Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.[F:18][C:19]1[C:24](F)=[C:23]([F:26])[C:22]([F:27])=[C:21]([F:28])[C:20]=1[F:29].O>CN(C)C=O>[CH3:17][C:14]1[CH:13]=[CH:12][C:11]([C:4]2([O:3][C:24]3[C:23]([F:26])=[C:22]([F:27])[C:21]([F:28])=[C:20]([F:29])[C:19]=3[F:18])[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(C2(O)CCN(C)CC2)cc1
Reactant: Fc1c(F)c(F)c(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C2(Oc3c(F)c(F)c(F)c(F)c3F)CCN(C)CC2)cc1
Temperature: 85 °C

Procedure:
To a suspension of sodium hydride (2.2 g, 60% in oil) in 20 ml of dimethylformamide, was added a solution of 11.0 g of 4-hydroxy-4-(4-methylphenyl)-1-methylpiperidine in 50 ml of dimethylformamide. After heating to 85° C. for thirty minutes, the mixture was cooled with an ice-bath, and treated over a period of ten minutes with a solution of 7 ml of hexafluorobenzene in 20 ml of dimethylformamide. After stirring at ambient temperature for twenty hours, the mixture was poured into 200 ml water, stirred for five minutes, then extracted with ethyl acetate (2×). The organic layer was washed with water (2×), followed by a saturated solution of sodium chloride, and dried over anhydrous magnesium sulfate. After filtering, evaporation of the solvent afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with 10% methanol/dichlormethane). The desired fractions were combined, and evaporated to yield 13 g of (4-(4-methylphenyl)-1-methyl-4-(2,3,4,5,6-pentafluorophenoxy) piperidine as an oil.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:13][C:14](O)=[O:15])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[O:11][CH3:12].C(OCC)(=O)C.O.[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[C:3]([CH2:13][CH2:14][OH:15])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[O:11][CH3:12]
Reactant: COc1c(F)c(CC(=O)O)cc2ccsc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1c(F)c(CCO)cc2ccsc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
In 8.1 mL of tetrahydrofuran is dissolved 1.42 g of 2-(6-fluoro-7-methoxybenzo[b]thiophen-5-yl)-acetic acid. At an ice-cooled temperature, 4.8 mL of 1 mol/L solution of borane-tetrahydrofuran complex in tetrahydrofuran is added to the solution obtained above, and the resulting mixture is stirred at ambient temperature for 2 hours. Ethyl acetate and water are added to the reaction mixture, pH is adjusted to 10 with 2 mol/L aqueous solution of sodium hydroxide, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Thus, 0.72 g of 2-(6-fluoro-7-methoxybenzo[b]thiophen-5-yl)-1-ethanol is obtained as an oily product.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH2:20][OH:21])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:22])=[CH:3]1.[BH4-].[Na+]>CO.O>[CH2:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH2:20][OH:21])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[OH:22])=[CH:3]1
Reactant: C=C1C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(CO)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=C1C=C2CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](O)CC[C@@H]34)[C@@]2(CO)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-methylene-androst-4-ene-19-ol-17-one in methanol was added a 2 molar excess of sodium borohydride. The mixture was stirred overnight at room temperature, diluted with water, extracted with ethyl acetate, washed with water, the organic layer separated, and dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by thick layer chromatography over silica gel using n-hexane-ethyl acetate as a solvent.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](B(O)O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:14]3[CH:15]=[C:16]([NH2:17])[CH:18]=[CH:19][CH:20]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: Nc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1cccc(-c2ccc3[nH]ccc3c2)c1
Temperature: 25 °C
Yield: 50 %

Procedure:
Indole-5-boronic acid (0.111 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (50-100% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.049 g in 50% yield.
Reaction SMILES: [NH2:1][C:2]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:17])OC(C)(C)C)[CH2:6][CH2:5]1)=[S:3].[Cl:18][C:19]1[C:23]([Cl:24])=[C:22](C)[NH:21][C:20]=1[C:26](NC1CCNCC1)=O>>[NH2:1][C:2]([N:4]1[CH2:5][CH2:6][CH:7]([NH:10][C:11]([C:22]2[NH:21][C:20]([CH3:26])=[C:19]([Cl:18])[C:23]=2[Cl:24])=[O:17])[CH2:8][CH2:9]1)=[S:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(C(N)=S)CC1
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Product: Cc1[nH]c(C(=O)NC2CCN(C(N)=S)CC2)c(Cl)c1Cl

Procedure:
The title compound was prepared by a procedure analogous to Intermediate 125 starting from 3,4-dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide (Intermediate 90, 0.5 g, 2 mmol). The product was concentrated to a solid which was purified on a silica flash column (gradient elution from 0-5% MeOH in DCM over 30 min). Purification yielded a white solid (0.22 g).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].N1C=CN=C1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].O>CN(C=O)C.C(OCC)C>[Si:10]([O:4][CH2:3][CH2:2][Br:1])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: OCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
Following a published procedure, 2-bromoethanol (10.0 mL, 141 mmol) was added to a mixture of imidazole (12.5 g, 184 mmol) and tert-butyldimethylsilyl chloride (21.1 g, 140 mmol) in anhydrous DMF (25 mL). The reaction mixture was stirred at room temperature for 12 h. Water and diethyl ether were added. The phases were separated. The aqueous phase was extracted with diethyl ether. The combined organic phases were washed with water and brine. The solution was dried (Na2SO4). Evaporation of the solvent followed by bulb-to-bulb distillation (40-45° C./0.05 mmHg) yielded a colorless liquid (32.5 g, 97%): IR (film, νmax cm−1) 2951, 2859, 1471; 1H NMR δ 0.07 (s, 6H), 0.89 (s, 9H), 3.36-3.41 (m, 2H), 3.85-3.90 (m, 2H); 13C NMR δ −5.06, 18.49, 26.04, 33.45, 63.74; EI-MS 137/139, 181/183, calcd 238.0389 (C8H19BrOSi); Anal. Calcd C, 40.17; H, 8.01. Found: C, 40.55; H, 8.25.
Reaction SMILES: CCO.[CH3:4][O:5][C:6]([C:8]1[C:9]([OH:27])=[C:10]2[C:15](=[CH:16][N:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13](=[O:25])[C:12](Br)=[CH:11]2)=[O:7].C([O-])(=O)C.[Na+]>[Pd].CCOC(C)=O>[CH3:4][O:5][C:6]([C:8]1[C:9]([OH:27])=[C:10]2[C:15](=[CH:16][N:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13](=[O:25])[CH2:12][CH2:11]2)=[O:7]
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ncc2c(c1O)CCC(=O)N2Cc1ccccc1
Reaction time: 16 h
Yield: 62.4 %

Procedure:
A flask was charged with EtOH (10 mL) and 10% palladium on carbon (200 mg). A solution of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (150 mg, 0.39 mmol) in EtOAc (40 mL) and sodium acetate (47 mg, 0.58 mmol) were added, and the resulting mixture was stirred under H2 atmosphere for 16 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed (0-60% EtOAc/hexanes+2% AcOH) to give 76 mg of the title compound as a white solid. MS: (+) m/z 325.11 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([N:22]1[CH:26]=[C:25]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[N:24]=[N:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:39][C:40]1[N:41]=[C:42]([CH:45]=[CH:46][C:47]2[CH:52]=[CH:51][C:50]([S:53]([F:58])([F:57])([F:56])([F:55])[F:54])=[CH:49][CH:48]=2)[O:43][CH:44]=1.O>CN(C)C=O>[F:56][S:53]([F:54])([F:55])([F:57])([F:58])[C:50]1[CH:51]=[CH:52][C:47](/[CH:46]=[CH:45]/[C:42]2[O:43][CH:44]=[C:40]([CH2:39][O:37][C:34]3[CH:33]=[CH:32][C:31]([CH2:30][CH2:29][CH2:28][CH2:27][C:25]4[N:24]=[N:23][N:22]([C:3]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=5)([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=5)[CH:26]=4)=[CH:36][CH:35]=3)[N:41]=2)=[CH:48][CH:49]=1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Oc1ccc(CCCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)nn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FS(F)(F)(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCc4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nn4)cc3)co2)cc1
Reaction time: 0.25 h
Yield: 63.7 %

Procedure:
7.8 mg (0.20 mmol) 95% sodium hydride were given at 0° C. to a solution of 90 mg (0.20 mmol) 4-[4-(1-trityl-1H-[1,2,3]triazol-4-yl)-butyl]-phenol in 3.0 ml N,N-dimethylformamide and stirred for 15 min. 66 mg (0.20 mmol) 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole were added and stirring continued at 25° C. for 2 h. The reaction mixture was poured into water, the precipitate isolated by filtration und purified by LC-MS to yield 98 mg (65%) of the title compound
Reaction SMILES: [CH:1]1([N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3Cl)[S:5][C@H:4]([CH2:6][OH:7])[CH2:3][CH2:2]1.[CH3:18][NH2:19]>O>[CH3:18][NH:19][C:13]1[C:14]2[N:15]=[CH:16][N:8]([C:9]=2[N:10]=[CH:11][N:12]=1)[C@@H:1]1[S:5][C@H:4]([CH2:6][OH:7])[CH2:3][CH2:2]1
Reactant: OC[C@@H]1CCC(n2cnc3c(Cl)ncnc32)S1
Reactant: CN
Solvent: O
Product: CNc1ncnc2c1ncn2[C@H]1CC[C@@H](CO)S1
Yield: 77 %

Procedure:
The anomeric mixture of 20 (0.132 g, 0.49 mmol) in a steel bomb was stirred with 20 mL 40% methylamine in water at 80° C. overnight. After solvent removal in vacuo, the residue was purified by preparative TLC with 9:1 chloroform/methanol to give 100 mg (77%) of the anomeric mixture. The anomers were partially separated by a Dowex 1×4 (--OH) column with 10% aqueous methanol to give 37 mg of impure β anomer which was recrystallized from hexane-ethyl acetate to afford 22.5 mg of pure β anomer by HPLC; mp. 131°-134° C.; FAB MS 266 (M +H)+ ; 1H NMR (DMSO-d6) δ 8.4 (s, 1, H-2), 8.2 (s, 1, H-8), 7.7 (brs, 1, NH), 6.2 (m, 1, i'-H), 5.15 (m, 1, 5'-OH), 3.75 (m, 1, 5'-H), 3.6 (m, 2, 4'-H, 5'-H), 2.95 (s, 3, CH3), 2.4 (m, 2, 4'-H's), 2.15 (m, 1, 3'-H), 2.0 (m, 1, 3'-H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][O:17][C:18]1[CH:27]=[CH:26][C:25](O)=[C:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[N:23]2.N1C=CC=CC=1>ClCCl>[CH3:16][O:17][C:18]1[CH:27]=[CH:26][C:25]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[C:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[N:23]2
Reactant: COc1ccc(O)c2ncccc12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(OS(=O)(=O)C(F)(F)F)c2ncccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.2 %

Procedure:
Trifluoromethanesulphonic anhydride (12 ml, 77.0 mmol) was added slowly, over approximately 5 minutes, to a stirred solution of 5-methoxy-quinolin-8-ol (Syn. Comm. 1997, 27(20), 3573-3579) (1.5 g, 8.6 mmol) and pyridine (5.5 ml, 68.5 mmol) in dichloromethane (34 ml) at 0° C., under nitrogen. The resulting mixture was allowed to warm to room temperature and stirred for a further 16 hours. The mixture was then partitioned between dichloromethane (100 ml) and saturated aqueous ammonium chloride solution (100 ml). The organic extract was further washed with water (100 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to provide a crude yellow solid. Purification by flash chromatography on silica gel, eluting with 5% ethyl acetate, 95% pentane, provided the title compound as a pale yellow solid (2.62 g, 99%). 1H-NMR (400 MHz, CDCl3): δ=4.02 (s, 3 H) 6.79 (d, 1 H) 7.50 (m, 2 H) 8.58 (dd, 1 H) 9.03 (dd, 1 H); LRMS: APCl+: m/z 308 [MH+].
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[CH:8]2)=[O:4].[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:29])[C:5]([C:3]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3cccnc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3cccnc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 47.5 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.090 mmol), β-alanine (806 mg, 9.0 mmol) and NaOMe solution (13.6 mL, 6.78 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in water and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 1 M HCl, and the resulting precipitate was isolated by filtration to give 19 mg of the title compound. MS: (+) m/z 445.33 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[C:8]([CH3:18])=[N:9][NH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C.ClCCl>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]2[NH:10][N:9]=[C:8]([CH3:18])[C:7]=2[N:6]=1
Reactant: Cc1n[nH]c(-c2ccccc2)c1NC(=O)c1ccccc1F
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1n[nH]c2c1nc(-c1ccccc1F)c1ccccc12
Reaction time: 4 h

Procedure:
The preparation took place in analogy to example 34 (D) using 182 mg of 2-fluoro-N-(3-methyl-5-phenyl-1H-pyrazol-4-yl)-benzamide, except 10.7 ml of phosphorous oxychloride was used and the reaction was stirred for 4 hrs. Trituration of the residue with ethyl acetate/dichloromethane (1/1) gave the title compound as a cream solid.
Reaction SMILES: [C:1]([CH2:9][CH:10]([OH:14])[C:11]([OH:13])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]([CH2:17][CH:18]([OH:21])[CH2:19][CH3:20])[NH2:16]>C(O)CCC>[OH:14][CH:10]1[CH2:9][C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:16][N:15]([CH2:17][CH:18]([OH:21])[CH2:19][CH3:20])[C:11]1=[O:13]
Reactant: CCC(O)CNN
Reactant: O=C(CC(O)C(=O)O)c1ccccc1
Solvent: CCCCO
Product: CCC(O)CN1N=C(c2ccccc2)CC(O)C1=O
Temperature: 120 °C

Procedure:
A mixture of 3.5 grams (18 mmol) of 3-benzoyl-2-hydroxy-propionic acid and 1.9 grams (18 mmol) of 1-hydrazino-2-butanol in 40 ml of n-butanol is refluxed under nitrogen at 120° C. for 18 hours. After evaporation of the solvent, the product is partitioned between ether and water. The ether layer is washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated. The resulting residue is dissolved in 2% ethanol-chloroform and filtered through 200 grams of silica gel yielding after evaporation 4,5-dihydro-4-hydroxy-2-(2-hydroxybutyl)-6-phenylpyridazin-3(2H)-one, m.p. 92°-94° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22](=[O:45])[C:23]([CH3:44])=[C:24]([CH2:30][C:31]2[C:32]([O:40][C:41](=[O:43])[CH3:42])=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22](=[O:45])[C:23]([CH3:44])=[C:24]([CH2:30][C:31]2[C:32]([O:40][C:41](=[O:43])[CH3:42])=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:35])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]
Reactant: C1COCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OC(C)=O)=C(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)N3CCOCC3)c2OC(C)=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 39 %

Procedure:
Morpholine (0.176 g, 2.02 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.581 g, 3.03 mmol) were added to a methylene chloride solution (50 ml) of 3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.380 g, 1.01 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=30:1) to obtain the titled compound (0.175 g, 0.394 mmol, 39%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][NH:15][N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1N2CCN(CC2)C1.[F:28][C:29]1([F:38])[CH2:32][N:31]([C:33](=[O:37])/[CH:34]=[CH:35]\I)[CH2:30]1.C(OCC)(=O)C.CCCCCC>CN(C=O)C>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:35]=[CH:34]\[C:33]([N:31]3[CH2:32][C:29]([F:38])([F:28])[CH2:30]3)=[O:37])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: O=C(/C=C\I)N1CC(F)(F)C1
Reactant: FC(F)(F)c1cc(-c2nc[nH]n2)cc(C(F)(F)F)c1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)N1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 25.7 %

Procedure:
In a 25-mL, three-necked, round-bottomed flask equipped with nitrogen inlet, 3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazole (0.18 g, 1.0 eq.) was dissolved in DMF (5.0 mL, 27.0 V), and DABCO (0.143 g, 2.0 eq) and (Z)-1-(3,3-difluoroazetidin-1-yl)-3-iodoprop-2-en-1-one (0.192 g, 1.1 eq) were added. The reaction mixture was stirred at RT for 2-3 hr. The progress of the reaction was followed by TLC analysis on silica gel with 80% ethyl acetate-hexane as mobile phase, SM Rf=0.60 and Product Rf=0.4. Reaction mixture was poured in to ice water (50 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine solution (3×25 mL), dried over MgSO4, filtered, and concentrated by rotary evaporation (25° C., 20 mmHg) to afford 0.3 g of crude compound which was purified by column chromatography using silica 60/120 using ethyl acetate:hexane as mobile phase. The column (5×10 cm) was packed in hexane and started eluting in ethyl acetate in gradient manner starting with fraction collection (50-mL fractions) from 40% to 45% ethyl acetate in hexane. Compound started eluting with 40% ethyl acetate in hexane. Fractions containing such TLC profile were combined to obtain 70 mg of desired compound (yield 25.64%).
Reaction SMILES: C(N(CC)CC)C.C([SiH](CC)CC)C.C([O:22][C:23]1[CH:24]=[C:25]([CH:35]=[C:36]([O:38][C@@H:39]([CH3:49])[CH2:40][O:41][Si](C(C)(C)C)(C)C)[CH:37]=1)[C:26]([NH:28][C:29]1[S:30][C:31]([CH3:34])=[CH:32][N:33]=1)=[O:27])C1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:22][C:23]1[CH:24]=[C:25]([CH:35]=[C:36]([O:38][C@@H:39]([CH3:49])[CH2:40][OH:41])[CH:37]=1)[C:26]([NH:28][C:29]1[S:30][C:31]([CH3:34])=[CH:32][N:33]=1)=[O:27]
Reactant: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cnc(NC(=O)c2cc(O)cc(O[C@@H](C)CO)c2)s1
Reaction time: 0.25 h
Yield: 21.4 %

Procedure:
Triethylamine (0.11 mL, 0.79 mmol) and triethylsilane (4.88 mL, 27.3 mmol) were added to palladium (11) acetate (56 mg, 9 mol %) in DCM (14 mL) under an atmosphere of argon. The reaction was stirred for 15 mins then 3-(benzyloxy)-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-N-(5-methyl-1,3-thiazol-2-yl)benzamide (1.4 g, 2.73 mmol) in DCM (14 mL) added dropwise and stirred for a further 48 hours. The reaction was filtered through celite and the filtrate concentrated in vacuo to give a residue which was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane, to give the desired compound (0.18 g).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([F:16])[CH:7]=1)=[N:4]O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)(=O)C(C(C(O)=O)O)O>C(OC(C)C)(C)C>[F:18][C:2]([F:1])([F:17])[CH:3]([C:6]1[CH:7]=[C:8]([F:16])[CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=1)[NH2:4]
Reactant: ON=C(c1cc(F)cc(C(F)(F)F)c1)C(F)(F)F
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CC(C)OC(C)C
Product: NC(c1cc(F)cc(C(F)(F)F)c1)C(F)(F)F
Temperature: 0 °C

Procedure:
2.18 g (7.92 mmol) of 2,2,2-trifluoro-1-[3-fluoro-5-(trifluoromethyl)phenyl]ethanone oxime were stirred in 35.4 ml of isopropyl ether, and admixed with 3.54 g (93.35 mmol) of lithium aluminium hydride in portions [cf, also synthesis of aryltrifluoroethylamines: DE 2723464, 1977)]. Thereafter, the reaction mixture was stirred at reflux temperature for approx. 3 hours. For workup, the reaction mixture was cooled to 0° C., and admixed cautiously with saturated tartaric acid solution, in order to destroy excess lithium aluminium hydride. After the vigorous evolution of gas had ended, the mixture was admixed with 2N sodium hydroxide solution (alkaline) and the organic phase was removed. The aqueous phase was extracted twice more with isopropyl ether. Thereafter, the combined phases were dried over magnesium sulphate and concentrated under reduced pressure at 40° C. (not less than 50 mbar). This gave 1.55 g (71.7% of theory) of α,3-bis(trifluoromethyl)-5-fluorobenzenemelthanamine, which was used for subsequent reactions without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][C:8]([NH:11][C:12](=[O:15])[CH:13]=[CH2:14])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.O1CCOCC1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([NH:11][C:12](=[O:15])[CH2:13][CH2:14][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)([CH3:9])[CH3:10])=[CH:16][CH:17]=1
Reactant: C=CC(=O)NC(C)(C)COc1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(COc1ccc(Cl)cc1)NC(=O)CCn1ccnc1
Temperature: 95 °C

Procedure:
A mixture of N-[2-(4-chlorophenoxy)-1,1-dimethylethyl]acrylamide (4.5 g), imidazole (1.24 g), benzyltrimethylammonium hydroxide (0.62 ml of a 40% solution in methanol, Triton®B) and 1,4-dioxane (40 ml) was heated at 95° C. for 7 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. This solution was extracted with 5M hydrochloric acid. The combined acid extracts were basified with 10M sodium hydroxide solution and extracted with dichloromethane to give N-[2-(4-chlorophenoxy)-1,1-dimethylethyl]-3-(imidazol-1-yl)propionamide.