Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([C@:8]1([OH:30])[C:13](=[CH2:14])[CH2:12][C@H:11]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:9]12[CH3:10])[C@:23]1([CH3:24])[C:18](=[CH:19][C:20](=[O:28])[CH2:21][CH2:22]1)[C:17]([CH3:29])=[CH:16]3)#[CH:7].P([O-])([O-])([O-])=[O:32]>O.CO.C1COCC1>[C:6]([C@:8]1([OH:30])[C:13](=[CH2:14])[CH2:12][C@H:11]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:9]12[CH3:10])[C@:23]1([CH3:24])[C:18](=[CH:19][C:20](=[O:28])[CH2:21][CH2:22]1)[C:17]([CH3:29])=[CH:16]3)(=[O:32])[CH3:7]
Reactant: C#C[C@]1(O)C(=C)C[C@H]2[C@@H]3C=C(C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: O=P([O-])([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C=C1C[C@H]2[C@@H]3C=C(C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@]1(O)C(C)=O
Reaction time: 8 h

Procedure:
Mercuric oxide (83 mg) dissolved in water (18 ml) containing sulfuric acid (0.11 ml) was added to 17α-ethynyl-17β-hydroxy-6-methyl-16-methyleneandrosta-4,6-diene-3-one (IVA, Example 20, 1.30 g) dissolved in a methanol (19 ml)-THF (3.8 ml) mixture. The mixture was heated at 40° (bath temperature) for 6 hr and then permitted to sit at 20°-25° overnight. Celite (1.7 g) and phosphate buffer (2 ml) were added, the mixture stirred and filtered. The solids were washed with methanol and THF. The filtrate was concentrated under reduced pressure until solids dropped out. Methanol was added and the mixture heated, seeded. The mixture was concentrated under reduced pressure, methylene chloride was added, the mixture was washed with buffer, dried over sodium sulfate, filtered. The filtrate was concentrated under reduced pressure to give the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:16][C:15]([CH3:18])([CH3:17])[S:14][C:9]=3[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([CH:19]([CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:20])[CH:3]=1.[BrH:28].[N:29]1([CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30]1.C1(N=C=NC2CCCCC2)CCCCC1>>[BrH:28].[CH3:27][CH:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:19]([C:4]1[CH:3]=[C:2]([O:1][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:7]2[C:8]3[CH2:16][C:15]([CH3:17])([CH3:18])[S:14][C:9]=3[C:10]([CH3:12])([CH3:13])[O:11][C:6]=2[CH:5]=1)[CH3:20]
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CC(C)(C)S1
Reactant: O=C(O)CCCN1CCCC1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCCC2)c2c(c1)OC(C)(C)C1=C2CC(C)(C)S1

Procedure:
By reacting 1,2-dihydro-9-hydroxy-7-(3-methyl-2-octyl)-2,2,4,4-tetramethyl-4H-thieno-[2,3-c][1]benzopyran with γ-pyrrolidinobutyric acid hydrobromide salt and dicyclohexylcarbodiimide according to the method of Example 10 there is obtained 1,2-dihydro-7-(3-methyl-2-octyl)-9-[4-(pyrrolidino)butyryloxy]-2,2,4,4-tetramethyl-4H-thieno-[2,3-c][1]benzopyran hydrobromide.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([CH:20]=[O:21])=[CH:5][N:4]=1.ClC1C=CC=C(C(OO)=O)C=1.[NH:33]1[CH2:39][CH2:38][CH2:37][C@H:34]1[CH2:35][OH:36].C(N(CC)CC)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[OH:36][CH2:35][C@@H:34]1[CH2:37][CH2:38][CH2:39][N:33]1[C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([CH:20]=[O:21])=[CH:5][N:4]=1
Reactant: OC[C@@H]1CCCN1
Reactant: COc1ccc(CNc2nc(SC)ncc2C=O)cc1Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(N3CCC[C@H]3CO)ncc2C=O)cc1Cl
Temperature: 25 °C
Yield: 83.5 %

Procedure:
A solution of 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-formylpyrimidine (2.057 g) in chloroform (20 ml) is treated with m-chloroperbenzoic acid (80%, 1.468 g) at 0° C. for 30 minutes. To the reaction mixture are is added L-prolinol (0.901 g), and then triethylamine (1.33 ml), and the mixture is reacted at 0° C. for one hour. The reaction mixture is warmed to room temperature, and diluted with ethyl acetate. The mixture is washed successively with a saturated aqueous sodium hydrogen carbonate solution, water and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The precipitates are removed by filtration through a silica plug. The filtrate is concentrated under reduced pressure to give (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-formylpyrimidine (1.9990 g) as colorless amorphous, MS (m/z): 377 (MH+).
Reaction SMILES: [CH3:1][C:2]1(C)[C:6](C)(C)OB(C(C)=C)O1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:20]1[C:21]([N:42]2[CH2:47][CH2:46][CH2:45][C@@H:44]([NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:43]2)=[C:22]2[C:28]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])=[CH:27][N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:23]2=[N:24][CH:25]=1.CC#N.O>O1CCOCC1.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>[C:52]([O:51][C:49]([NH:48][C@@H:44]1[CH2:45][CH2:46][CH2:47][N:42]([C:21]2[C:20]([C:2]([CH3:6])=[CH2:1])=[CH:25][N:24]=[C:23]3[N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:27]=[C:28]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[C:22]=23)[CH2:43]1)=[O:50])([CH3:54])([CH3:53])[CH3:55]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)C(=O)Nc1cn(C(=O)OC(C)(C)C)c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
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: O
Solvent: CC#N
Solvent: C1COCCO1
Product: C=C(C)c1cnc2c(c(NC(=O)C(C)C)cn2C(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 120 °C
Yield: 50.3 %

Procedure:
4,4,5,5-Tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (174 mg, 1.03 mmol), PS-palladium tetrakis (470 mg, 0.0517 mmol, 0.10 mmol/g) and 2N sodium carbonate (775 μL, 1.55 mmol) were added to (R)-tert-butyl 5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-isobutyramido-1H-pyrrolo[2, 3-1)]pyridine-1-carboxylate (300 mg, 0.517 mmol; Example 81, Step A) in degassed dioxane (1 mL). The reaction was heated to 120° C. for 1 hour under microwave irradiation. 4,4,5,5-Tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (174 mg, 1.03 mmol) and 2N sodium carbonate (775 μL, 1.55 mmol) were added, and the reaction was heated to 120° C. for an additional 2 hours. The reaction mixture was then cooled down and filtered. The filtrate was diluted with DCM washed with water. The layers were separated. The organic phase was dried (MgSO4) and concentrated, and the resulting residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 15-100% CH3CN/water) to yield (R)-tert-butyl 4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-isobutyramido-5-(prop-1-en-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (141 mg, 50% yield) as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:22]Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+]>CN1CCCC1=O>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:22][NH:1][C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1nc(C)c(Cl)c(N)n1
Reactant: COc1ccc(CCl)cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nc(C)nc(C)c2Cl)cc1OCc1ccccc1

Procedure:
In analogy to the method described in example A1, 6.11 g (38 mmol) of 4-amino-5-chloro-2,6-dimethylpyrimidine, 10.5 g (40 mmol) of 3-benzyloxy-4-methoxybenzyl chloride and 1.52 g (38 mmol) of sodium hydride (60% suspension in liquid paraffin) are reacted in a total of 225 ml of N-methylpyrrolidone. After chromatography on silica gel (mobile phase: toluene/dioxane=10:1) and crystallization from petroleum ether, the title compound is isolated as a pale beige solid. Yield: 5.2 g (36% of theory). m.p.: 111-117° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:12])[C:10]=2[CH:11]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]=[C:22]=[O:23])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][NH:21][C:22]([NH:12][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[CH:11]=[C:2]([CH3:1])[N:3]=[CH:4]3)=[O:23])=[CH:18][CH:19]=1
Reactant: O=C=NCc1ccc(Br)cc1
Reactant: Cc1cc2c(N)cccc2cn1
Solvent: Cc1ccccc1
Product: Cc1cc2c(NC(=O)NCc3ccc(Br)cc3)cccc2cn1
Temperature: 80 °C

Procedure:
The product from Example 63A (500 mg, 3.1 mmol) in toluene (10 mL) was treated with 1-bromo-4-(isocyanatomethyl)benzene (0.5 mL, 3.57 mmol) with stirring and then the mixture was heated at 80° C. overnight. The mixture was allowed to cool to room temperature, filtered, the filter cake was washed with toluene, and allowed to air-dry to provide the title compound. The corresponding hydrochloride salt was prepared using methanolic HCl to afford a tan solid (919 mg, 73%). 1H NMR (300 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.54 (s, 1H), 8.63 (s, 1H), 8.57 (dd, J=7.8 Hz, 1.0 Hz, 1H), 8.02 (d, J=8.2 Hz, 1H), 7.78-7.83 (m, 1H), 7.67-7.71 (m, 1H), 7.52-7.57 (m, 2H), 7.30-7.35 (m, 2H), 4.36 (d, J=5.7 Hz, 2H), 2.78 (s, 3H); MS (ESI+) m/z 370/372 (M+H, 79Br/81Br).
Reaction SMILES: [CH2:1]([S:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:18]([C:26](OC)=[O:27])(=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(C(=CC2C=CC=CC=2)C(O)=O)C=CC=CC=1.SC(C1C=CC=CC=1)C(O)=O>CN(C)C=O>[OH:27][C:26]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CSCc2ccccc2)cc1
Reactant: COC(=O)C(=O)c1ccccc1
Agent: O=C(O)C(=Cc1ccccc1)c1ccccc1
Agent: O=C(O)C(S)c1ccccc1
Agent: [H-]
Solvent: CN(C)C=O
Product: Oc1c(-c2ccccc2)sc(-c2ccccc2)c1-c1ccccc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To an ice cooled, stirred solution of dibenzyl sulfide (2.14 g, 0.01 m) in dried N,N-dimethylformamide was added sodium hydride (0.88 g, 0.022 mmol of a 60% suspension in mineral oil). The mixture was gradually heated to 60° C. (bath temperature), kept 2 hours and allowed to cool. Methyl benzoylformate (1.42 ml, 0.01 mmol) was then added and the mixture heated at 60° C. for 1 hour, cooled, added to a stirred ice-dilute hydrochloric acid-ether mixture, separated, the aqueous layer re-extracted 1 time with ether, and the combined organic layer washed 2 times with water, dried over sodium sulfate, filtered and concentrated to a residue. Chromatography on silica gel (1 time flush with 10% ethyl acetate/hexane followed by a careful chromatography with a methylene chloride/hexane mixture) yielded 50 mg. of product compound as a pale yellow-white crystalline material. M.S.: M+ =328; NMR: consistent, identical to the nmr spectrum of material prepared from α-phenylcinnamic acid and α-mercaptophenylacetic acid via Michael addition and ring closure. ##STR28##
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.Cl.O.[NH:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:12][C:11]([F:14])([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:17]3[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: O=C1CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 90 °C
Yield: 82.8 %

Procedure:
6-Chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (10.0 g, 44.93 mmol), 4-piperidone monohydrate hydrochloride (8.48 g, 49.43 mmol) and DIPEA (16.3 mL, 98.85 mmol) in DMF (100 mL) were stirred and heated at 90° C. for 1 hour. The DMF was then evaporated in vacuo and the residue purified by flash silica chromatography, eluting with 2% MeOH in DCM. Pure fractions were concentrated to give a pale yellow precipitate. The precipitate was collected by filtration, washed with ether and air dried to afford 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-one (10.61 g, 83%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].BrC1C=CC(S(O[CH2:26][C@@H:27]2[O:41][C:31]3=[C:32]4[C:37](=[CH:38][CH:39]=[C:30]3[O:29][CH2:28]2)[N:36]=[C:35]([CH3:40])[CH:34]=[CH:33]4)(=O)=O)=CC=1>>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:10][CH2:11][N:12]([CH2:26][C@@H:27]3[O:41][C:31]4=[C:32]5[C:37](=[CH:38][CH:39]=[C:30]4[O:29][CH2:28]3)[N:36]=[C:35]([CH3:40])[CH:34]=[CH:33]5)[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(N2CCNCC2)cc1C
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN1CCN(c2ccc(C)c(C)c2)CC1)O3
Yield: 55.9 %

Procedure:
This compound was prepared as described for Example 10, using 1-(3,4-dimethylphenyl)-piperazine (1.01 g, 5.33 mmol), and 804 mg (1.79 mmol) of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzene-sulfonate, to afford 404 mg (68%) of the title compound as a white foam: mp 118–120° C.; MS (ESI) m/z404 [M+H]+.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[CH2:6]([OH:10])[CH2:7][CH2:8][CH3:9]>O>[CH2:6]([O:4][CH:1]([OH:5])[C:2]([O:10][CH2:6][CH2:7][CH2:8][CH3:9])=[O:3])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCO
Reactant: O=CC(=O)O
Solvent: O
Product: CCCCOC(=O)C(O)OCCCC
Temperature: 82.5 °C

Procedure:
In a suitable reactor flask equipped with stirrer, heating mantle, Dean Stark trap, condenser, nitrogen inlet, vacuum take off and dropping funnel were added 1980 grams (13.0 moles) of 50% glyoxylic acid in water and 1215 grams (16.4 moles) of n-butanol. The contents of the flask were heated to 80-85° C. under nitrogen sparge and vacuum to remove approximately 760 grams of an n-butanol/water azeotrope. Thereafter, an additional 1210 grams of n-butanol were added and strip distillation continued until no water was seen in the azeotrope. An additioral 810 grams of n-butanol were then added and the mixture refluxed for two hours at 80-85° C. under vacuum, followed by vacuum stripping of excess n-butanol. Product weight was 2850 grams.
Reaction SMILES: [CH:1]12[CH2:12][CH:9]([CH:10]=[CH:11]1)[CH2:8][C:7]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]2=1.[OH2:13].[OH2:14].C[N+]([O-])(C)C.C(O)(C)(C)C>ClCCl.[Os](=O)(=O)(=O)=O>[CH:1]12[CH2:12][CH:9]([CH:10]([OH:14])[CH:11]1[OH:13])[CH2:8][C:7]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]2=1
Reactant: O
Reactant: C1=CC2CC1Cc1cccnc12
Agent: O=[Os](=O)(=O)=O
Agent: C[N+](C)(C)[O-]
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: OC1C2Cc3cccnc3C(C2)C1O
Reaction time: 18 h

Procedure:
3-Aza-tricyclo[7.2.1.02,7]dodeca-2(7),3,5,10-tetraene (960 mg, 6.1 mmol) and trimethylamine N-oxide dihydrate (748 mg, 6.73 mmol) were stirred in dichloromethane (15 mL) and treated with osmium tetroxide (OsO4, 0.2 mL of a 15 mol % t-butanol solution) and the mixture was stirred vigorously. After 18 h, the residue was poured onto a silica gel column (2×6 inch) and eluted with hexanes (100 mL) then EtOAc to elute product as an oil that crystallizes on standing (1.16 g, 100%). (TLC EtOAc Rf 0.17); 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J=4.9 Hz, 1H), 7.40 (d, J=7.5 Hz, 1H), 7.07 (dd, J=7.5, 4.9 Hz, 1H), 4.19 (d, J=6.0 Hz, 1H), 3.90 (d, J=6.0 Hz, 1H), 3.45 (s, 1H), 3.00 (dd, J=17.3, 4.8 Hz, 1H), 2.67 (d, J=17.3 Hz, 1H), 2.43 (m, 2H), 1.59 (d, J=11.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 159.4, 147.6, 138.1, 130.9, 122.3, 77.1, 75.4, 51.6, 42.2, 33.9, 28.5; APCl MS m/z 192.1 (M)+.
Reaction SMILES: [C:1]1([C:7]([CH:9]=O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[NH2:20])=[CH:14][CH:13]=1>>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([NH:20][CH2:9][CH:7]([OH:8])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([CH3:21])[CH3:22])=[CH:14][CH:13]=1
Reactant: Cc1ccc(CC(C)(C)N)cc1
Reactant: O=CC(=O)c1ccccc1
Product: Cc1ccc(CC(C)(C)NCC(O)c2ccccc2)cc1

Procedure:
The title compound was prepared in the manner described in Example 9 using phenylglyoxal and 2-(4-methylphenyl)-1,1-dimethylethanamine. The chromatographed material was recrystallized from cyclohexane to give the title compound m.p. 137. τ(CDCl3 +d6DMSO) 8.95 (6H, s), 7.7 (3H, s), 7.35 (2H, s), 7.0-7.3 (2H, dd), 5.3 (1H, dd), 2.9 (4H, s), 2.5-2.7 (5H, m).
Reaction SMILES: II.[BH4-].[Na+].[CH3:5][NH:6][C:7](=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.CO>O1CCCC1>[CH3:5][NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:18])[F:17])[CH:10]=1
Reactant: CNC(=O)Cc1cccc(C(F)(F)F)c1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNCCc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 20.4 %

Procedure:
At 0° C., a solution of iodine (23.1 g, 91 mmol) in tetrahydrofuran (100 ml) was added dropwise to a suspension of sodium borohydride (8.6 g, 227 mmol) and of N-methyl-2-(3-trifluoromethylphenyl)acetamide (19.8 g, 91 mmol) in THF (150 ml). The reaction mixture was heated to reflux for 16 hours. It was cooled to 0° C. Methanol (200 ml) was added dropwise. The solvent was removed in vacuo. The residue was dissolved in a mixture of tert-butyl methyl ether (200 ml) and a 20% aqueous solution of sodium hydroxide (200 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (2×100 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (300 g), using a mixture of DCM/methanol/25% aqueous ammonia (first: 100:10:1, then 100:20:2, then 100:30:3) as eluent, to give 3.77 g of N-methyl-N-[2-(3-(trifluoromethyl)phenyl)ethyl]amine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][C@H:16]3[CH2:20][CH2:19][O:18][CH2:17]3)=[CH:10][C:9]=2[CH3:21])=[CH:4][C:3]=1[CH2:22][O:23][C:24]1[CH:37]=[CH:36][C:27]2[C@H:28]([CH2:31][C:32]([O:34]C)=[O:33])[CH2:29][O:30][C:26]=2[CH:25]=1.[OH-].[Li+]>O1CCCC1.CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:21])=[CH:10][C:11]([O:15][C@H:16]3[CH2:20][CH2:19][O:18][CH2:17]3)=[CH:12][C:13]=2[CH3:14])=[CH:4][C:3]=1[CH2:22][O:23][C:24]1[CH:37]=[CH:36][C:27]2[C@H:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:29][O:30][C:26]=2[CH:25]=1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cc(-c4c(C)cc(O[C@H]5CCOC5)cc4C)ccc3F)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(O[C@H]2CCOC2)cc(C)c1-c1ccc(F)c(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Reaction time: 12 h
Yield: 67.7 %

Procedure:
Methyl 2-((S)-6-((4-fluoro-2′,6′-dimethyl-4′-(((S)-tetrahydrofuran-3-yl)oxy) biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 18e (150 mg, 0.30 mmol) was dissolved in 4.5 mL of a mixture of the solvents tetrahydrofuran, methanol and water (V/V=1:3:0.5), followed by addition of 1M aqueous lithium hydroxide solution (1 mL, 1 mmol). The reaction solution was stirred for 12 hours. The resulting solution was concentrated under reduced pressure. The residue was mixed with 10 mL of water, 2M hydrochloric acid was added dropwise to adjust the pH to 2˜3, and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by TLC with elution system A to obtain the title compound 2-((S)-6-((4-fluoro-2′,6′-dimethyl-4′-(((S)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 18 (100 mg, yield 66.7%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7](F)=[CH:8][CH:9]=2)[N:4]([CH:12]2[CH2:14][CH2:13]2)[CH:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][OH:22].[H-].[Na+]>CS(C)=O.CO>[Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([O:22][CH2:21][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=3)=[CH:8][CH:9]=2)[N:4]([CH:12]2[CH2:14][CH2:13]2)[CH:3]=1
Reactant: OCc1ccccn1
Reactant: Fc1ccc2c(Br)cn(C3CC3)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: Brc1cn(C2CC2)c2nc(OCc3ccccn3)ccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77.6 %

Procedure:
To a solution of 3-bromo-1-cyclopropyl-6-fluoro-1H-pyrrolo[2,3-b]pyridine (0.249 g, 0.98 mmol) in dimethyl sulfoxide (5 mL) is added 2-pyridinemethanol (188 μL, 1.95 mmol), followed by portionwise addition of sodium hydride (97.6 mg, 2.44 mmol). The mixture is stirred at room temperature for 5 min., then poured onto brine and extracted with EtOAc. The organic layers are combined, dried (magnesium sulphate) and concentrated in vacuo to give a brown oil. This is taken up in methanol and poured onto a SCX-2 ion-exchange column. This is washed with 3 column volumes of MeOH, and then the product collected in the subsequent one column volume flush with 7 M methanolic ammonia. The solution is then concentrated in vacuo to give the title compound as a yellow oil (0.263 g, 0.76 mmol). MS (m/z): 344/346 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[N:11]=[C:10]([C:20]3[S:21][CH:22]=[CH:23][C:24]=3[Cl:25])[CH2:9]2)=[CH:4][CH:3]=1.ClC1C=C(NN)C=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[N:11]=[C:10]([C:20]3[S:21][CH:22]=[CH:23][C:24]=3[Cl:25])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2CC(c3sccc3Cl)=NN2c2cccc(Cl)c2)cc1
Agent: NNc1cccc(Cl)c1
Product: Clc1ccc(-c2cc(-c3sccc3Cl)nn2-c2cccc(Cl)c2)cc1

Procedure:
5-(4-Chloro-phenyl)-1-(3-chloro-phenyl)-3-(3-chloro-thiophen-2-yl)-4,5-dihydro-1H-pyrazole: The title compound was prepared from 3-(4-chloro-phenyl)-1-(3-chloro-thiophen-2-yl)-propenone and 3-chloro-phenylhydrazine by a procedure similar to that of Example 105a as a yellowish solid (93.8 mg, 43%). 1H NMR (CDCl3): 7.29 (m, 7H), 6.92 (m, 3H), 5.25 (m, 1H), 4.08 (m, 1H), 3.83 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:21])[N:9]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[NH:14][C:10]3=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:22][CH2:23][CH2:24]Br>>[CH2:22]([N:14]1[C:10]2=[N:11][C:12]3[C:7]([C:8](=[O:21])[N:9]2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]1=2)=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=3)[CH2:23][CH3:24]
Reactant: CCCBr
Reactant: O=c1c2ccc([N+](=O)[O-])cc2nc2[nH]c3ccccc3n12
Product: CCCn1c2ccccc2n2c(=O)c3ccc([N+](=O)[O-])cc3nc12

Procedure:
6-(n-Propyl)-3-nitrobenzimidazo[2,1-b]quinazolin-12(6H)-one is prepared with 3-nitrobenzimidazo[2,1-b]quinazolin-12(6H)one and n-propyl bromide.
Reaction SMILES: [CH3:1][C:2]1[C@H:6]([O:7][N+]([O-])=O)[CH2:5][C:4](=[O:11])[C:3]=1[CH2:12][CH:13]=[CH2:14].C(=O)([O-])[O-].[Ca+2].O>C(Cl)(Cl)Cl>[OH:7][C@H:6]1[CH2:5][C:4](=[O:11])[C:3]([CH2:12][CH:13]=[CH2:14])=[C:2]1[CH3:1]
Reactant: C=CCC1=C(C)[C@H](O[N+](=O)[O-])CC1=O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=CCC1=C(C)[C@@H](O)CC1=O
Reaction time: 3 h
Yield: 78.9 %

Procedure:
A mixture of 1.97 g of (R)-3-methyl-4-nitroxy-2-(2-propenyl)-2-cyclopenten-1-one prepared in Example 10, 0.20 g of calcium carbonate and 30 ml of water was stirred at 85°-90° C. for 3 hours. Thereafter, with the same operations as in Example 3, 1.20 g of (S)-4-hydroxy-3-methyl-2-(2-propenyl)-2-cyclopenten-1-one (chemical purity: 93.6%, [α]D24 : +11.2° (C=1.23, in chloroform), (R)-isomer/(S)-isomer=14.8/85.2) was obtained.