Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:13].[C:14]([O:17][CH2:18][CH2:19]Cl)(=[O:16])[CH3:15]>CN(C)C=O>[C:14]([O:17][CH2:18][CH2:19][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:13])(=[O:16])[CH3:15]
Reactant: O=C1CCc2ccccc2N1
Reactant: CC(=O)OCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCN1C(=O)CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
A suspension of sodium hydride (3.0 g, 60% in mineral oil) and dimethyl formamide (100 mL) was kept at 15-18° C. followed by the addition of a solution of 3,4-dihydroquinolin-2(1H)-one (10.0 g) in dimethyl formamide (150 mL). The resulting mixture was stirred at room temperature for 60 min followed by the addition of a solution of 2-chloroethyl acetate (10.0 g) in dimethyl formamide (50 mL) at a temperature of 20° C. The resulting mixture was heated at 80° C. for 2½ h, cooled and poured onto ice. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography on silicagel (eluent: ethyl acetate/heptane 1:1) to give crude 1-(2-acetoxyethyl)-3,4-dihydroquinolin-2(1H)-one (10.2 g). A mixture of crude 1-(2-acetoxyethyl)-3,4-dihydroquinolin-2(1H)-one, sodium methanolate (2.5 mL, 30% in methanol) and methanol (250 mL) was stirred at room temperature for 16 h and subsequently concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate/heptane 1:1) to give the corresponding alcohol as a red crystalline compound (4.9 g). This alcohol was dissolved in tetrahydrofuran (100 mL) followed by the addition of triethylamine (8.2 mL). The resulting mixture was cooled to 5-6° C. followed by the addition of a solution of methane sulfonic acid chloride (2 mL) in tetrahydrofuran (25 mL). The mixture was filtered and evaporated to dryness in vacuo. The residue was dissolved in dimethyl formamide (50 mL) followed by addition of lithium chloride (4.9 g), and the resulting mixture was heated at 70° C. for 5 min. The mixture was poured onto brine, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate/heptane 1:1) to give the product as a red oil (2.9 g).
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CN(P(N(C)C)(N(C)C)=O)C.C1OC1C>CCN(CC)CC>[CH3:13][O:12][C:11]1[C:2]([O:1][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:3]2[C:8](=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=1)[N:7]=[CH:6][CH:5]=[C:4]2[CH3:17]
Reactant: BrCCCCCCCCc1ccccc1
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1O
Agent: CC1CO1
Solvent: CCN(CC)CC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCCCCc1ccccc1
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a stirred mixture of 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline (4.98 g, 0.02 mol), 1-bromo-8-phenyloctane (4.7 g, 0.017 mol) and HMPA (13 ml), at 120° C., was added, dropwise, during 1 h, a mixture of propylene oxide (6 ml) and Et3N (1 ml). The reaction was continued for 3.5 h, allowed to cool and extracted successively with pet ether, Et2O and Me2CO leaving 1 g of insoluble starting material, 5-hydroxy-6-methoxy-4methyl-8-nitroquinoline. The combined pet ether and Et2O extracts were washed (H2O, dil NaOH, H2O), dried (Na2SO4) and concentrated. The residue was dissolved in CHCl3, placed on a silica gel column and eluted with CHCl3. Concentration of the eluates left an oil which was triturated with pet ether to give 4.35 g (60%) of 6-methoxy-4-methyl-8-nitro-5(8-phenyloctoxy) quinoline as yellow solid, mp 39.5°-41° C. Crystallization from hexane (Darco) provided the analytical sample as yellow crystals, mp 41°-42° C.
Reaction SMILES: [S:1]([C:5]1[O:13][C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].ClC1C=CC=C(C(OO)=[O:22])C=1>CO.C(OCC)(=O)C>[S:1]([C:5]1[O:13][C:12]2[CH:11]=[CH:10][N+:9]([O-:22])=[CH:8][C:7]=2[CH:6]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: NS(=O)(=O)c1cc2cnccc2o1
Solvent: CCOC(C)=O
Solvent: CO
Product: NS(=O)(=O)c1cc2c[n+]([O-])ccc2o1
Reaction time: 18 h
Yield: 83 %

Procedure:
To a warm (40° C.) solution of 2-sulfamoylfuro[3,2-c]pyridine (2.68 g, 13.5 mmol) in methanol (30 ml) and ethyl acetate (10 ml) was added dropwise a solution of m-chloroperbenzoic acid (3.22 g, 15 mmol) in ethyl acetate (13 ml). The reaction mixture was stirred for 18 hours as product precipitated. The pure product was collected by filtration and crystallized from hot dimethyl sulfoxide by dilution with ethanol to give 2.4 g (83% yield), m.p. 247°-248° C.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[F:14][C:15]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:16]=1[C:17](Cl)=[O:18]>CN(C1C=CN=CC=1)C>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:17]([C:16]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:15]=1[F:14])=[O:18])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[n+]1c(C)sc(C)c1C
Reactant: O=C(Cl)c1cc(F)ccc1F
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 2,5-difluorobenzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.94 (t, 3 H) 1.33-1.41 (m, 2 H) 1.60-1.69 (m, 2 H) 2.19 (s, 3 H) 2.22 (s, 3 H) 3.93-4.00 (m, 2 H) 6.38 (s, 1 H) 7.24-7.35 (m, 2 H) 7.51-7.59 (m, 1 H); MS (ESI) m/z 324 (M+H)+.
Reaction SMILES: C(OC([N:11]1[CH2:17][C@H:16]([OH:18])[C@@H:15]([NH:19][C:20](=[O:34])[C@@H:21]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:14][CH2:13][C@H:12]1[CH3:35])=O)C1C=CC=CC=1.CO.[H][H]>CCOC(C)=O.[Pd]>[C:30]([O:29][C:27](=[O:28])[NH:26][C@H:21]([C:20](=[O:34])[NH:19][C@H:15]1[CH2:14][CH2:13][C@@H:12]([CH3:35])[NH:11][CH2:17][C@@H:16]1[OH:18])[CH2:22][CH:23]([CH3:25])[CH3:24])([CH3:32])([CH3:33])[CH3:31]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H](C)N(C(=O)OCc2ccccc2)C[C@@H]1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H](C)NC[C@@H]1O
Reaction time: 8 h

Procedure:
(2R,5S,6S)-5-((S)-2-tert-Butoxycarbonylamino-4-methyl-pentanoylamino)-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester (0.169 g, 0.344 mmol) was dissovled in EtOAc (3 ml), MeOH (1 ml). Then 10% Pd/C (0.183 g, 0.172 mmol) was added and the reaction was stirred overnight under a balloon filled with hydrogen gas. The reaction mixture was filtered through Celite, concentrated in vacuo by rotary evaporation and was used in the next reaction without further purification (0.126 g): Electrospray mass spec: M+H+=358.11.
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([O:23][CH3:24])[C:17]=2[Cl:25])=[C:10]([OH:27])[CH:9]=1)=[O:7])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[CH3:39][C:40]([CH3:59])([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:41][C:42](Cl)=[O:43]>>[CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([O:23][CH3:24])[C:17]=2[Cl:25])=[C:10]([O:27][C:42](=[O:43])[CH2:41][C:40]([CH3:59])([CH3:39])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH:9]=1)=[O:7])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCC(C)(C)CC(=O)Cl
Reactant: COc1c(C)ccc(C(=O)Oc2ccc(C(=O)CNC(C)C)cc2O)c1Cl
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: CCCCCCCCCCCCCCC(C)(C)CC(=O)Oc1cc(C(=O)CNC(C)C)ccc1OC(=O)c1ccc(C)c(OC)c1Cl

Procedure:
Following a procedure similar to that described above in Example 2A, when 3-hydroxy-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate is reacted with 3,3-dimethylheptadecanoyl chloride there is obtained 3-(3,3-dimethylheptadecanoyloxy)-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-(3,3-dimethylheptadecanoyloxy-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:8][NH:9][C:10](=O)[CH3:11])=[N:4][CH:5]=[CH:6][CH:7]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]2[N:4]([C:10]([CH3:11])=[N:9][N:8]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)NNc1ncccc1Br
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1nnc2c(Br)cccn12
Temperature: 25 °C
Yield: 82.8 %

Procedure:
To a solution of 0.17 g (0.74 mmol) of N′-(3-bromopyridin-2-yl)acetohydrazide from step A above in 40 mL of anhydrous toluene was added 3 mL of glacial acetic acid and the resulting mixture was heated to reflux for 20 h employing a Dean-Stark trap. The reaction mixture was cooled to ambient temperature then evaporated to dryness in vacuo to afford the title compound (0.13 g, 84%) LC-MS: m/z (ES) 212, 214 (MH)−.
Reaction SMILES: [NH2:1][CH:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])[OH:4].[C:24]1([CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[CH:3]([OH:4])[CH:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(2,4-difluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.21 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (269 ml, 1.81 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (498 mg, 89%).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.O=[C:24]1[C@H:30]([NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:29][CH2:28][C:27]2[CH:42]=[CH:43][CH:44]=[CH:45][C:26]=2[NH:25]1>C1(C)C=CC=CC=1>[S:10]=[C:24]1[CH:30]([NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:29][CH2:28][C:27]2[CH:42]=[CH:43][CH:44]=[CH:45][C:26]=2[NH:25]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(N[C@@H]1CCc2ccccc2NC1=O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(NC1CCc2ccccc2NC1=S)OCc1ccccc1
Yield: 104.3 %

Procedure:
Add Lawesson's Reagent (6.52 g, 16.11 mmol) to a solution of benzyl N-[(3R)-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]carbamate (10.0 g, 32.22 mmol) in toluene (120 mL) and heat the reaction under nitrogen at 100° C. for 2.5 hours. Allow the reaction to cool and collect the precipitate by filtration. Wash (ether) the cake and dry it in a vacuum oven to give the title compound (5.5 g, 16.8 mmol). Concentrate the filtrate under reduced pressure and purify it by flash chromatography (30% hexane/CH2Cl2 to 100% CH2Cl2) to give the title compound (3.48 g, 10.7 mmol). The compound is partially racemized. The total yield of the title compound is 85%: MS (m/z): 327 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([OH:10])=[O:9].[CH2:11](O)[CH3:12].C(N(C(C)C)CC)(C)C>S(Cl)(Cl)=O>[CH2:11]([O:9][C:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:10])[CH3:12]
Reactant: CCO
Reactant: O=C(O)c1cnccc1Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnccc1Cl
Temperature: 80 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
A suspension of 4-chloro-pyridine-3-carboxylic acid (5.0 g, 31.7 mmol) in thionyl chloride (100 ml) is heated at 80° C. for 1.5 h. The reaction mixture is cooled to RT and excess thionyl chloride is distilled off. The crude product is azeotropped with toluene (3×30 ml) to afford a solid, which is added in portions to a mixture of ethanol (40 ml) and diisopropylethylamine (25 ml) at 0° C. The resulting reaction mixture is stirred at RT for 4 h. After completion of the reaction, the mixture is evaporated to dryness; the residue is diluted with water (20 ml) and extracted with EtOAc (3×25 ml). The combined organic layers are washed with water (30 ml), brine (30 ml), dried over anhydrous sodium sulfate and evaporated to get 4-chloro-pyridine-3-carboxylic acid ethyl ester (4.50 g, 24.3 mmol, 77%), which is used in the next step without further purification.
Reaction SMILES: C([O-])(=O)C.[NH4+].C([BH3-])#[N:7].[Na+].[CH3:10][C:11]([CH3:26])=[CH:12][CH2:13][O:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][C:21](=O)[CH3:22])=[CH:17][CH:16]=1>CO>[CH3:10][C:11]([CH3:26])=[CH:12][CH2:13][O:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][CH:21]([NH2:7])[CH3:22])=[CH:17][CH:16]=1
Reactant: CC(=O)COc1ccc(OCC=C(C)C)cc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(C)=CCOc1ccc(OCC(C)N)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Ammonium acetate (3.29 g, 42.7 mmol), sodium cyanoborohydride (0.20 g, 3.0 mmol) and 3A molecular sieves are added to the above phenoxyacetone (1.0 g, 4.3 mmol) in 20 ml of anhydrous methanol under N2 and at RT. The reaction is stirred at RT for 4 days. The methanol is removed by rotoevaporation, and ether and water are added to the residue, followed by 10% NaOH. The mixture is extracted with ether (3×), and the combined organic layers are washed with water until neutral, dried and filtered and the solvent evaporated off to give 2-[4-(3-methyl-2-butenoxy)phenoxy]-1-methylethylamine.
Reaction SMILES: [CH:1]1[C:15](=[NH:16])[N:14]=[C:13]2[N:3]([C@@H:4]3[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@@H:5]3[O:12]2)[CH:2]=1.[OH-:17].[NH4+]>>[CH:1]1[C:15]([NH2:16])=[N:14][C:13](=[O:12])[N:3]([C@@H:4]2[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@@H:5]2[OH:17])[CH:2]=1
Reactant: [OH-]
Reactant: N=c1ccn2c(n1)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Agent: [NH4+]
Product: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Reaction time: 1.17 h

Procedure:
Cyclocytidine salt (8.0023 g., 18.25 mmole) and 80 ml. of 2N ammonium hydroxide are stirred at 58°. Hydrolysis is complete at 70 minutes.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(Cl)Cl.Cl>[Si:17]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: O=C(O)c1ccc(CO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.2 %

Procedure:
To a solution of 4-hydroxymethylbenzoic acid (1 g) in DCM (66 mL) was added imidazole (985 mg, 2.2 equiv) followed by the addition of t-butyldimethylsilyl chloride (TBSCl) (1.09 g, 1.1 equiv). The reaction mixture was stirred at room temperature for 3 days and was diluted with DCM (50 mL) and 1 N HCl. The aqueous phase was extracted with DCM, and the combined organic extracts were dried over sodium sulfate and concentrated in vacuo to provide the title compound (1.44 g, 82% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=O.Cl.[NH2:15][OH:16].O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[N:15][OH:16]
Reactant: NO
Reactant: Cc1cc(C)c2c(c1)C(=O)CCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2c(c1)C(=NO)CCC2
Temperature: 80 °C
Yield: 93.9 %

Procedure:
A solution of 5,7-Dimethyl-1-tetralone (5.0 g) in ethanol (100 mL) was treated with hydroxylamine hydrochloride (2.2 g) and sodium carbonate monohydrate (3.6 g). The reaction mixture was heated overnight at 80° C. with a condenser and behind a blast shield. Cooled to room temperature after seventeen hours, transferred to a 300 mL flask and concentrated. The residue was triturated in water and filtered to yield the title product as a beige solid (5.1 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([S:25]([N:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=3Cl)=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:31])[CH:5]=1)(=[O:3])[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([S:25]([N:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=3[N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:31])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(=O)(=O)N(C)C)ccc3Cl)CC2)c(F)c1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(=O)(=O)N(C)C)ccc3N3CCOCC3)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described for example 1 from 3-[4-(4-Acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-chloro-N,N-dimethyl-benzenesulfonamide and morpholine (60%, light yellow solid, MS (m/e): 519.2 (M+H, 100%)
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:29]([O:31][C:32](=[O:48])[CH2:33]P(OCC(F)(F)F)(OCC(F)(F)F)=O)[CH3:30].[S:49]1[CH:53]=[CH:52][C:51]([CH:54]=O)=[CH:50]1>C1COCC1>[CH2:29]([O:31][C:32](=[O:48])[CH:33]=[CH:54][C:51]1[CH:52]=[CH:53][S:49][CH:50]=1)[CH3:30]
Reactant: CCOC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reactant: O=Cc1ccsc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1ccsc1
Reaction time: 3 h
Yield: 75.2 %

Procedure:
Potassium bis(trimethylsilyl)amide (3.92 g, 19.7 mol) was added to a solution of 18-Crown-6 (9.95 g, 37.6 mmol) and [Bis-(2,2,2 trifluoro-ethoxy)-phosphoryl]-acetic acid ethyl ester (6.54 g, 19.7 mmol) in dry THF (200 mL) at −78° C. After 30 minutes of stirring at this temperature, thiophene-3-carbaldehyde (2.0 g, 19.7 mmol) was added and the reaction was stirred for 3 hours at −780C after which the reaction was quenched with saturated ammonium chloride (200 mL). The reaction mixture was allowed to come to room temperature and was extracted with ethyl acetate (3×250 mL) and the combined organic extracts were washed with 10% HCl (200 mL), brine (200 mL) and dried with MgSO4 Evaporation of the solvent in vacuo gave the crude product that was purified by silica-gel chromatography using a 0-40% ethylacetate-hexane gradient to afford the subtitle compound (2.7 g, 82.7%). MS calculated for C9H10O2S+H: 183, observed: 183; 1H NMR (300 MHz, CDCl3, ppm) 1.31 (t, J=7 Hz, 3H); 4.22 (q, J=7 Hz, 2H); 5.83 (d, J=13 Hz, 1H); 6.87 (d, J=7 Hz, 1H); 7.24-7.28 (m, 1H); 7.54 (dd, J1=5 Hz, J2=1 Hz, 1H); 8.07 (br d, J=3 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[NH:4][N:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16].[OH-].[Na+].[H][H]>[Pd].C(Cl)Cl.O>[F:17][C:15]([F:16])([F:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][C:7]1[CH:6]=[N:5][NH:4][C:3](=[O:19])[CH:2]=1
Reactant: O=c1[nH]ncc(Oc2ccccc2C(F)(F)F)c1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=c1cc(Oc2ccccc2C(F)(F)F)cn[nH]1
Reaction time: 96 h
Yield: 70.1 %

Procedure:
A pressure vial containing a mixture of 4-chloro-5-(2-trifluoromethyl-phenoxy)-2H-pyridazin-3-one (3.66 g, 12.59 mmol), water (70 mL), and a 2N aqueous sodium hydroxide solution (7 mL, 14 mmol) was treated with 10% palladium on carbon (0.37 mg, 10% weight of 4-chloro-5-(2-trifluoromethyl-phenoxy)-2H-pyridazin-3-one). The reaction was then pressurized with hydrogen (50 psi), where it shook for 4 d. The resulting reaction mixture was diluted with methylene chloride (100 mL) and water (100 mL) and filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo. The aqueous residue was acidified with a 2N aqueous hydrochloric acid solution and was then extracted with a 90/10 methylene chloride/methanol solution. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel column chromatography (ISCO, 120 g, 50%-70% ethyl acetate/hexanes) afforded 5-(2-trifluoromethyl-phenoxy)-2H-pyridazin-3-one (2.26 g, 70%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 5.79 (d, J=2.7 Hz, 1H), 7.52-7.60 (m, 2H), 7.82 (t, J=8.5 Hz, 1H), 7.89 (d, J=8.2 Hz, 1H), 8.00 (d, J=2.7 Hz, 1H), 13.04 (br. s., 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.Br.BrC[CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>>[CH3:16][C:6]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:2]([CH3:1])[N:3]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:23][CH2:24][N:25]([CH2:32][C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[CH2:26][CH2:27]2)=[O:20])[N:5]=1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Reactant: BrCCc1cccnc1
Agent: Br
Product: Cc1nc(OCC(=O)N(C)C2CCN(Cc3cccnc3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31 and 3-(bromo ethyl)pyridine hydrobromide in the same manner as in Example 32.