8% trimer.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH2:10]([O:12][C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17](B(O)O)[CH:18]=1)[CH3:11].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:15]2[CH:14]=[C:13]([O:12][CH2:10][CH3:11])[CH:18]=[CH:17][C:16]=2[F:22])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: CCOc1ccc(F)c(B(O)O)c1
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOc1ccc(F)c(-c2cc(C)nc(Cl)n2)c1
Temperature: 80 °C
Yield: 96.6 %

Procedure:
To a solution of 2,4-dichloro-6-methyl-pyrimidine (2.66 g, 16.31 mmol) and (5-ethoxy-2-fluoro-phenyl)boronic acid (2 g, 10.87 mmol) in 1,2-dimethoxyethane (25 mL) and water (15 mL) was added sodium carbonate (3.46 g, 32.62 mmol). This was degassed with nitrogen for 5 minutes. Bis(triphenylphosphine)palladium (II) dichloride (0.38 g, 0.54 mmol) was then added and the reaction was heated to 80° C. overnight. The solvent was evaporated and the residue was partitioned between water (300 mL) and EtOAc (300 mL). The organics were washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo to afford a yellow oil. The material was purified using a Biotage SP4 eluting with 0 to 30% i-hexane/EtOAc and the product containing fractions were collected and the solvent evaporated to give a colourless solid (2.8 g) mainly 2-chloro-4-(5-ethoxy-2-fluoro-phenyl)-6-methyl-pyrimidine (D16)
Reaction SMILES: [CH2:1]([N:4]([CH2:14][CH:15]=[CH2:16])[CH2:5][C:6]([C:8]1[S:9][C:10]([F:13])=[CH:11][CH:12]=1)=O)[CH:2]=[CH2:3].N1C=CC=CC=1.Cl.[NH2:24][OH:25]>C(O)C>[F:13][C:10]1[S:9][C:8]([C:6](=[N:24][OH:25])[CH2:5][N:4]([CH2:14][CH:15]=[CH2:16])[CH2:1][CH:2]=[CH2:3])=[CH:12][CH:11]=1
Reactant: NO
Reactant: C=CCN(CC=C)CC(=O)c1ccc(F)s1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: C=CCN(CC=C)CC(=NO)c1ccc(F)s1
Temperature: 70 °C
Yield: 98.7 %

Procedure:
To a stirred solution of 2-(diallylamino)-1-(5-fluoro-2-thienyl)ethanone (4.051 g, 16.93 mmol) in ethanol (34 mL) under nitrogen is added pyridine (4.8 mL, 59.2 mmol) and hydroxylamine hydrochloride (2.94 g, 42.3 mmol). The mixture is heated to 70° C. for 4 hours. The mixture is allowed to cool and then concentrated under reduced pressure. The residue is diluted with ethyl acetate (100 mL) and water (50 mL). The phases are separated and the aqueous phase extracted with ethyl acetate (50 mL). The combined organic extracts are dried over sodium sulfate, filtered, and concentrated to give the title compound (4.25 g, 99%) (approximately a 1.4:1 mixture of oxime isomers by 1H-NMR (CDCl3). ES/MS (m/e): 255 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH3:13])([O-:3])=[O:2].[CH2:14]=[O:15]>C(O)(C)(C)C.CS(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH2:13][CH2:14][OH:15])([O-:3])=[O:2]
Reactant: Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: C=O
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1CCO
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 64.1 %

Procedure:
A solution of potassium tertiary-butylate (1.8 g, 8 mmol) in tert.-butanol (20 ml, synthesis quality, 99%) was added to 2,6-dinitrotoluene (18.2 g, 0.1 mol, dried for 3 d in high vacuum over silica gel) and paraformaldehyde (3 g, 0.1 mol) in DMSO (50 ml, synthesis quality, additionally dried for 2 d over molecular sieve 4 Å). After the addition of the potassium tertiary-butylate solution, a color change from yellow to deep violet occurred. The solution was stirred for 5 min at room temperature and for 10 min at 70° C. (oil bath temperature). It was then left to cool to room temperature, and the mixture was neutralized with conc. HCl, and diluted with H2O (300 ml) before NaCl was added until the mixture was saturated. The aqueous phase was extracted with EtOAc (3×500 ml). The combined organic phases were washed with a saturated NaCl solution (300 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product (24.3 g) was dissolved in a little EtAOc at boiling temperature, mixed with petroleum ether (henceforth referred to as PE) (100 ml) and crystallized inside a freezer. The precipitate was filtered by suction and purified by column chromatography (20.7 g crude product, 300 g SiO2, 18×6.5 cm, solvent: toluene/EtOAc 5:1, 4:1, 3:1). Mixed fractions were concentrated under reduced pressure and purified by renewed column chromatography (200 g SiO2, 20×5.3 cm, solvent: toluene/EtOAc 7:1). After concentrating the pooled pure product fractions in a rotating evaporator under reduced pressure, 2-(2,6-dinitrophenyl)ethanol (13.6 g, 64%) was obtained as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]([CH3:22])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[C:23]1(=[O:30])[O:29][C:27](=[O:28])[CH2:26][CH2:25][CH2:24]1>ClCCl>[C:27]([CH2:26][CH2:25][CH2:24][C:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]([CH3:22])=[N:10][N:9]=2)=[CH:4][CH:3]=1)=[O:30])([OH:29])=[O:28]
Reactant: O=C1CCCC(=O)O1
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Solvent: ClCCl
Product: CC1=NN=C(c2ccc(NC(=O)CCCC(=O)O)cc2)c2cc3c(cc2C1)OCO3
Yield: 86.6 %

Procedure:
A solution of 0.50 g (1.7 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in 30 ml of anhydrous dichloromethane was stirred with 0.18 g (1.87 mmol) of glutaric acid anhydride at 20°-25° C. for 6 hours. Next day the crystals formed were filtered at 0°-5° C., washed with 3×2 ml of dichloromethane and dried at 60°-80° C. to give 0.60 g (87.0%) of the pure aimed product, m.p. 225°-227° C. (decomp.).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:22])=[C:10](B3OC(C)(C)C(C)(C)O3)[CH:11]=2)[C:6]([CH3:24])([CH3:23])[CH2:5][C:4]1=[O:25])[CH3:2].[Br:26][C:27]1[CH:32]=[CH:31][C:30](I)=[C:29]([O:34][C:35]([F:38])([F:37])[F:36])[CH:28]=1>>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([C:10]2[CH:11]=[C:12]3[C:7]([C:6]([CH3:23])([CH3:24])[CH2:5][C:4](=[O:25])[N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[CH3:22])=[C:29]([O:34][C:35]([F:36])([F:37])[F:38])[CH:28]=1
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: FC(F)(F)Oc1cc(Br)ccc1I
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3ccc(Br)cc3OC(F)(F)F)cc21

Procedure:
Compound 5B was prepared from Compound 5A and 4-bromo-1-iodo-2-trifluoromethoxy-benzene using a the conditions described for Example 1B. MS (electrospray): mass calculated for C21H21BrF3NO2, 455.07; m/z found 456.1 [M+H]+.
Reaction SMILES: [S:1]1(=[O:13])(=[O:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][C:3](=[O:11])[NH:2]1.Cl[CH:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[C:30](=[O:33])([O-:32])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:3]([OH:11])(=[O:21])/[CH:4]=[CH:5]/[C:30]([OH:32])=[O:33].[O:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH:15]([N:2]2[C:3](=[O:11])[CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[S:1]2(=[O:12])=[O:13])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:20]1
Reactant: O=C([O-])[O-]
Reactant: ClC(CCN1CCOCC1)c1ccccc1
Reactant: O=C1Cc2ccccc2S(=O)(=O)N1
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)/C=C/C(=O)O
Product: O=C1Cc2ccccc2S(=O)(=O)N1C(CCN1CCOCC1)c1ccccc1
Yield: 53.6 %

Procedure:
In toluene (7 mL) were suspended 2H-1,2-benzothiazin-3(4H)-one 1,1-dioxide (250 mg, 1.3 mmol.), 1-chloro-3-morpholino-1-phenylpropane (340 mg, 1.4 mmol.), potassium carbonate (250 mg, 1.8 mmol.) and a catalytic amount of cupper powder. The suspension was heated for 12 hours under refluxing. The reaction liquid was cooled, and the insolubles were filtered off. The solvent was distilled off to leave a residue. To the residue were added water and ethyl acetate, and the organic layer was taken out. The organic solution was washed with water and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue was treated by silica gel column chromatogrpahy (ethyl acetate) to give the free base of the desired compound (180 mg) as an oil. The free base was treated in the conventional manner to convert into the desired fumarate.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[Cl:12][C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([NH2:21])=[O:20])=[CH:15][CH:14]=1.CN1CCCC1=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]2[O:20][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=3)[N:21]=2)=[CH:22][CH:23]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: NC(=O)COc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Oc1ccc(-c2coc(COc3ccc(Cl)cc3)n2)cc1
Temperature: 100 °C
Yield: 40.1 %

Procedure:
2-Bromo-1-(4-hydroxyphenyl)ethanone (2.90 g) and 2-(4-chlorophenoxy)acetamide (5.0 g) were added to N-methylpyrrolidone (5 ml), and the mixture was stirred at 100° C. under a nitrogen atmosphere. After being cooled to room temperature, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture and separated into layers. The organic layer was washed with water, dried over sodium sulfate, and then concentrated under reduced pressure. Sodium acetate (11.1 g) in DMF (20 ml) were added to the residue and then stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and the prepared insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1) and recrystallized from hexane-ethyl acetate to afford the title compound as a pale yellow powder (1.63 g).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([CH:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:16][C:17]1[C:18]([F:28])=[C:19]([O:26][CH3:27])[CH:20]=[C:21]2[C:25]=1[NH:24][CH2:23][CH2:22]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:26][CH3:27])=[C:18]([F:28])[C:17]=3[Cl:16])[CH2:22][CH2:23]2)[C:3](=[O:15])[N:4]([CH:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: CCC(COC)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc2c(c(Cl)c1F)NCC2
Product: CCC(COC)n1cc(Cl)nc(N2CCc3cc(OC)c(F)c(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 7-chloro-6-fluoro-5-methoxyindoline as the starting materials. mp 140–142° C.; 1H NMR (300 MHz, CDCl3): δ 7.00 (s, 1 H), 6.79 (d, J=7.3 Hz, 1 H), 4.97–4.85 (m, 1 H), 4.34 (t, J=7.6 Hz, 2 H), 3.86 (s, 3 H), 3.65 (dd, J=10.6, 5.8 Hz, 1 H), 3.54 (dd, J=10.6, 3.7 Hz, 1 H), 3.33 (s, 3 H), 3.07 (t, J=7.5 Hz, 2 H), 1.90–1.72 (m, 2 H), 0.92 (t, J=7.5 Hz, 3 H); HRMS (ESI) calcd for C18H21N3O3Cl2F (M+H)+: 416.0944; found m/z 416.0955.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH2:8]([O:10][C:11](=[O:15])[C@H:12]([CH3:14])N)[CH3:9].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:24](#[N:26])[CH3:25]>>[CH2:16]([N:26]([CH2:24][C:25]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1)[CH2:14][CH2:12][C:11]([O:10][CH2:8][CH3:9])=[O:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC#N
Reactant: CCOC(=O)[C@H](C)N
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)CCN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium carbonate (21.1 g, 199 mmol) was added to a suspension of fl-alanine ethyl ester hydrochloride (10.2 g, 66.4 mmol) and benzyl bromide (16.2 mL, 136 mmol) in acetonitrile (265 mL). The reaction mixture was stirred at ambient temperature overnight and then filtered through a layer of CELITE filter aid. The filter cake was rinsed with acetonitrile (100 mL). The filtrate was concentrated under reduced pressure to provide 20.28 g of ethyl 3-dibenzylaminopropionate as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([C:23](=O)[CH3:24])[CH:21]=[CH:22][C:17]3=[N:16][N:15]=2)[CH3:13])=[C:10]([F:26])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl.[NH2:28][O:29][CH2:30][CH2:31][OH:32].[OH-].[Na+]>CO>[OH:32][CH2:31][CH2:30][O:29]/[N:28]=[C:23](/[C:20]1[CH:21]=[CH:22][C:17]2[N:18]([C:14]([CH:12]([C:11]3[C:2]([F:1])=[C:3]4[C:8](=[CH:9][C:10]=3[F:26])[N:7]=[CH:6][CH:5]=[CH:4]4)[CH3:13])=[N:15][N:16]=2)[N:19]=1)\[CH3:24]
Reactant: NOCCO
Reactant: CC(=O)c1ccc2nnc(C(C)c3c(F)cc4ncccc4c3F)n2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C/C(=N\OCCO)c1ccc2nnc(C(C)c3c(F)cc4ncccc4c3F)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
To a suspension of 1-{3-[1-(5,7-difluoro-quinolin-6-yl)-ethyl]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl}-ethanone (4.2 g, 11.9 mmol) in methanol (250 mL) was added 2-(aminooxy)ethanol hydrochloride (intermediate S) (2.70 g, 23.8 mmol). The mixture was stirred at rt overnight. LC-MS showed the reaction was complete. An aqueous 1N NaOH solution was added slowly until pH 8-9. The mixture was concentrated, extracted with EtOAc, washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and purified by gradient column chromatography (EtOAc:hexane=2:1, then 100% EtOAc, and then MeOH:EtOAc=1:12 as eluent) to afford 4.8 g (98%) of the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.97 (dd, 1H), 8.44 (m, 1H), 8.25 (d, 1H), 7.64-7.70 (m, 2H), 7.59 (dd, 1H), 5.25 (q, 1H), 4.70 (t, 1H), 4.19 (t, 2H), 3.62 (dd, 2H), 2.02 (d, 3H), 1.88 (s, 3H). LCMS (method A): [MH]+=413, tR=5.09 min.
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].[Cl:5][CH:6]([C:11]([O:18][CH3:19])([O:16][CH3:17])[C:12]([F:15])([F:14])[F:13])C(F)(F)F.S(=O)(=O)(O)O.[CH2:25]([OH:27])[CH3:26]>>[Cl:5][CH:6]([C:11]([O:16][CH3:17])([O:18][CH3:19])[C:12]([F:13])([F:14])[F:15])[CH2:1][C:2]([O:27][CH2:25][CH3:26])=[O:3]
Reactant: COC(OC)(C(Cl)C(F)(F)F)C(F)(F)F
Reactant: CC[O-]
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)CC(Cl)C(OC)(OC)C(F)(F)F
Temperature: 25 °C

Procedure:
265 g of a 20% strength solution of sodium ethylate in ethanol were added dropwise to 100 g of 2-chloro-1,1,1,4,4,4-hexafluoro-3,3-dimethoxy-butane in 50 ml of ethanol at room temperature. The reaction mixture was then stirred under reflux for 12 hours and cooled to room temperature, and 100 ml of 50% strength sulfuric acid were added dropwise. After the mixture had been refluxed again for 3 hours, it was poured onto water and extracted with methylene chloride and the organic phase was dried over sodium sulfate. After removal of the solvent, the residue was distilled in vacuo.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[O:12][CH:13]([CH3:15])[CH3:14])([O-])=O.[H][H]>CO.[Pt]=O>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[C:5]([O:12][CH:13]([CH3:15])[CH3:14])[CH:6]=1
Reactant: COc1ccc([N+](=O)[O-])c(OC(C)C)c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: COc1ccc(N)c(OC(C)C)c1
Yield: 101.6 %

Procedure:
A solution of 5.0 g of 1-nitro-4-methoxy-2-(propan-2-yloxy)benzene in 300 ml of methanol is hydrogenated on 2.5 g of platinum oxide at a hydrogen pressure of 15 bar, for 2 h at ambient temperature. The mixture is filtered and the filtrate is concentrated to dryness under reduced pressure, so as to obtain 4.36 g of 4-methoxy-2-(propan-2-yloxy)aniline.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH:23]=[N:22][C:21]([C:24]([F:27])([F:26])[F:25])=[N:20]1)=[O:11].Br[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][N:30]=1>>[F:35][C:32]1[CH:33]=[CH:34][C:29]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[CH:23]=[N:22][C:21]([C:24]([F:27])([F:26])[F:25])=[N:20]2)=[O:11])=[N:30][CH:31]=1
Reactant: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Fc1ccc(Br)nc1
Product: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(F)cn2)c1

Procedure:
The title compound was synthesized following the same general protocol as described in Example A44, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)phenyl)methanone and 2-bromo-5-fluoropyridine. ESI-MS (m/z): 477 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:21]([C@H:22]4[CH2:26][CH2:25][O:24][CH2:23]4)[N:20]=[CH:19][C:18]=3[C:27]([O:29]CC)=O)=[C:13]([N+:32]([O-])=O)[CH:12]=2)=[C:6]([CH3:35])[CH:5]=1)[CH3:2].O>C(O)(=O)C.[Fe]>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([C:11]2[CH:16]=[CH:15][C:14]3[C:17]4[N:21]([C@H:22]5[CH2:26][CH2:25][O:24][CH2:23]5)[N:20]=[CH:19][C:18]=4[C:27](=[O:29])[NH:32][C:13]=3[CH:12]=2)=[C:6]([CH3:35])[CH:5]=1)[CH3:2]
Reactant: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1ccc(-c2c(C)cc(OCC)nc2C)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CCOc1cc(C)c(-c2ccc3c(c2)[nH]c(=O)c2cnn([C@H]4CCOC4)c23)c(C)n1
Temperature: 90 °C
Reaction time: 4 h
Yield: 19.6 %

Procedure:
Ethyl 5-[4-(6-ethoxy-2,4-dimethylpyridin-3-yl)-2-nitrophenyl]-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate (97 mg) was dissolved in acetic acid (1 mL). Iron powder (56 mg) was added to the solution, and the mixture was stirred at 90° C. for four hours. The reaction mixture was returned to room temperature, and water (2 mL) was added to the reaction mixture. The precipitated solid was collected by filtration and washed with water. The resulting solid was dissolved in ethanol (1 mL) at 90° C. The solution was ice-cooled, and the precipitated solid was collected by filtration. The resulting solid was washed with MTBE to give the title compound (16 mg).