Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:11]([CH2:13][C:14](OCC)=[O:15])#[N:12]>CN(C)C=O.C(OCC)(=O)C>[C:11]([CH2:13][C:14]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[O:15])#[N:12]
Reactant: NCCc1ccc(O)cc1
Reactant: CCOC(=O)CC#N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCC(=O)NCCc1ccc(O)cc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
1.28 g (9.33 mmol) of tyramine is added to a solution containing 1.00 g (8.84 mmol) of ethyl cyanoacetate in 13 mL of dimethylformamide under an inert atmosphere. The mixture is stirred at 110° C. for 4 hours, then at room temperature for 12 h. The reaction medium is then diluted in 100 mL of ethyl acetate and washed with 50 mL of an aqueous acid solution at pH=3. The aqueous phase is again extracted with 50 mL of ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and the solvent is evaporated under reduced pressure. The resulting viscous brown solid is then dissolved several times in toluene and the toluene azeotrope/DMF is evaporated. Finally, the solid is washed with dichloromethane and ether. The product is isolated in the form of a pale brown solid with a yield of 65%.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](N1C=CN=C1)(N1C=CN=C1)=[S:20]>CN(C)C=O>[CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[CH:14][C:15]([N:18]=[C:19]=[S:20])=[CH:16][CH:17]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(N2CCN(C3CCCC3)CC2)cc1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: S=C=Nc1ccc(N2CCN(C3CCCC3)CC2)cc1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 93.2 %

Procedure:
A solution of 4-[4-(1-cyclopentyl)-1-piperazinyl]benzenamine (5.7 g, 22.4 mmol) (from Step B above) in N,N-dimethylformamide (75 mL) was added dropwise over 20 min to a cooled (−15° C.) solution of thiocarbonyldiimidazole (4 g, 22.5 mmol) (Aldrich) in N,N-dimethylformamide (40 mL). After the addition was complete, the mixture was stirred at −15° C. for 20 min, then the cooling bath was removed and the solution was stirred for 1 hr. then poured into ice-water (1500 mL), stirred for 30 min. then the precipitate filtered and washed with water and dried under vacuum to give 4-cyclopentyl-1-(4-isothiocyanatophenyl)piperazine (6 g, 93%)
Reaction SMILES: [C:1]([CH2:4]/[CH:5]=[CH:6]/[C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=[C:9]([CH3:26])[N:8]=1)([OH:3])=[O:2].ClC1C=C(C=CC=1)C(OO)=[O:32].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([CH2:4]/[CH:5]=[CH:6]/[C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=[C:9]([CH3:26])[N+:8]=1[O-:32])([OH:3])=[O:2]
Reactant: CCCCCCCCCCCCOc1ccc(C)nc1/C=C/CC(=O)O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCCCCCCOc1ccc(C)[n+]([O-])c1/C=C/CC(=O)O
Reaction time: 0.5 h

Procedure:
2-(E-2-Carboxymethylethenyl)-3-dodecyloxy-6-methylpyridine (2.15 g, 5.95 mmol) was dissolved in dry CH2Cl2 (20 mL) and cooled to 0∞C.; 85% m-chloroperoxybenzoic acid (1.45 g, 7.14 mmol) was added and the reaction was stirred at 0∞C. for 30 minutes and at room temperature for 16 hours. The reaction solution was poured into saturated aqueous NaHCO3 (20 mL). The aqueous phase was extracted with CH2Cl2 (3×20 mL) and the combined CH2Cl2 extracts were washed with H2O (20 mL) and brine and dried (MgSO4). The crude pale yellow solid was used directly in the next step without further purification: 1H NMR (250 MHz, CDCl3): δ8.23 (d, J=16.2 Hz, 1H, olefin), 7.58 (d, J=16.2 Hz, 1H, olefin), 7.13 (d, J=8.8 Hz, 1H, 5-pyridyl), 6.79 (d, J=8.8 Hz, 1H, 4-pyridyl), 4.06 (t, J=6.6 Hz, 2H, OCH2), 3.81 (s, 3H, CO2CH3), 2.45 (s, 3H, CH3), 1.92-0.85 (m, 23H, aliphatic); MS (CI): 378.2 (M+H).
Reaction SMILES: C1(C=[CH:8][C:9]([C:11]2[CH:16]=C[CH:14]=[CH:13][CH:12]=2)=[O:10])C=CC=CC=1.[Li].C(=O)C.C(#[N:23])C>>[C:9]([C:11]1[CH:16]=[N:23][CH:14]=[CH:13][CH:12]=1)(=[O:10])[CH3:8]
Reactant: CC#N
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Agent: CC=O
Agent: [Li]
Product: CC(=O)c1cccnc1

Procedure:
In a variation on this chalcone procedure, the lithium compound IV can be reacted with acetonitrile or with acetaldehyde followed by oxidation to give the corresponding 3-acetylpyridine. This acetylpyridine is then reacted with an appropriate substituted aldehyde in a Claisen-Schmidt condensation to give a chalcone as described earlier although it would be an isomeric ("reverse") chalcone. That is, reduction of the carbonyl group of the chalcone would give an alcohol of type III which would be similar to that obtained according to scheme I discussed earlier.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:8][C:7]=1OCCCCCOC(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)CCc1cc(C(C)=O)ccc1OCCCCCOC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)CCc1cccc(C(C)=O)c1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A solution of 4.22 g (12.06 mmol) of 2-[[5-(acetoxy)pentyl]oxy]-5-acetylbenzenepropanoic acid methyl ester and 0.1 g of p-toluenesulfonic acid monohydrate in 50 mL of methanol was stirred and refluxed for 3.5 hr and stirred at room temperature for 21 hr. Most of the methanol was removed in vacuo and the residue was diluted with water and worked-up with ether in the usual manner (the combined ether extracts were additionally washed with saturated aqueous sodium bicarbonate). The product was purified by flash chromatography on silica gel, eluting with 1:2 hexane-ethyl acetate. There was obtained 3.6 g (97%) of 2-[[5-(acetoxy)pentyl]oxy]phenyl]-2-propenoic hydroxypentyl)oxy]-5-acetylbenzenepropanoic acid methyl ester as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[C:4]([O:34][CH3:35])[CH:3]=1.[S:36]1[CH:40]=[N:39][N:38]=[C:37]1[NH2:41].C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>CCOC(C)=O.Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:41][C:37]4[S:36][CH:40]=[N:39][N:38]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[C:4]([O:34][CH3:35])[CH:3]=1
Reactant: Nc1nncs1
Reactant: COc1cc(Cl)c(F)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(Cl)c(F)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Reaction time: 8 h
Yield: 60.7 %

Procedure:
A vial was charged with perfluorophenyl 1-(4-chloro-5-fluoro-2-methoxyphenyl)isoquinoline-6-sulfonate (INTERMEDIATE GGGGG, 1.233 g, 2.310 mmol) 1,3,4-thiadiazol-2-amine (0.280 g, 2.77 mmol), and cesium carbonate (2.258 g, 6.93 mmol). Acetonitrile (11.55 ml) was added, and the mixture was stirred overnight. The mixture was diluted with EtOAc and 0.5 N aq. HCl. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (25-g SNAP Ultra column, 0-5% MeOH/DCM) to give 1-(4-chloro-5-fluoro-2-methoxyphenyl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (632 mg, 1.402 mmol, 60.7% yield) as an off-white solid. m/z (ESI) 451.0 (M+H)+.
Reaction SMILES: [Mg].BrCCBr.C(Cl)(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1.[CH3:21][C:22]([CH3:24])=[O:23].S(=O)(=O)(O)O>O1CCCC1>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]([C:22]([OH:23])([CH3:24])[CH3:21])[C:18]([OH:20])=[O:19])=[CH:15][CH:16]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CC(C)=O
Agent: CC(C)Cl
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CC(C)(O)C(C(=O)O)c1ccc(F)cc1
Yield: 109.6 %

Procedure:
24.3 g (1.00 mol) of magnesium shavings were suspended in 50 ml of tetrahydrofuran under argon and while stirring in a 1.5 l four-necked sulphonation flask fitted with a reflux condenser, mechanical stirrer, 500 ml dropping funnel, thermometer and a device for inert gasification. After the dropwise addition of 0.5 ml of 1,2-dibromoethane, a solution of 86.4 g (1.10 mol) of isopropyl chloride in 225 ml of tetrahydrofuran was added dropwise within 90 minutes, with the reaction temperature being held at about 30°. The resulting dark grey suspension was stirred at RT for a further 18 hours. Then, a solution of 73.0 g (0.473 mol) of p-fluorophenylacetic acid in 150 ml of tetrahydrofuran was added dropwise to the mixture within 90 minutes while maintaining the temperature at about 25° and thereafter the suspension was heated to 35-40° and stirred at this temperature for a further 1 hour. After cooling 30.0 g (0.516 mol) of acetone were added dropwise at about 25° within 30 minutes and subsequently the mixture was stirred at 35-40° for a further 1 hour. The reaction mixture was treated with 350 ml of 14.2% sulphuric acid while cooling with an ice bath at <30°. The aqueous phase was separated, extracted with 200 ml of tetrahydrofuran and the organic phases were combined and evaporated at 50° on a rotary evaporator. 110 g of crude 2-(p-fluorophenyl)-3-hydroxy-3-methylbutyric acid were obtained as a dark viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][CH:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]([CH3:30])[CH:20]=1>C(C(CC)=O)C>[CH3:30][N:21]1[C:22]2[C:27](=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:19]([CH2:18][CH2:17][N:11]2[CH2:12][CH2:13][CH:9]([CH2:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:15][CH:14]=3)[CH2:10]2)=[CH:20]1
Reactant: COc1ccc2c(c1)c(CCBr)cn2C
Reactant: O=C(CC1CCNC1)c1ccc(F)cc1
Solvent: CCC(=O)CC
Product: COc1ccc2c(c1)c(CCN1CCC(CC(=O)c3ccc(F)cc3)C1)cn2C

Procedure:
Alkylation of 3-(4-fluorobenzoylmethyl)pyrrolidine by the brominated compound obtained in Stage 3 is carded out in diethyl ketone by following the procedure described in Stage 3 of Example 1.
Reaction SMILES: [CH2:1]([C:3](=[CH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[CH2:4][CH2:5]Br)[CH3:2].[I-:20].[Na+]>CC(C)=O>[CH2:1]([C:3](=[CH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[CH2:4][CH2:5][I:20])[CH3:2]
Reactant: CCC(=CCCc1ccc(OC)c(OC)c1)CCBr
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCC(=CCCc1ccc(OC)c(OC)c1)CCI

Procedure:
3-Ethyl-6-(3,4-dimethoxyphenyl)-3-hexenyl iodide [VI; Ar is 3,4-(CH3O)2C6H3, R is C2H5 ] was prepared from 13.8 g. of 3-ethyl-6-(3,4-dimethoxyphenyl)-3-hexenyl bromide (Preparation C4) and 9 g. of sodium iodide in 120 ml. of acetone, to give 15 g. of product as an oil.
Reaction SMILES: Cl.[C:2](=[O:14])([O:12][CH3:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([NH2:11])[CH:5]=1.[CH3:15][N:16]1[C:20]([C:21](Cl)=[O:22])=[CH:19][C:18]([CH3:24])=[N:17]1>CN(C)C(=O)C>[C:2](=[O:14])([O:12][CH3:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([NH:11][C:21]([C:20]2[N:16]([CH3:15])[N:17]=[C:18]([CH3:24])[CH:19]=2)=[O:22])[CH:5]=1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: COC(=O)Oc1ccc(F)c(N)c1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: COC(=O)Oc1ccc(F)c(NC(=O)c2cc(C)nn2C)c1
Yield: 87.2 %

Procedure:
Using a solution of 3-amino-4-fluorophenyl methyl carbonate hydrochloride (740 mg, 3.34 mmol) and 1,3-dimethyl-1H-pyrazole-5-carbonylchloride (556 mg, 3.51 mmol) in N,N-dimethylacetamide (10 mL), and by a reaction in the same manner as in Example 148, the title compound (895 mg, 87%) was obtained as a white powder.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH2:4][CH2:3]2.CCN(C(C)C)C(C)C.[CH:58]1([S:61](Cl)(=[O:63])=[O:62])[CH2:60][CH2:59]1>ClCCl>[CH:58]1([S:61]([N:46]2[CH2:45][CH2:44][N:43]([CH2:42][CH2:41][NH:40][C@:5]34[CH2:36][CH2:35][C@@H:34]([C:37]([CH3:39])=[CH2:38])[C@@H:6]3[C@@H:7]3[C@@:2]([CH3:1])([CH2:3][CH2:4]4)[C@@:19]4([CH3:20])[C@@H:10]([C@:11]5([CH3:33])[C@@H:16]([CH2:17][CH2:18]4)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]4[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=4)=[CH:13][CH2:12]5)[CH2:9][CH2:8]3)[CH2:48][CH2:47]2)(=[O:63])=[O:62])[CH2:60][CH2:59]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCNCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=S(=O)(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(S(=O)(=O)C4CC4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 20 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (26 mg, 0.040 mmol) and Hunig's Base (0.035 mL, 0.198 mmol) in dichloromethane (1 mL) was added a solution of cyclopropanesulfonyl chloride (11.14 mg, 0.079 mmol) in dichloromethane (1 mL) at room temperature. The reaction mixture was stirred for 2 hours at 20° C. or LCMS indicated the formation of desired product and consumption of starting material. The reaction mixture was diluted with distilled water (4 mL), extracted with dichloromethane (3×4 mL), the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the desired product as a yellow solid (30 mg, 100%). LCMS: m/e 760.61 (M+H)+, 2.40 min (method 11).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:12][C:8]=1[C:9]([OH:11])=O)[CH:2]=[C:3]([CH3:5])[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:12][C:8]=1[C:9]([NH:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1)=[O:11])[CH:2]=[C:3]([CH3:4])[CH3:5]
Reactant: NCCc1ccncc1
Reactant: CC(C)=CCOc1ccc(OCC=C(C)C)c(C(=O)O)c1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)=CCOc1ccc(OCC=C(C)C)c(C(=O)NCCc2ccncc2)c1
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
2,5-diprenyloxybenzoic acid(1.99 g) was dissolved in chloroform(38 ml) and triethylamine(1.91ml), and then diphenylphosphinic chloride(1.31 ml) was added thereto while being cooled with ice. After being stirred for 30 minutes, the mixture, with 4-(2-aminoethyl)pyridine(0.85 g) added thereto, was stirred for 1 hour at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 2.41 g of the aimed compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6](Cl)=[O:7])=[N:2]1.[NH2:9][C:10]1[S:11][CH:12]=[CH:13][C:14]=1[C:15]([NH2:17])=[O:16].N1C=CC=CC=1>CC#N.CN(C1C=CN=CC=1)C>[C:15]([C:14]1[CH:13]=[CH:12][S:11][C:10]=1[NH:9][C:6]([C:3]1[CH:4]=[CH:5][NH:1][N:2]=1)=[O:7])(=[O:16])[NH2:17]
Reactant: O=C(Cl)c1cc[nH]n1
Reactant: NC(=O)c1ccsc1N
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CC#N
Product: NC(=O)c1ccsc1NC(=O)c1cc[nH]n1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A solution of 1H-Pyrazole-3-carbonyl chloride (5 mmol) in MeCN (5 mL) is added drop wise to a solution of 2-amino-thiophene-3-carboxylic acid amide (570 mg, 4 mmol), pyridine (0.5 mL, 6 mmol) and DMAP (25 mg, 0.20 mmol) in MeCN (5 mL). The resulting solution is than stirred at 60° C. over 2 days. Next, the mixture is quenched with aqueous NaHCO3. Evaporation of the MeCN gives a suspension that is filtered, the cake is dried, and used as such.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]#[N:22].[O:23]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)[N:5]=[CH:4][C:3]([C:21]#[N:22])=[C:2]2[NH:34][C:33]1[CH:32]=[CH:31][C:30]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:36][CH:35]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1N1CCN(C)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2c(Nc3ccc(Oc4ccccc4)cc3)c(C#N)cnc2cc1N1CCN(C)CC1
Temperature: 115 °C
Reaction time: 0.75 h
Yield: 62.2 %

Procedure:
A reaction mixture of 0.12 g (0.38 mmol) of 4-chloro-6-methoxy-7-(4-methylpiperazin-1-yl)-quinoline-3-carbonitrile, 0.077 g (0.42 mmol) of 4-phenoxyaniline and 0.044 g (0.38 mmol) of pyridine hydrochloride in 2 ml of 2-ethoxyethanol is heated at 115° C. for 45 minutes. After cooling, the mixture is filtered, washed with cold 2-ethoxyethanol, then ethyl acetate. After drying in vacuo, the solid is suspended in a saturated solution of sodium carbonate, stirred for 45 minutes and collected by filtration. The reaction product is washed with water and dried in vacuo, to provide 0.11 g of 6-methoxy-7-(4-methylpiperazin-1-yl)-4-(4-phenoxyphenylamino)-quinoline-3-carbonitrile as a yellow solid, mp softens at 93° C.
Reaction SMILES: CNCCC(OC1C=CC(C(F)(F)F)=CC=1)C1C=CC=CC=1.[Cl:23][CH2:24][CH2:25][C@@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[OH:27].[F:34][C:35]1[CH:36]=[C:37](O)[CH:38]=[CH:39][CH:40]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(OCC)C>[F:34][C:35]1[CH:40]=[C:39]([CH:38]=[CH:37][CH:36]=1)[O:27][C@@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:25][CH2:24][Cl:23]
Reactant: O[C@@H](CCCl)c1ccccc1
Reactant: Oc1cccc(F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: CNCCC(Oc1ccc(C(F)(F)F)cc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1cccc(O[C@H](CCCl)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 15.7 %

Procedure:
Following a similar procedure for the chiral synthesis of fluoxetine [Srebnik, M. et al., J. Org. Chem. 25 53(13), 2916–20 (1988), hereby incorporated by reference herein], a solution of (S)-(−)3-chloro-1-phenyl-1-propanol (4.00 g, 23.4 mmol), 3-fluorophenol (2.63 g, 23.4 mmol), and diethyl azodicarboxylate (4.00 g, 23.4 mmol) were dissolved in THF (200 mL). The mixture was cooled to 0° C. and triphenylphosphine (6.77 g, 25.8 mmol, 1.1 equiv) was added slowly over 10 min. The reaction mixture was then stirred at room temperature for 18 h. The THF was subsequently evaporated under vacuum to afford a gel which was washed with pentane (3×50 mL). The pentane washings were filtered and the filtrate was evaporated under vacuum to give a clear oil. This oil was dissolved in diethyl ether (150 mL) and washed with 1% HCl-satd. NaCl (25 mL), 0.1N NaOH-satd. NaCl (2×25 mL), and finally H2O (2×25 mL). The organic layer was then dried (anh. Na2SO4), filtered, and evaporated to dryness under vacuum to give an orange oil. The crude product was chromatographed on silica gel (25×180 mm, gravity column), elution with 40:1 hexane-EtOAc, to provide 971 mg (15.7%) of product as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[O:19])[CH:13]=1)[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl.O.C[Si](C)(C)[C:43]([F:46])([F:45])[F:44]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([OH:19])[C:43]([F:46])([F:45])[F:44])[CH:13]=1)[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(=O)c1cccnc1Oc1cccc(C=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cccnc1Oc1cccc(C(O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(3-Formyl-phenoxy)-nicotinic acid ethyl ester (2.0 grams, 7.4 mmole) in 0.5 M trimethyl(trifluoromethyl)silane (18 ml) in tetrahydrofuran (20 ml) at 0° C. was added tetrabutyl ammonium fluoride (0.050 g). The mixture was stirred at 0° C. for 1 hour. To the mixture was added 1.0 N hydrochloric acid (10 ml) and stirred at room temperature for 30 minutes. The mixture was poured into 200 ml water and extracted with diethyl ether. The combined extracts were washed with saturated NaHCO3, and water, dried over magnesium sulfate and concentrated to give an oil which was purified via flash chromatography on silica using 60% ethyl acetate/hexane as eluent to give an oil (1.97 g). MW 341.31; MS (m/e) 341 (M+).
Reaction SMILES: [CH:1]([N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[C:8]([NH2:17])[CH:9]=2)([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>ClCCl>[CH:1]([N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[C:8]([NH:17][C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27])[CH:9]=2)([CH3:3])[CH3:2]
Reactant: CC(C)n1c2c(c3cc(N)ccc31)CCCC2
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)n1c2c(c3cc(NC(=O)Oc4ccccc4)ccc31)CCCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.1 %

Procedure:
The N-isopropyl-6-amino-1,2,3,4-tetrahydrocarbazole (9.84 g) and 5.05 g of triethylamine were dissolved in 100 mL of dichloromethane, and added dropwise with 7.85 g of phenyl chloroformate. The reaction mixture was stirred at room temperature for 3 hours, then washed with 10% aqueous citric acid and then with saturated aqueous sodium hydrogencarbonate, and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=8/2) and recrystallized from a mixture of hexane and ethyl acetate, to obtain 2.27 g of N-isopropyl-6-phenoxycarbonylamino-1,2,3,4-tetrahydrocarbazole.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:24]#[N:25])=[N:18][C:19]=3Cl)[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2].[CH3:31][C:32]1[CH:33]=[C:34]([CH:38]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[CH:42]=2)[CH2:39][NH2:40])[CH:35]=[CH:36][CH:37]=1>>[C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:24]#[N:25])=[N:18][C:19]=3[NH:40][CH2:39][CH:38]([C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([CH3:31])[CH:33]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[CH:42]=2)[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: Cc1cccc(C(CN)c2cccc(C)c2)c1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4cccc(C)c4)c4cccc(C)c4)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
The title compound was prepared from (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-cyano-9H-purin-9-yl)tetrahydro-3-furanyl acetate (Preparation 45) and 2,2-bis(3-methylphenyl)ethanamine (J. Med. Chem., 1988, 31(7), 1282) using a similar procedure to that of Preparation 64.