Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][C:12]([N:16]3[CH2:21][CH2:20][CH:19]([O:22][CH2:23][C:24]4[C:25]([C:32]5[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=5[Cl:39])=[N:26][O:27][C:28]=4[CH:29]4[CH2:31][CH2:30]4)[CH2:18][CH2:17]3)=[CH:13][CH:14]=2)[N:9]([CH3:40])[CH:8]=1)=[O:6]>O1CCOCC1>[CH:29]1([C:28]2[O:27][N:26]=[C:25]([C:32]3[C:33]([Cl:39])=[CH:34][CH:35]=[CH:36][C:37]=3[Cl:38])[C:24]=2[CH2:23][O:22][CH:19]2[CH2:20][CH2:21][N:16]([C:12]3[CH:11]=[C:10]4[C:15]([C:7]([C:5]([OH:6])=[O:4])=[CH:8][N:9]4[CH3:40])=[CH:14][CH:13]=3)[CH2:17][CH2:18]2)[CH2:30][CH2:31]1
Reactant: COC(=O)c1cn(C)c2cc(N3CCC(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)CC3)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cn1cc(C(=O)O)c2ccc(N3CCC(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)CC3)cc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
A solution of 2M lithium hydroxide (1.2 mL, 2.46 mmol) is added to a solution of 6-{4-[5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-piperidin-1-yl}-1-methyl-1H-indole-3-carboxylic acid methyl ester (195 mg, 351.7 μmoles) in 1,4-dioxane (5 mL) and the mixture is stirred at 80° C. overnight. The organic solvent is removed and HCl (1M) is added until the solution reaches pH 3-4. The solid is filtered and washed with water and acetonitrile to provide the title compound (165 mg, 87%) as a white solid. ES/MS m/z 540.0 (M+1).
Reaction SMILES: CO[CH2:3][CH2:4][O:5][C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][N:13]([C:28]([O:30]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:12]2)[O:8][N:7]=1.Cl.[OH:41][CH:42]1[CH2:45][NH:44][CH2:43]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:4]([O:5][C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)[CH2:14][N:13]([C:28]([N:44]3[CH2:45][CH:42]([OH:41])[CH2:43]3)=[O:30])[CH2:12]2)[O:8][N:7]=1)[CH3:3]
Reactant: COCCOc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)n1
Reactant: OC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)N3CC(O)C3)C2)n1
Temperature: 150 °C
Yield: 17.8 %

Procedure:
110 mg (0.211 mmol) of the compound from Example 67A, 69.3 mg (0.633 mmol) of 3-hydroxyazetidine hydrochloride and 72.9 mg (0.527 mmol) of potassium carbonate were added to 3.5 ml of DMF and heated in a single-mode microwave (Emrys Optimizer) at 150° C. for 20 min. For workup, the reaction solution was combined and filtered, and the residue was purified by means of preparative HPLC. Enantiomer separation of 47.7 mg of the racemate according to Method 8D gave 14.7 mg of the title compound from Example 96 (enantiomer 1) and 17.1 mg of the title compound from Example 97 (enantiomer 2).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[CH:6][CH:5]=[CH:4][N:3]=1.S(OC(CC#C)C(=O)C)([C:21]1[CH:27]=[CH:26][C:24](C)=[CH:23][CH:22]=1)(=O)=O>C(O)C>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]2[N:3]([C:21]([CH2:22][C:23]#[CH:24])=[C:27]([CH3:26])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: C#CCC(OS(=O)(=O)c1ccc(C)cc1)C(C)=O
Reactant: COc1ccccc1COc1cccnc1N
Solvent: CCO
Product: C#CCc1c(C)nc2c(OCc3ccccc3OC)cccn12
Yield: 32 %

Procedure:
A solution of 2-amino-3-(2-methoxybenzyloxy)pyridine (3.50 g) and 3-tosyloxy-5-hexyn-2-one (4.86 g) in ethanol (30 ml) was stirred and refluxed for 24 hours and then evaporated in vacuo. To the residue was added an aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The oily residue was purified by column chromatography on silica gel (50 g) using chloroform as an eluent to give a solid, which was recrystallized from a mixture of ethyl acetate and n-hexane to give 8-(2-methoxybenzyloxy)-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (1.49 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH:6]=[O:7].[CH2:17]([Mg]Br)[CH3:18]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]([OH:7])[CH2:17][CH3:18])[CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: COc1cc(C=O)ccc1-c1ccccn1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1ccc(-c2ccccn2)c(OC)c1
Reaction time: 2 h

Procedure:
A solution of 3-methoxy-4-pyridin-2-ylbenzaldehyde (150 mg, 0.7 mmol) in THF (3 mL) was cooled to 0° C. and was treated with ethyl magnesium bromide (0.9 mL of a 1M solution in THF, 0.9 mmol). The reaction mixture was kept at 0° C. for 2 h before quenching with water (5 mL). The product was extracted into CH2Cl2 (3×10 mL), dried (MgSO4) and concentrated. The residue was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (1:4 to 1:1) to afford 1-(3-methoxy-4-pyridin-2-ylphenyl)propan-1-ol.
Reaction SMILES: Cl.[NH2:2][OH:3].O=[C:5]([C:11]1[N:12]=[CH:13][S:14][CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]>C(O)C>[OH:3][N:2]=[C:5]([C:11]1[N:12]=[CH:13][S:14][CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: NO
Reactant: CCOC(=O)C(=O)c1cscn1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(=NO)c1cscn1
Reaction time: 3 h

Procedure:
Hydroxylamine hydrochloride (1.37 g) was added to a stirred solution of ethyl 2-oxo-2-(4-thiazolyl)acetate (2.54 g) in ethanol (50 ml). The mixture was stirred for 3 h, the solvent was evaporated and the residue partitioned between ethyl acetate and sodium bicarbonate solution. The organic phase was washed with brine, dried over magnesium sulphate and evaporated. The residue was recrystallised from ethyl acetate to give the title oxime as a single isomer (1.315 g), m.p. 171-175° C.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([O:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[CH2:5][CH:4]([CH:14]=[CH:15][C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:3]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30].C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Na+].[Na+].[Na+].[BH4-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.CC(C)=O>[OH:1][CH:2]1[CH:6]([O:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[CH2:5][CH:4]([CH:14]=[CH:15][CH:16]([OH:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:3]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30]
Reactant: CCCCCC(=O)C=CC1CC(OC2CCCCO2)C(=O)C1CCCCCCC(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [BH4-]
Solvent: CO
Solvent: CC(C)=O
Product: CCCCCC(O)C=CC1CC(OC2CCCCO2)C(O)C1CCCCCCC(=O)O
Reaction time: 1.5 h
Yield: 74.9 %

Procedure:
A solution of 7-[2-oxo-5-(3-oxooct-1-enyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanoic acid [0.45 g.; prepared as described above in Example 2(g)] in methanol (10 ml.) was added to a stirred 2% w/v aqueous solution of sodium citrate (100 ml.) at -5°C. Potassium borohydride (1.6 g.) was then added portionwise, allowing the pH to change to pH 8 and then maintaining at pH 8 by the addition, when necessary, of quantities of 10% w/v aqueous citric acid solution. When the addition of the potassium borohydride was complete, the solution was stirred for 90 minutes, meanwhile maintaining the pH at pH 8 by means of the addition of further quantities of the citric acid solution, and allowing it to attain room temperature. The solution was then treated with acetone (50 ml.), treated with a further quantity of the citric acid solution to bring the pH to pH 4, saturated with sodium chloride and extracted three times with diethyl ether. The combined ethereal extracts were washed with a saturated solution of sodium chloride in 2N hydrochloric acid, and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulphate. The solvent was removed in vacuo to give crude 7-[2-hydroxy-5-(3-hydroxyoct-1-enyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanoic acid (0.34 g.), νmax 1700 cm-1, 980 cm-1, which was used as starting material in the following preparation (i) of 7-[2,3-dihydroxy-5-(3-hydroxyoct-1-enyl)cyclopentyl]heptanoic acid without further purification being necessary.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][C:18]=1[S:26](=[O:29])(=[O:28])[NH2:27].[NH2:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH3:44])[CH2:33][CH2:32]1.Cl.[OH-].[Na+]>O1CCCC1>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:30][N:31]2[CH2:32][CH2:33][N:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])[CH2:35][CH2:36]2)=[O:23])=[CH:19][C:18]=1[S:26](=[O:29])(=[O:28])[NH2:27]
Reactant: COc1ccccc1N1CCN(N)CC1
Reactant: NS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(NC(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)CC1
Temperature: 25 °C

Procedure:
To a solution of 1.8 g of N,N'-dicyclohexylcarbodiimide in 5 ml tetrahydrofuran was added a solution of 2.1 g of 4-chloro-3-sulfamoylbenzoic acid in 20 ml of tetrahydrofuran under stirring at room temperature. After the addition was completed, the mixture was stirred at room temperature for 20 minutes, then 0.83 g of 1-amino-4-(2-methoxyphenyl)piperazine was added, and the reaction mixture was stirred for 5 hours. Then 5 ml of 10% hydrochloric acid was added and stirred at room temperature for 10 minutes. 250 ml of 2% sodium hydroxide solution was added and insoluble materials were filtered off. The filtrate was alkalized with 2% sodium hydroxide solution to give white precipitate. The resulting precipitate was filtered, washed with water and recrystallized from ethanol to afford a title compound in a yield of 0.84 g (49%) as colorless crystals, mp 232°-235° C.
Reaction SMILES: BrCC1CC1(F)F.Br[CH2:9][CH:10]([CH3:12])[CH3:11].[CH3:13][C:14]1[N:15]=[C:16]([N:24]2[CH2:28][CH2:27][NH:26][C:25]2=[O:29])[S:17][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:9]([N:26]1[CH2:27][CH2:28][N:24]([C:16]2[S:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]([CH3:13])[N:15]=2)[C:25]1=[O:29])[CH:10]([CH3:12])[CH3:11]
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: CC(C)CBr
Agent: FC1(F)CC1CBr
Product: CCOC(=O)c1sc(N2CCN(CC(C)C)C2=O)nc1C
Yield: 98 %

Procedure:
Following the procedure as described in Preparation 13, making variations to replace bromomethyl-2,2-difluorocyclopropane with 1-bromo-2-methylpropane to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 98% yield: MS (ES+) m/z 311.8 (M+1).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.Cl.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]1[N:38]=[C:37]([CH:39]2[CH2:44][CH2:43][NH2+:42][CH2:41][CH2:40]2)[O:36][N:35]=1>ClCCl>[C:2]1([C:1]([N:42]2[CH2:43][CH2:44][CH:39]([C:37]3[O:36][N:35]=[C:34]([C:30]4[S:29][CH:33]=[CH:32][CH:31]=4)[N:38]=3)[CH2:40][CH2:41]2)=[O:9])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1csc(-c2noc(C3CC[NH2+]CC3)n2)c1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCC(c2nc(-c3cccs3)no2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
67.40 mg (1 eq.) of benzoic acid, 106 mg (1 eq.) of EDCI and 165 μl (2 eq.) of triethylamine were dissolved in 2 ml of dichloromethane. 150 mg (1 eq.) of 4-(3-thiophen-2-yl[1,2,4]oxadiazol-5-yl)piperidinium hydrochloride dissolved in 2 ml of dichloromethane and 165 μl (2 eq.) of triethylamine were added to the reaction medium, which was stirred at room temperature overnight. The reaction medium was evaporated under reduced pressure and the residue was chromatographed on a thick layer (eluent: CH2Cl2/MeOH (98/2: v/v)) to give 98 mg (52%) of the expected product.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH2:7][NH:8][C:9](=O)[CH3:10])=[CH:5][CH:4]=1.B.CSC.Cl>C1COCC1>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:13]=[CH:12][C:6]([CH2:7][NH:8][CH2:9][CH3:10])=[CH:5][CH:4]=1
Reactant: CC(=O)NCc1ccc(C(F)(F)F)cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: CCNCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
N-[4-(trifluoromethyl)benzyl]acetamide (3.085 g, 14.204 mmol) was dissolved in THF (100 ml) and was cooled to zero degrees under argon atmosphere. (Methylthio)methane compound with borane (1:1) (2.698 g, 35.511 mmol) was added and the mixture was refluxed over night at RT. HCl (15 ml, 10%) was gently added and was stirred overnight. The solvent was removed by evaporation Diethyl ether (20 ml) was added and the product was extracted to the water phase by K2CO3 (3×15 ml), the water phase was acidified by HCl (10 ml, 10%) and the product was extracted to the organic phase by EtOAc (3×15 ml). The organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 0.809 g of N-[4-(trifluoromethyl)benzyl]ethanamine (yield 28%).
Reaction SMILES: Cl.[CH2:2]([N:4]1[C:16]2[CH:15]=[CH:14][C:13]([CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24](=[NH:27])OC)[CH2:19]3)=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[CH:28]([NH:30][NH2:31])=O>N1C=CC=CC=1.O>[N:30]1[NH:31][C:24]([CH:20]2[CH2:21][CH2:22][CH2:23][N:18]([CH2:17][C:13]3[CH:14]=[CH:15][C:16]4[N:4]([CH2:2][CH3:3])[C:5]5[C:10]([C:11]=4[CH:12]=3)=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH2:19]2)=[N:27][CH:28]=1
Reactant: CCn1c2ccccc2c2cc(CN3CCCC(C(=N)OC)C3)ccc21
Reactant: NNC=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCn1c2ccccc2c2cc(CN3CCCC(c4ncn[nH]4)C3)ccc21
Temperature: 110 °C
Reaction time: 8 h
Yield: 0.8 %

Procedure:
A 100-mL round-bottomed flask was charged with a solution of methyl 1-((9-ethyl-9H-carbazol-3-yl)methyl)piperidine-3-carbimidate hydrochloride (1.44 g, 3.94 mmol, 1.00 equiv, 1.44%) in pyridine (20 mL) and formohydrazide (0.249 g, 4.07 mmol, 1.03 equiv, 0.249%). The resulting solution was stirred overnight at 110° C. in an oil bath. Upon completion, the resulting solution was cooled down to room temperature and diluted with water. This mixture was then extracted with ethyl acetate (3×30 mL). Combined organic layers were dried over anhydrous sodium sulfate. After filtration, organic later was concentrated on a rotary evaporator to give a residue that was purified by a silica gel column chromatography eluted with ethyl acetate/hexane (1:10) affording 3-((3-(2H-1,2,4-triazol-3-yl)piperidin-1-yl)methyl)-9-ethyl-9H-carbazole as white solid (0.011 g, 1%). LCMS: [M+H]+: 360. 1H NMR (CDCl3, 300 MHz) δ 11.55 (s, 1H), 8.10 (m, 3H), 7.68 (d, 1H), 7.50 (t, 1H), 7.38 (m, 2H), 7.25 (t, 1H), 4.35 (t, 3H), 3.76 (d, 2H), 3.50 (d, 1H), 2.66 (s, 1H), 2.32 (d, 1H), 2.12 (d, 1H), 2.01 (d, 1H), 1.84 (d, 1H), 1.55 (d, 1H), 1.39 (t, 3H).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][C:13]1([CH3:16])[CH2:15][CH2:14]1)[N:8]([CH3:17])[C:7]2=[O:18].[CH3:19][C@@H:20]1[C:24]2[NH:25][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:23]=2[C:22](=[O:37])[NH:21]1>>[CH3:17][N:8]1[C:7](=[O:18])[C:6]2[C:11](=[C:2]([C:26]3[NH:25][C:24]4[C@@H:20]([CH3:19])[NH:21][C:22](=[O:37])[C:23]=4[CH:27]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]1[O:12][C:13]1([CH3:16])[CH2:15][CH2:14]1
Reactant: Cn1c(OC2(C)CC2)nc2c(I)cccc2c1=O
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(C)c(OC5(C)CC5)nc34)[nH]c21
Yield: 30.7 %

Procedure:
This compound (66 mg, 31% yield) as a brown solid was prepared according to the procedure described for Example 448, using 8-iodo-3-methyl-2-(1-methylcyclopropoxy)quinazolin-4(3H)-one (717) (210 mg, 0.59 mmol) and (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705) (201 mg, 0.76 mmol) as the starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.21 (1H, br.), 8.18 (1H, d, J=7.8 Hz), 7.94 (1H, d, J=7.6 Hz), 7.74 (1H, s), 7.41 (1H, t, J=7.7 Hz), 7.16 (1H, s), 4.65 (1H, d, J=6.5 Hz), 3.36 (3H, S), 1.78 (3H, s), 1.39 (3H, d, J=6.5 Hz), 1.25 (2H, m), 0.94 (2H, m). m/z (ESI, +ve) 365.0 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:42]/[CH:43]=[CH:44]/[C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:50][CH3:51])[CH2:46][CH3:47]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:42]/[CH:43]=[CH:44]/[C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:54][CH3:55])([CH2:50][CH3:51])[CH2:52][CH3:53])[CH2:46][CH3:47])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(/C=C/CBr)(CC)O[Si](CC)(CC)CC
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(/C=C/CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Yield: 100.5 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5(10 μl) and (E)-1-bromo-4-ethyl-4-triethylsilyloxy-2-hexene (134 mg, 0.420 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) to give the title compound as a colorless oil (86.0 mg, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][C@@:5]12[C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[N:25][CH:26]=1>>[Cl:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[S:8][CH2:7][CH2:6][C@@:5]23[C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]2)[CH:24]=[N:25][CH:26]=1
Reactant: OB(O)c1cncc(Cl)c1
Reactant: NC1=N[C@@]2(CCSc3ccc(Br)cc32)C(F)(F)CO1
Product: NC1=N[C@@]2(CCSc3ccc(-c4cncc(Cl)c4)cc32)C(F)(F)CO1
Yield: 70 %

Procedure:
In a manner analogous to that described in Example 19, the cross coupling reaction of (R)-6′-bromo-5,5-difluoro-5,6-dihydrospiro[[1,3]oxazine-4,4′-thiochroman]-2-amine (intermediate B6.9) with 5-chloropyridin-3-ylboronic acid yielded the title compound (70% yield) as a white solid. MS (ISP): m/z=382.0 [M+H]+.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH2:5]([OH:11])[CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[H-].[Na+].C(O)(O)CCCC>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:11])[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: OCCCCCO
Agent: CCCCC(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOCCCCCO
Reaction time: 8 h
Yield: 22.3 %

Procedure:
Allyl bromide (2.5 mL, 0.029 mol) was added dropwise to the mixture of 1,5-pentanediol (3 g, 0.029 mol) and sodium hydride (1.2 g, 80% dispersion in oil) in dry dimethylformamide. Stirring was continued overnight at room temperature. Tol.c. (2:1 - toluene and ethyl acetate) still indicated the presence of some unreacted pentanediol. The unreacted sodium hydride was destroyed by addition of methanol. The mixture was concentrated to 50 mL by evaporation in vacuo. After dilution with methylene chloride (150 mL), the solvents were washed with water (three times), dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel using a 2:1 mixture of toluene and ethyl acetate as eluant. The appropriate fractions gave compound 29 (0.931 g, 30%). 1H-n.m.r. (CDCl3): 5.83 (m, 1H, --CH=), 5.20 (m, 2H, =CH2), 3.95 (dd, 1H, J=5.5 and 1.0 Hz, allylics), 3.66 and 3.46 (two t, 2H each, J=6.5 Hz, O--CH2), 1.64 (m, 4H) and 1.44 (m, 2H): methylenes); 13C-n.m.r.(CDCl3): 134.7 and 116.6 (ethylenics), 71.6, 70.1 (CH2 --O--CH2), 62.1 (CH2OH) 32.2, 29.2 and 22.2 (methylenes).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[CH:19]1(B(O)O)[CH2:21][CH2:20]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH:19]1([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[CH2:10][C@H:9]3[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=2)[CH2:21][CH2:20]1
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(Br)cc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(C2CC2)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 76.2 %

Procedure:
To a 30-mL microwave tube were added tert-butyl (trans-2-(4-bromophenyl)cyclopropyl)carbamate (400 mg, 1.281 mmol), cyclopropylboronic acid (143 mg, 1.666 mmol), potassium phosphate (952 mg, 4.48 mmol), tricyclohexylphosphine (35.9 mg, 0.128 mmol), toluene (4 mL) and water (0.2 mL), and the mixture was degassed by bubbling N2. Palladium(II) acetate (14.38 mg, 0.064 mmol) was added and the tube was sealed. The mixture was heated at 100° C. with stirring for 4 h. The mixture was cooled and quenched with water (5 mL) and extracted with EtOAc (3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica gel, 0 to 70% EtOAc/hexanes) to give 267 mg of product as pale yellow solid. MS: (M+H)+=274.2. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.61-0.73 (m, 2H), 0.90-1.01 (m, 2H), 1.08-1.24 (m, 2H), 1.42-1.52 (s, 9H), 1.81-1.94 (m, 1H), 1.98-2.12 (m, 1H), 2.70 (br. s., 1H), 6.91-7.12 (m, 4H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:5]=2[O:4][CH2:3]1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH:34]=O)=[CH:26]1>CO.N1CCCCC1>[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](/[CH:34]=[C:3]2\[O:4][C:5]3[C:10]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]4)=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]\2=[O:1])=[CH:26]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2OCC3=O)CC1
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
A solution of tert-butyl 4-[(3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0251 g, 0.0755 mmol) in methanol (2 mL) was added with 1H-indole-3-carboxaldehyde (0.0115 g, 0.0793 mmol) and piperidine (5 drops), and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0305 g, 88%).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([CH:16]=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH2:18]([O:25][NH2:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][N:26]=[CH:16][C:14]1[O:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCc1cc(-c2ccc(C=O)o2)c(C)[nH]c1=O
Reactant: NOCc1ccccc1
Product: CCc1cc(-c2ccc(C=NOCc3ccccc3)o2)c(C)[nH]c1=O

Procedure:
Example 198 is substantially repeated except for utilizing 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl]furan-2-carbaldehyde and benzyloxyamine to afford the title compound. MS: m/e=337 (M+H).