Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:18](OCC)(=O)[CH2:19][OH:20].Cl>C(O)C.O>[CH:2]1([N:7]2[C:11]3=[N:12][C:18]([CH2:19][OH:20])=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CO
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(CO)nc(=O)c1-2
Yield: 23.4 %

Procedure:
Sodium (0.68 g) was dissolved in ethanol and 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (3.0 g, 13.5 mmol), followed by ethyl glycolate (2.8 g, 27 mmol) were added. The reaction mixture was refluxed overnight, the ethanol was stripped and water, followed by 2N HCl were added to the residue. A precipitate formed which was collected by filtration, washed with saturated NaHCO3, and then water. The product was recrystallized from ethyl acetate, then ether to afford 0.83 g of 1-cyclopentyl-3-ethyl-6-(hydroxymethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 183-184° C.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C@@H:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([OH:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:4][CH:3]=1.C1C(=O)N([Br:36])C(=O)C1>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([OH:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]2[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])=[CH:27][C:28]=1[Br:36]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(N)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(N)c(Br)c2)CC[C@@H]1[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a solution of tert-butyl (2S,5R)-2-(4-aminobenzyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidine-1-carboxylate (intermediate i-13a, 214 mg, 0.559 mmol) in DMF (2 mL) cooled to 0° C. via ice/water bath was added NBS (100 mg, 0.559 mmol) and the resulting solution stirred for 1.5 h allowing to warm to rt. The mixture was evaporated under vacuum and the residue purified via Biotage Horizon MPLC using a gradient of 0-40% ethyl acetate in hexane to afford the product (232 mg, 90%) as a white foam. LC-MS: m/z (ES) 483 (MNa)+and 485 (MNa+2)+.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[C:14]1([NH:13][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1
Reactant: O=C1Nc2ccccc2C1=CO
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=CNc1ccccc1

Procedure:
E & Z 3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one is reacted with 0.022 gms. of aniline by refluxing in tetrahydrofuran (1.2 mL) for 12 hours to yield a quantitative amount (39 mg) of the named compound as a solid following concentration in vacuo, dilution with isopropanol and filtration.
Reaction SMILES: [C:1]([N:4]1[CH:9]=[CH:8][C:7]([C:16](=[O:18])[CH3:17])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5]1)(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([N:4]1[CH2:5][CH2:6][C:7]([C:16](=[O:18])[CH3:17])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1C=CC(C(C)=O)(c2ccccc2)C=C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)N1CCC(C(C)=O)(c2ccccc2)CC1
Temperature: 25 °C

Procedure:
1.2 grams of 1,4-Diacetyl 4-phenyl 1,4-dihydropyridine from Example 1 was dissolved in methanol (100 ml) and subjected to hydrogenation in an autoclave in presence of Palladium/carbon (10%) at 60° C. with hydrogen pressure of 5-6 kg for 10 hrs. Thin layer chromatography showed the completion of the reduction. The reaction mixture was cooled to room temperature and filtered to remove palladium/carbon. The filtrate was concentrated completely and the product was precipitated using chilled isopropyl alcohol. The product was filtered and the solid product 1,4 diacetyl 4-phenyl piperidine was dried under vacuum.
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)([F:4])[F:3].BrBr.[Cl:15]Cl>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][Cl:15])=[CH:8][CH:7]=1)([F:4])[F:3]
Reactant: Cc1ccc(SC(F)(F)F)cc1
Reactant: ClCl
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)Sc1ccc(CCl)cc1
Yield: 87.6 %

Procedure:
700 g of 4-trifluoromethylmercapto-toluene in 2,000 ml of CCl4 were initially introduced into a glass chlorination apparatus and heated to the reflux temperature. The solution was irradiated with a UV lamp. 3 ml of bromine were added before the start of the chlorination. When the color of the bromine had disappeared, 200 g of chlorine were passed in over a period of 6 hours. By fractional distillation over a 40 cm packed column, in addition to non-chlorinated starting material, 560 g of 4-trifluoromethylmercaptobenzyl chloride were obtained. Boiling point=97°-8° C./14 mm Hg, nD20 =1.5072.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH2:11]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[CH2:27][C:28]([OH:30])=[O:29])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[CH2:27][C:28]([O:30][CH2:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:29])=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)CC1CCCCN1C(=O)OCc1ccccc1
Reactant: O=C(CBr)c1ccccc1
Product: O=C(CC1CCCCN1C(=O)OCc1ccccc1)OCC(=O)c1ccccc1

Procedure:
The title compound (4.0 g) was prepared from 2-bromoacetophenone (2.20 g) and 2-carboxymethyl-piperidine-1-carboxylic acid benzyl ester according to the method of description 36
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[CH:14][C:15]3[C:23]4[C:18](=[CH:19][C:20]([Cl:25])=[CH:21][C:22]=4[Cl:24])[NH:17][C:16]=3[C:26]([OH:28])=[O:27])[CH2:10][N:9]2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:4][CH:3]=1.C[Si]([N:40]=[C:41]=[O:42])(C)C>O1CCCC1>[C:32]([O:31][C:29]([N:9]1[CH2:10][C:11](=[CH:14][C:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:25])=[CH:21][C:22]=3[Cl:24])[NH:17][C:16]=2[C:26]([OH:28])=[O:27])[C:12](=[O:13])[N:8]1[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:41]([NH2:40])=[O:42])=[CH:3][CH:4]=1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)(C)OC(=O)N1CC(=Cc2c(C(=O)O)[nH]c3cc(Cl)cc(Cl)c23)C(=O)N1c1ccc(N)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(=Cc2c(C(=O)O)[nH]c3cc(Cl)cc(Cl)c23)C(=O)N1c1ccc(NC(N)=O)cc1

Procedure:
To a solution of example 16 (0.070 g) in tetrahydrofuran (4 ml) under nitrogen at room temperature was added trimethylsilylisocyanate (0.080 ml). The solution was refluxed for 4 hrs, after which time the product was seen to precipitate from the solution. The solid was filtered off and washed with tetrahydrofuran (10 ml) affording the title compound as an orange solid. (0.042 g).
Reaction SMILES: CO[C:3](=O)[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].CC(C[AlH]CC(C)C)C.[CH3:33][O:34][C:35]([CH2:37]P(OC)(OC)=O)=[O:36]>>[CH2:9]([O:8][C:6]([NH:5][CH:4]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:3]=[CH:37][C:35]([O:34][CH3:33])=[O:36])=[O:7])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Product: COC(=O)C=CC(Cc1ccccc1)NC(=O)OCc1ccccc1

Procedure:
N-Benzyloxycarbonyl phenylalanine methyl ester is reduced with DIBAL to the aldehyde using the procedure of Boger et al., J. Med. Chem. (1985) 28, 1779, which is homologated with the sodio derivative of trimethyl phosphonoacetate using the procedure of Wadsworth and Emmons, Org. Synth. (1965) 45, 44 to give methyl 4-(benzyloxycarbonyl)amino-5-phenyl-2-pentenoate.
Reaction SMILES: [Na].[CH2:2]([O:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:12][C:11]=1[C:28](=[O:30])[CH3:29])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:31](OCC)(=[O:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33].Cl>C(O)C>[CH2:35]([O:34][C:32](=[O:33])[C:31](=[O:37])[CH2:29][C:28]([C:11]1[CH:12]=[C:13]([CH2:24][CH:25]([CH3:26])[CH3:27])[C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:15][C:10]=1[O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:30])[CH3:36]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cc(CC(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)c1cc(CC(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Sodium (3 eq) was added to ethanol under nitrogen at room temperature and stirred until complete dissolution occured. 1-(2,4-Bis-benzyloxy-5-isobutyl-phenyl)-ethanone (1 eq) was added, followed by diethyl oxalate (1.5 eq) and the reaction mixture heated to reflux for 4 hours. The mixture was allowed to cool to room temperature and acidified with 2M HCl (aq) to give a yellow precipitate of 4-(2,4-Bis-benzyloxy-5-isobutyl-phenyl)-2,4-dioxo-butyric acid ethyl ester, which was obtained by filtration.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[S:41][C:40]([N:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]2=[O:48])=[N:39][CH:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[S:41][C:40]([N:42]4[CH:47]=[CH:46][CH:45]=[CH:44][C:43]4=[O:48])=[N:39][CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: O=c1ccccn1-c1ncc(Br)s1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cnc(-n3ccccc3=O)s2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one and 1-(5-bromothiazol-2-yl)pyridin-2(1H)-one following a procedure analogous to that described in Example 31. LC (method 5): tR=1.72 min; Mass spectrum (ESI+): m/z=472, 530 [M+H]+; 1H NMR (CDCl3) δ 1.12 (s, 3H), 1.18 (s, 3H), 1.56 (d, 3H), 2.19 (s, 2H), 2.25 (m, 1H), 2.39 (m, 1H), 2.60 (m, 1H), 2.86 (m, 1H), 5.69 (q, 1H), 6.45 (t, 1H), 6.80 (d, 1H), 6.99 (d, 2H), 7.25-7.40 (7H), 7.46 (m, 1H), 7.77 (s, 1H), 8.81 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].CS(C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][F:27]>[I-].[K+].O>[F:27][CH2:26][CH2:25][O:12][C:11]1[C:2]([OH:1])=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][C:10]=1[OH:13]
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc(O)c(OCCF)c(O)c1
Reaction time: 18 h
Yield: 18.1 %

Procedure:
To a 100 mL round bottom flask was added methyl 3,4,5-trihydroxybenzoate (7.00 g, 88.0 mmol) followed by 25 mL of dimethyl sulfoxide. Potassium Carbonate (7.88 g, 57.0 mmol), potassium iodide (31.6 mg, 0.19 mmol) and 1-bromo-2-fluoroethane (5.79 g, 45.6 mmol) were successively added followed by 25 mL more of dimethyl sulfoxide. The reaction mixture was stirred for 18 h after which it was diluted by adding water (100 mL). The mixture was poured into a separatory funnel and extracted with DCM (3×40 mL). The organic layer was then washed with water (4×120 mL) and brine, and dried over magnesium sulfate. The organic layer was then concentrated to obtain an oil. The crude oil was purified using silica gel flash chromatography (DCM/ether 39:1) to obtain 1.9 g (22%) of the title compound (Rf˜0.17 in 19:1 DCM/ether). 1H NMR (600 MHz, CDCl3): δ 7.25 (s, 2H), 5.96 (s, 2H), 4.7 (t of d, 2H, J=48, 1.2 Hz), 4.37 (t of d, 2H, J=24, 1.2 Hz), 3.87 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 166.8, 149, 136.8, 126.4, 109.8, 82.16 (d, J=334 Hz), 72.6 (d, J=37.5), 52.3. MS (ESI): 231.4 (M+H, 100); FIRMS: Calc'd for C10H11FO5 (M+H): 231.06633; Found: 231.0664.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:24]([CH3:25])=[CH:23][S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[C:24]([CH3:25])=[CH:23][S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: NCCc1ccccc1
Reactant: Cc1csc2nc(-c3ccno3)nc(Cl)c12
Product: Cc1csc2nc(-c3ccno3)nc(NCCc3ccccc3)c12

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(isoxazol-5-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-phenethylamino-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]3)[O:11][C:7]=2[C:6](F)=[C:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:4]=1[CH3:30])#[N:2].C(N(CC)CC)C.[CH3:38][N:39]([CH3:45])[C@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1>CS(C)=O>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]3)[O:11][C:7]=2[C:6]([N:42]2[CH2:43][CH2:44][C@H:40]([N:39]([CH3:45])[CH3:38])[CH2:41]2)=[C:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:4]=1[CH3:30])#[N:2]
Reactant: CCOC(=O)C1CCN(c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)CC1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)C1CCN(c2nc3c(C#N)c(C)c(-c4ccccc4)c(N4CC[C@H](N(C)C)C4)c3o2)CC1
Temperature: 150 °C
Reaction time: 4 h

Procedure:
Ethyl 1-(4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazol-2-yl)piperidine-4-carboxylate (I-161) (0.27 g, 0.66 mmol) was dissolved in dimethyl sulfoxide (5 ml), then triethylamine (0.19 ml, 1.37 mmol) and (3S)-3-(dimethylamino)pyrrolidine (0.17 ml, 1.34 mmol) were added, followed by stirring in a sealed tube at an external temperature of about 150° C. for 4 hours.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[OH:15])=[O:5])[CH3:2].CCN(C(C)C)C(C)C.[F:25][C:26]([F:41])([C:37]([F:40])([F:39])[F:38])[C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[S:29](F)(=[O:31])=[O:30]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[O:15][S:29]([C:28]([F:33])([F:34])[C:27]([F:35])([F:36])[C:26]([F:25])([F:41])[C:37]([F:40])([F:39])[F:38])(=[O:31])=[O:30])=[O:5])[CH3:2]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCOC(=O)c1sc2ccncc2c1O
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1sc2ccncc2c1OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 3-hydroxy-thieno[3,2-c]pyridine-2-carboxylic acid ethyl ester (1.3 g, 5.82 mmol) and DMAP (35 mg, 0.29 mmol) in DCM (10 ml) at 0° C. was added DIPEA (2.5 ml, 14.0 mmol) and nonafluorobutylsulfonyl fluoride (1.36 ml, 7.56 mmol). After 10 minutes the reaction mixture was warmed to room temperature and stirred for an additional 20 hours. The reaction mixture was diluted with DCM (50 ml) and washed with water (30 ml). The organic phase was isolated, dried over sodium sulphate, filtered and evaporated to give a brown oil. The oil was purified by flash chromatography (Si-SPE, pentane:diethyl ether, gradient 100:0 to 70:30) to afford the title compound as a colourless oil which crystallised on standing (420 mg, 14%). LCMS (method B): RT=4.46 min, M+H+=508.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[N:17]([CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH3:19])C1C=CC=CC=1.[ClH:27].[H][H]>C(O)C.[Pd]>[ClH:27].[ClH:27].[CH2:18]([NH:17][CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[CH3:19]
Reactant: [H][H]
Reactant: CCN(CCCN(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCNCCCN(C)C
Yield: 89.5 %

Procedure:
To a solution of the (3-dimethylaminopropyl)-ethyl-carbamic acid benzyl ester trifluoroacetate (0.84 g, 2.2 mmol) in ethanol (30 mL) and concentrated hydrochloric acid (0.5 mL, 6 mmol) was added palladium on carbon (10%, 50 mg). The suspension was shaken under 50 psi hydrogen. When the consumption of hydrogen was observed to have ceased, the mixture was filtered through a pad of diatomaceous earth and then concentrated under reduced pressure to give N′-ethyl-N,N-dimethylpropane-1,3-diamine dihydrochloride (400 mg, 89%) as a white solid. MS (ES+): m/z (M+H)=131.3 To a suspension of the N′-ethyl-N,N-dimethylpropane-1,3-diamine dihydrochloride (0.26 g, 1.3 mmol) in dichloromethane (5 mL) was added triethylamine (0.51 mL, 3.9 mmol). After stirring for 10 minutes, the mixture was treated with 17-hydroxywortmannin (0.28 g, 0.65 mmol). After stirring overnight at room temperature, the mixture was concentrated under reduced pressure and then purified by reverse-phase HPLC (employing a gradient elution of 5% acetonitrile/95% water to 95% acetonitrile over 45 minutes). The title compound was obtained as a rust-colored solid (11.6 mg). MS (ES+): m/z (M+H)=561.4.
Reaction SMILES: Cl[Si](C)(C)C.Br[CH2:7][C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9].[CH3:14][NH:15][C:16]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]([C:30]3[N:31]=[CH:32][N:33]([C:35]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:34]=3)=[O:29])[CH:24]=2)[CH:19]=1)=[O:17]>C1COCC1.C(OCC)(=O)C.Cl.[Zn]>[OH:29][C@@:28]([C:23]1[CH:22]=[CH:21][C:20]2[C:25](=[CH:26][CH:27]=[C:18]([C:16]([NH:15][CH3:14])=[O:17])[CH:19]=2)[CH:24]=1)([C:30]1[N:31]=[CH:32][N:33]([C:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:34]=1)[CH2:7][C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9]
Reactant: CNC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reactant: CC(C)OC(=O)CBr
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc2cc([C@@](O)(CC(=O)OC(C)C)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reaction time: 0.17 h
Yield: 69.5 %

Procedure:
50 mL of 0.1N hydrochloric acid was added to 5 g of zinc powders, the mixture was stirred vigorously for 10 minutes, filtered, and washed successively with 30 mL of water, 30 mL of ethanol, and 30 mL of ether. Zinc was filtered, followed by vacuum drying at 100° C. for 8 hours. Under argon atmosphere, 4 mL of THF and 0.075 mL (0.59 mmol) of chlorotrimethylsilane were added to 0.52 g (8 mmol) of the zinc powders. The mixture was stirred at 25˜28° C. for 2 minutes, and a solution of 1.04 mL (8 mmol) of isopropyl bromoacetate in 10 mL of THF was added over 10 minutes. The mixture was stirred at 45˜50° C. for 45 minutes. A solution of 0.94 g (1.8 mmol) of N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide in 7.5 mL of THF was added dropwise at −33˜−35° C. over 5 minutes. The mixture was stirred at −43˜−35° C. for 30 minutes, at 15˜25° C. for 3 hours, and at 45˜50° C. for 50 minutes. 5 mL of 1N hydrochloric acid was added dropwise at 25° C., diluted with 25 mL of ethyl acetate, 5 mL of 1N hydrochloric acid was added, and the layers were separated. The organic layer was washed successively with 5 mL of 1N hydrochloric acid two times, 10 mL of water, 5 mL of an aqueous saturated sodium bicarbonate solution, and 5 mL of an aqueous saturated sodium chloride solution. After concentrated under reduced pressure, 2 mL of ethyl acetate was added to the concentration residue. Crystals were filtered, and washed with 1 mL of ethyl acetate. Vacuum drying (40° C.) to a constant weight afforded 0.78 g of isopropyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate. (yield 70%).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=1[Cl:14])[NH2:10].[CH:15]([S:17]([F:20])(=[O:19])=[O:18])=[CH2:16]>O>[Cl:6][C:7]1[CH:8]=[C:9]([NH:10][CH:16]=[CH:15][S:17]([F:20])(=[O:19])=[O:18])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: C=CS(=O)(=O)F
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(F)C=CNc1ccc(Cl)c(Cl)c1

Procedure:
A N,N-dimethylformamide solution (DMF, 100ml) of 3,4-dichloroaniline (6.48 g, 40 mmol) and ethenesulfonyl fluoride (6.7 g, 57.9 mmol) was warmed to 110° C. for three hours. The cooled dark solution was diluted to 400 ml with water and the resulting dark oily precipate was decanted from the supernatant layer. This layer was extracted with ether (4×50 ml). The combined ether extracts were added to the oily precipitate and this dark solution was washed with brine and dried over MgSO4. The organic solution was evaporated to give the crude 2-[(3,4-dichlorophenyl)amino]ethenesulfonyl fluoride as a dark liquid in quantitative yield.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[N+:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Br)=[CH:32][CH:31]=1)([O-:23])=[O:22]>>[CH2:1]([C:5]1[N:6]([CH2:36][C:33]2[CH:32]=[CH:31][C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N+:21]([O-:23])=[O:22])=[CH:35][CH:34]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)[nH]1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Yield: 91 %

Procedure:
By the procedure of Example 13, Step A, 5-n-butyl-2,4-dihydro-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 16, Step A) was alkylated with (2'-nitrobiphenyl-4-yl)methyl bromide (from Step B). Flash chromatography of the crude product on silica gel (gradient elution with 0.5-5% MeOH in CH2Cl2) gave a 91% yield of the title compound as a sticky foam; satisfactory purity by TLC in 98:2 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 497 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:12]2[C:13]2[CH:14]=[N:15][NH:16][C:17]=2[CH2:18]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:23](Cl)(=[O:25])[CH3:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:12]2[C:13]2[C:17]([CH2:18]3)=[N:16][N:15]([C:23](=[O:25])[CH3:24])[CH:14]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1cn[nH]c1C2
Reactant: CC(=O)Cl
Product: CC(=O)n1cc2c(n1)CC1CCCC2N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared by acylation of 12-(4-chloro-benzenesulfonyl)-4,5,12-triaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene using acetyl chloride.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[I-].[K+]>O>[F:9][C:8]([F:11])([F:10])[C:5]1[N:4]=[N:3][C:2]([NH:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Agent: [I-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(F)(F)F)nn2)CC1
Temperature: 150 °C
Yield: 84.6 %

Procedure:
A mixture of 3-chloro-6-trifluoromethyl-pyridazine (4.4 g, 24.1 mmol) (prepared by a procedure similar to that described in Tetrahedron, 1999, 55 (52), 15067-15070), 4-amino-1-tert-butyloxycarbonylpiperidine (9.63 g, 48.1 mmol) and potassium iodide (cat.) were heated in a melt at 150° C. for 30 min. After this period, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was separated, dried and the solvent evaporated in vacuo. The crude product was purified by chromatography (silica; 1%-4% ammonia in methanol (7 M)/dichloromethane) to give D1 (7.06 g, 85%). C15H21F3N4O2 requires 346; Found 347 (MH+)