Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[S:15][C:5]=2[NH:6][C:7]2[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:8]=2[N:9]=1.[C:22]1([CH3:28])C=CC=CC=1>>[F:14][C:12]1[CH:11]=[CH:10][C:8]2[N:9]=[C:3]([N:2]3[CH2:28][CH2:22][N:6]([CH3:7])[CH2:5][CH2:4]3)[C:4]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[S:15][C:5]=3[NH:6][C:7]=2[CH:13]=1
Reactant: Cc1ccccc1
Reactant: NC1=Nc2ccc(F)cc2Nc2sc3ccccc3c21
Agent: Cl
Product: CN1CCN(C2=Nc3ccc(F)cc3Nc3sc4ccccc4c32)CC1
Temperature: 70 °C

Procedure:
12-Amino-8-fluoro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine hydrochloride (102 g) was suspended in toluene (600 ml), and the mixture was stirred under reflux with heating for 3 hours to remove water. The mixture was cooled to 70° C. under a nitrogen atmosphere, and N-methylpiperazine (300 ml) was added. The mixture was stirred with heating under a nitrogen atmosphere until the inside temperature reached 120° C. while removing toluene for 1.5 hours. The mixture was heated under a nitrogen atmosphere at 120° C. for 2.5 hours and cooled to 25° C. under a nitrogen atmosphere. Ethyl acetate (600 ml) and water (450 ml) were added to the reaction mixture for extraction and the obtained ethyl acetate layer was washed three times with water (300 ml). After confirming pH 7-8 of washing water, the solvent was concentrated under reduced pressure. Acetonitrile (100 ml) was added and the mixture was azeotropically concentrated to dryness under reduced pressure. To the residue was added acetonitrile (300 ml) and the mixture was heated for dissolution. The solution was cooled and stirred at −10° C.-−5° C. for 2.5 hours to allow precipitation of crystals. The precipitated crystals were filtered by suction and washed with acetonitrile (100 ml), followed by drying to give 8-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine (65.5 g).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:3]12[CH3:4])[C@:16]1([CH2:20][C:21]#[CH:22])[C:11](=[CH:12][C:13](=O)[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[CH3:24][C@@]12[C@@H](O)CC[C@H]1[C@@H]1CCC3[C@@](C)([C@H]1CC2)CCC(=O)C=3>>[CH2:24]=[C:13]1[CH2:14][CH2:15][C@@:16]2([CH2:20][C:21]#[CH:22])[C:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:17]2[CH2:18][CH2:19][C@@:3]2([CH3:4])[C@H:5]3[CH2:6][CH2:7][C@@H:2]2[OH:1])=[CH:12]1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: C#CC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Product: C#CC[C@]12CCC(=C)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12

Procedure:
To obtain the compounds of the present invention in which R4 is =CH2, 17β-hydroxy-10-(2-propynyl)estr-4-en-3-one is used as the starting material. This testosterone derivative is subjected to a Wittig reaction to give 3-methylene-10-(2-propynyl)estr-4-en-17β-ol. The 17-hydroxy group is then oxidized to the corresponding ketone and a hydroxyacetyl side chain is introduced at the 17-position using methyl methoxyacetate and the general procedure described earlier.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[OH:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>>[OH:25][CH:26]1[CH2:30][CH2:29][N:28]([CH2:22][C:17]2[CH:16]=[C:15]3[C:20]([CH:21]=[C:12]([C:10]4[N:11]=[C:7]([C:4]5[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=5)[S:8][CH:9]=4)[C:13](=[O:24])[NH:14]3)=[CH:19][CH:18]=2)[CH2:27]1
Reactant: OC1CCNC1
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Product: O=c1[nH]c2cc(CN3CCC(O)C3)ccc2cc1-c1csc(-c2ccncc2)n1

Procedure:
This compound was prepared according to the method described in example 8768 employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and 3-hydroxypyrrolidine to give a yellow solid. MS m/z: 405.4 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.O1CCCC1.[F-].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)C>[NH2:22][C:21]1[CH:20]=[CH:19][C:4]([CH2:5][CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:10][CH2:11]2)=[CH:3][C:2]=1[F:1]
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2ccc([N+](=O)[O-])c(F)c2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(N)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
A flask was charged with palladium (II)acetate (1.486 mmol, 0.334 g), tert-butyl 4-(3-fluoro-4-nitrobenzylidene)piperidine-1-carboxylate (29.7 mmol, 10 g) and tetrahydrofuran (15 mL) and sealed and purged with nitrogen. A solution of potassium fluoride (59.5 mmol, 3.45 g, in 50 ml water) was added via a syringe. Polymethylhydrosiloxane (119 mmol, 7.13 mL) was added dropwise (caution, gas evolution) and the reaction stirred at room temperature for 1 hour. Diethyl ether (10 mL) was added to the reaction mixture. After 5 minutes of stirring the reaction mixture was filtered through celite and diluted with water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by silica column chromatography (eluent: 20%-50% ethyl acetate in heptane) to give the intermediate tert-butyl 4-(4-amino-3-fluorobenzyl)piperidine-1-carboxylate (9.23 g).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]=[CH2:13])=[CH:7][C:6]=1[O:14][CH3:15])=[O:3].[CH2:16]([OH:20])[CH2:17][CH2:18][OH:19]>>[CH3:15][O:14][C:6]1[CH:7]=[C:8]([CH2:11][CH:12]=[CH2:13])[CH:9]=[CH:10][C:5]=1[O:4][C:2]([O:19][CH2:18][CH2:17][CH2:16][OH:20])=[O:3]
Reactant: OCCCO
Reactant: C=CCc1ccc(OC(=O)Cl)c(OC)c1
Product: C=CCc1ccc(OC(=O)OCCCO)c(OC)c1

Procedure:
The reaction of 2-methoxy-4-allylphenyl chloroformate with 1,3-propanediol yields 1-(2-methoxy-4-allylphenoxycarbonyloxy)-3-propanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([O:16][CH3:17])[NH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:18]([O:21][CH2:22][C:23]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=[CH:25][C:24]=1[N:38]1[CH2:50][CH2:49][N:41]2[C:42]3[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=3[CH:48]=[C:40]2[C:39]1=[O:51])(=[O:20])[CH3:19].COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>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.CO.CCOCC.O.CCOC(C)=O>[C:18]([O:21][CH2:22][C:23]1[C:24]([N:38]2[CH2:50][CH2:49][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[CH:48]=[C:40]3[C:39]2=[O:51])=[CH:25][CH:26]=[CH:27][C:28]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([O:16][CH3:17])[NH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: COc1cc(Nc2cc(Br)cn(C)c2=O)n[nH]1
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
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cc(-c3cccc(N4CCn5c(cc6c5CCCC6)C4=O)c3COC(C)=O)cn(C)c2=O)n[nH]1
Temperature: 130 °C
Yield: 19.8 %

Procedure:
A microwave tube equipped with a magnetic stirrer was charged with 157a (94 mg, 0.3 mmol), 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a (180 mg, 0.4 mmol), DME (4 mL) and 1M aqueous sodium carbonate (0.9 mL). After bubbling N2 for 15 min, Pd(PPh3)4 (18 mg, 0.02 mmol) was added. The mixture was heated in microwave to 130° C. for 25 min. After this time, EtOAc (5 mL) and water (5 mL) were added. The separated aqueous layer was extracted with EtOAc (2×5 mL). The combined organics were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography eluting with a gradient of CH2Cl2-60:35:5 CH2Cl2:Et2O:MeOH to afford a 19% yield (33 mg) of 157b.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.[NH2:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>C([O-])([O-])=O.[Na+].[Na+].C(#N)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([C:23]3[CH:24]=[C:19]([NH2:18])[CH:20]=[CH:21][CH:22]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Reactant: Nc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Nc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Yield: 99 %

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (300 mg), 3-aminophenylboronic acid (134 mg), and bis(triphenylphosphine)palladium(II) dichloride (55 mg) in 0.6 mL of 1M Na2CO3 aqueous solution and 0.6 mL of acetonitrile was heated to 100° C. in a sealed microwave reactor for 15 min. The reaction mixture was diluted with ethyl acetate (80 mL), washed with H2O (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to yield 270 mg of 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine.
Reaction SMILES: [C-]#N.[Na+].C1(C)C=CC=CC=1.C[NH:12][CH2:13][CH2:14]NC.Br[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25]C=2)[CH:21]=[CH:20][CH:19]=1>N.[Cu]I>[C:14]1([C:13]#[N:12])[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: CNCCNC
Reactant: Brc1cccc2ccccc12
Agent: [Cu]I
Agent: N
Agent: [C-]#N
Solvent: Cc1ccccc1
Product: N#Cc1cccc2ccccc12
Temperature: 130 °C
Reaction time: 24 h
Yield: 94.3 %

Procedure:
A Schlenk tube was charged with NaCN (95 mg, 1.94 mmol), CuI (31 mg, 0.16 mmol, 10 mol %), and KI (54 mg, 0.33 mmol, 20 mol %), briefly evacuated and backfilled with argon three times. Anhydrous toluene (1.2 mL), N,N′-dimethylethylenediamine (175 μL, 1.64 mmol), and 1-bromonaphthalene (225 μL, 1.62 mmol) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 130° C. for 24 h. The resulting suspension was allowed to reach room temperature, diluted with 30% aqueous ammonia (2 mL) and extracted with ethyl acetate (4×2 mL). The combined organic phases were dried over MgSO4, concentrated, and the residue was purified by flash chromatography on silica gel (hexane/ethyl acetate 20:1) to provide the desired product as a pale yellow solid (234 mg, 94% yield). Mp 35-36° C. (lit. 37° C., See Blum, J.; Oppenheimer, E.; Bergmann, E. J. Am. Chem. Soc. 1967, 89,2338). 1H NMR (400 MHz, CDCl3, J values are reported in Hz, lit. See Abraham, R. J.; Reid, M. Magn. Reson. Chem. 2000, 38, 570): δ 8.27 (d, J=8.4, 1H), 8.11 (d, J=8.3, 1H), 7.96 (d, J=8.1, 1H), 7.94 (dd, J=7.2, J=1.1, 1H), 7.73 (ddd, J=8.3, J=6.9, J=1.34, 1H), 7.65 (ddd, J=8.3, J=7.1, J=1.2, 1H), 7.55 (dd, J=8.3, J=7.1, 1H); 13C NMR (100 MHz, CDCl3): 133.7, 133.2, 133.1, 132.8, 129.1, 129.0, 128.0, 125.6, 125.4, 118.3, 110.6; IR (neat, cm−1): 2222, 1604, 1513, 1376, 855, 802, 772, 684, 451. Anal. Calcd. for C11H7N: C, 86.25; H, 4.61; N, 9.14. Found: C, 86.04; H 4.61; N 9.05.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:10]([O:18]C)=[N:11][C:12]([CH3:17])=[CH:13][C:14]=1[O:15][CH3:16])(C)(C)C>Cl.CCO>[NH2:7][CH2:8][C:9]1[C:10]([OH:18])=[N:11][C:12]([CH3:17])=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1cc(C)nc(OC)c1CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: COc1cc(C)nc(O)c1CN
Yield: 63 %

Procedure:
tert-butyl((2,4-dimethoxy-6-methylpyridin-3-yl)methyl)carbamate (83 g, 294 mmol) was dissolved in 4 N HCl/H2C (830 ml). Then the mixture was refluxed for 4.5 h. (The reaction mixture was monitored by MS spectrum to make sure the methyl group at 2-position de-protect completely.) After the reaction completed, the mixture was concentrated under vacuum to give a brown oil. The oil was suspended in EtOH (300 ml) for 15 min to give a yellow precipitate. The precipitate was filtered, washed with ethanol (100 ml) and MTBE (100 ml) and dried under high vacuum to give 38 g of fraction 1 3-(aminomethyl)-4-methoxy-6-methylpyridin-2-ol (Purity 98% by LCMS, yield 63%) as a yellow powder. In the meantime, the filtration from fraction 1 was concentrated under vacuum and the residue was solidified by ethanol (100 ml). The precipitate was filtered, washed with ethanol (100 ml) and MTBE (100 ml) and dried under high vacuum to give 20 g of fraction 2 3-(aminomethyl)-4-methoxy-6-methylpyridin-2-ol (Purity 94% by LCMS, yield 33%) as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[C:6]([F:8])[CH:7]=1.[Cl:11][CH2:12][CH2:13][C:14](Cl)=[O:15].Cl>[Cl-].[Zn+2].[Cl-].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.O1CCCC1>[Cl:11][CH2:12][CH2:13][C:14]([C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:15]
Reactant: O=C(Cl)CCCl
Reactant: Fc1cc(Cl)cc([Mg]Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=C(CCCl)c1cc(F)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A reaction flask (500 mL) containing zinc chloride (6.98 g, 51.2 mmol) was dried by heating using a heat gun under vacuum. After cooling to room temperature, a solution of 3-chloro-5-fluorophenylmagnesium bromide (0.5 M in dry tetrahydrofuran, 100 mL, 50.0 mmol) was added to the reaction flask via a cannula, and the mixture was stirred until all zinc chloride solid was dissolved and the formation of a sluggish bright yellow solution (˜1 h). A warm bath (40° C.) may be applied to complete this process. Anhydrous tetrahydrofuran (100 mL) was added, followed by tetrakis(triphenylphosphine)palladium (2.89 g, 2.50 mmol, 0.05 equiv.). After cooling to 0° C., 3-chloropropionyl chloride (5.05 mL, 52.5 mmol, 1.05 equiv.) was added dropwise and the mixture was stirred at 0° C. for 2 h. The reaction mixture was acidified with an aqueous hydrochloric acid solution (3N), then extracted with diethyl ether (2×250 mL). The combined ether extracts were washed with a saturated aqueous sodium bicarbonate solution, brine, dried (anhydrous sodium sulfate), and concentrated. The crude oil was purified by Isco CombiFlash Companion column chromatography (silica gel, 0-15% ethyl acetate/hexane) and the resulting white solid was recrystallized (minimal diethyl ether/hexane/−25° C.) to give pure 3-chloro-1-(3-chloro-5-fluorophenyl)propan-1-one as a white powder. Yield: 5.54 g (50%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([CH:11](OCC)[O:12]CC)[N:8]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[C:6]=2[N:7]=1.Cl.[OH-].[Na+].C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([CH:11]=[O:12])[N:8]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[C:6]=2[N:7]=1
Reactant: CCOC(OCC)c1cc2cnc(Cl)nc2n1C(CC)CC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCC(CC)n1c(C=O)cc2cnc(Cl)nc21
Reaction time: 0.5 h
Yield: 107.3 %

Procedure:
To a solution of 2-chloro-6-diethoxymethyl-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine (67 mg, 0.2 mmol) in 1,4-dioxane (0.7 mL) is added conc. HCl (0.2 mL) at ambient temperature. The reaction mixture is stirred for 30 min, then neutralized with 2N NaOH aqueous solution and saturated NaHCO3 aqueous solution. The mixture is extracted with EtOAc. The extracts are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 54 mg of 2-chloro-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde as a yellow solid. The crude product is used as it is.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][C:9]=1[OH:10])([O-:3])=[O:2].[CH2:18](Br)[CH:19]=[CH2:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][C:9]=1[O:10][CH2:20][CH:19]=[CH2:18])([O-:3])=[O:2]
Reactant: CCOC(=O)C(C)c1ccc(O)c([N+](=O)[O-])c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(C)C(=O)OCC)cc1[N+](=O)[O-]

Procedure:
A mixture of 2.39g of ethyl 2-(3-nitro-4-hydroxyphenyl)propionate, 1.45g of allylbromide and 1.65g of potassium carbonate in 20ml of acetone was refluxed for 4 hours. After cooling, the solvent was distilled under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. After the solution was dried over magnesium sulfate, the solvent was distilled off. The thus obtained oily substance was purified by means of silica gel chromatography, to give the object compound in a yield of 2.51g (90%).
Reaction SMILES: C1C(=O)N(Cl)C(=O)C1.[CH:9](=[N:16][OH:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br:18][C:19]1[N:20]=[C:21]([C:40]#[CH:41])[C:22]([N:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:23][CH:24]=1.CCN(CC)CC>CN(C=O)C>[Br:18][C:19]1[N:20]=[C:21]([C:40]2[O:17][N:16]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:41]=2)[C:22]([N:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[N:23][CH:24]=1
Reactant: C#Cc1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: ON=Cc1ccccc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc(-c2ccccc2)no1
Temperature: 55 °C
Reaction time: 0.75 h
Yield: 44.3 %

Procedure:
NCS (12.19 g, 91.26 mmol) was added to a solution of benzaldehyde oxime (10.05 g, 82.96 mmol) in DMF (40.20 mL) and the mixture heated at 55° C. for 15 minutes. The reaction mixture was cooled to ambient temperature and tert-butyl N-(5-bromo-3-ethynyl-pyrazin-2-yl)-N-tert-butoxycarbonyl-carbamate (36.34 g, 91.26 mmol) and DMF (30.15 mL) were added followed by the dropwise addition of Et3N (10.07 g, 13.87 mL, 99.55 mmol). The reaction mixture was stirred at ambient temperature for 45 minutes and then heated to 65° C. for 1 hour. The reaction mixture was cooled to ambient temperature and the solvent removed under high vacuum. The residue was taken up in ethyl acetate (50 ml). Remaining solid was filtered off and the filtrate concentrated in vacuo and then purified by column chromatography on silica using the ISCO column companion system, eluting with ethyl acetate/petroleum ether (0-40% EtOAc). Product fractions were combined and concentrated in vacuo to give tert-butyl (5-bromo-3-(3-phenylisoxazol-5-yl)pyrazin-2-yl)-N-tert-butoxycarbonyl-carbamate as a pale yellow solid (19 g, 46%). LC/MS m/z 419 [M−100+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.CC(C)([O-])C.[Na+]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)cc1
Reactant: C1COCCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: Cc1ccc(N2CCOCC2)cc1
Yield: 97.9 %

Procedure:
According to the general procedure B, 4-methylchlorobenzene (71 mg, 0.56 mmol) reacted with morpholine (46 mg, 0.53 mmol) using 1 mol % of catalyst and sodium tert-butoxide (60 mg, 1.03 mmol) at 70° C. for 27 h to give the title compound (92 mg, 98%) as a solid: 1H-NMR (300 MHz, CDCl3): δ 7.12 (d, 2H, J=8.7 Hz), 6.87 (d, 2H, J=8.7 Hz), 3.89 (t, 4H, J=4.8 Hz), 3.14 (t, 4H, J=4.8 Hz), 2.31 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 149.09, 129.64, 129.51, 115.97, 66.90, 49.86, 20.38. GC/MS(EI): m/z 177 (M+).
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][C@@H:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[C@H:6]([CH:14]=O)[CH2:5]1)[CH:2]=[CH2:3].[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N1C[C@@H](C2C=CSC=2)[C@H](C=O)C1)C1C=CC=CC=1>>[CH2:1]([N:4]1[CH2:8][C@@H:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[C@H:6]([CH2:14][N:26]2[CH2:27][CH2:28][CH:23]([C:20]3[CH:19]=[CH:18][C:17]([F:16])=[CH:22][CH:21]=3)[CH2:24][CH2:25]2)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: C=CCN1C[C@@H](C=O)[C@H](c2ccsc2)C1
Agent: O=C[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccsc1
Product: C=CCN1C[C@@H](CN2CCC(c3ccc(F)cc3)CC2)[C@H](c2ccsc2)C1

Procedure:
The title compound was prepared from 1-allyl-3-(S)-formyl-4-(R)-(3-thienyl)pyrrolidine and 4-(4-fluorophenyl)piperidine by according to procedures described in Example 241, Step 5 with the change that 1-Allyl-3-(S)-formyl-4-(R)-(3-thienyl)pyrrolidine replaced 1-benzyl-3-(S)-formyl-4-(R)-(3-thienyl)pyrrolidine. 1H NMR (CDCl3) is consistent with structure.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1
Reactant: C1CCNC1
Reactant: O=Cc1ccc(Cl)cc1F
Product: O=Cc1ccc(Cl)cc1N1CCCC1

Procedure:
The title compound was prepared from 4-chloro-2-fluorobenzaldehyde and pyrroldine according to the representative procedures of Example 56, Step 1: 1H NMR 400 MHz (CDCl3) δ 10.04 (s, 1H), 7.64 (d, J=8.1 Hz, 1H), 6.82 (s, 1H), 6.77 (d, J=8.4 Hz, 1H), 3.41-3.33 (m, 4H), 2.06-1.96 (m, 4H). LCMS (ESI, m/z): 210 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[C:47]1([CH2:53][CH2:54][C:55](Cl)=[O:56])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(N(CC)CC)C>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:55](=[O:56])[CH2:54][CH2:53][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:43]=[CH:44][CH:45]=2)=[N:8]1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCc1ccccc1)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) in 2.5 mL of tetrahydrofuran was added 3-phenyl propanoyl chloride (0.084 g, 0.498 mmol), followed by triethyl amine (0.173 mL, 1.24 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was then partitioned between ethyl acetate and water. (Yield not calculated) ES-MS (m/z) 735 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C:15]([OH:17])=O)[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:21])=O>C(Cl)(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C:15]([Cl:21])=[O:17])[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)c1ccc(-c2csc(C(=O)O)n2)cc1
Solvent: ClC(Cl)Cl
Product: CC(C)c1ccc(-c2csc(C(=O)Cl)n2)cc1
Reaction time: 3 h

Procedure:
4-(4-Isopropyl-phenyl)-thiazole-2-carbonyl chloride was prepared by refluxing a mixture of 4-(4-Isopropyl-phenyl)-thiazole-2-carboxylic acid (50 mg) and oxalyl chloride (300 μl) in chloroform (5 mL). After 3 h, the volatiles were evaporated and the residue was dried under high vacuum to provide the acid chloride (50 mg).