Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([P:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].OO.[O-:26]S([O-])=O.[Na+].[Na+].Cl>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([P:11](=[O:26])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=S([O-])[O-]
Reactant: COc1ccc(P(c2ccccc2)c2ccccc2)cc1OC
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(P(=O)(c2ccccc2)c2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
da) 75 g of 3,4-dimethoxyphenyl-diphenylphosphine were taken up in 300 ml of methanol. 29.3 ml of 35% H2O2 solution were added dropwise to the suspension while cooling with an ice bath. The clear yellow solution was stirred at room temperature overnight, then treated with 100 ml of sat. Na2SO3 solution and 30 ml of 1N HCl and stirred for a further 1 hour. The resulting suspension was treated with 150 ml of water and the solution was evaporated on a rotary evaporator in order to remove the majority of the methanol. The precipitated yellow crystals were filtered off under suction, taken up in CH2Cl2, the solution was dried over MgSO4, filtered and evaporated. The residue was dissolved in 450 ml of hot ethyl acetate and the solution was treated with 450 ml of hexane. After standing overnight the crystallizate was filtered off under suction, washed with a small amount of hexane and dried at 0.1 mbar. There were obtained 54 g of (3,4-dimethoxyphenyl)diphenylphosphine oxide as a light beige powder. M.p. 154.5°-156° C.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]C.C[C:22]1(C)[O:27][C:26](=[O:28])[CH2:25][C:24](=[O:29])O1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>C(Cl)Cl>[O:29]=[C:24]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:25][C:26]([O:27][CH3:22])=[O:28]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)CC(=O)OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Stearic acid (5.0 g, 17.6 mmoles) is suspended in methylene chloride (88 mL) and 2,2-dimethyl-1,3-dioxane-4,6-dione (2.7 g, 18.5 mmoles), triethylamine (6.7 mL, 48.0 mmoles) and diethyl cyanophosphonate (2.7 mL, 17.6 mmoles) are added. All solids dissolve quickly. The solution is stirred for 16 hours at ambient temperature. The reaction mixture is then diluted with methylene chloride (100 mL) and carefully washed three times with aqueous hydrochloric acid (3 M, 50 mL each), three times with water (50 mL each) and once with saturated aqueous sodium chloride (50 mL). The reaction mixture is then dried over anhydrous sodium sulfate, filtered and evaporated. The resulting syrup is dissolved in anhydrous methanol (100 mL) and heated to reflux for 16 hours. The methanol is evaporated and the crude product dissolved in hexanes with slight heating. The crude product was then loaded on silica gel (150 mL bed volume) eluting with hexanes (500 mL) then hexane:acetone (98:2 [v/v], 1000 mL). Fractions containing pure product by thin layer chromatography are pooled and evaporated to dryness. The resulting oil is dried well in vacuo. The yield is 5.2 g (87%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([Br:12])[C:9](=[O:13])[NH:8][C:7]=1[C:14]([F:17])([F:16])[F:15])=[O:5])[CH3:2].O[CH2:19][CH:20]1[CH2:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:5])[C:6]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][CH2:19][CH:20]2[CH2:22][CH2:21]2)=[N:8][C:7]=1[C:14]([F:17])([F:15])[F:16])[CH3:2]
Reactant: OCC1CC1
Reactant: CCOC(=O)c1cc(Br)c(=O)[nH]c1C(F)(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Br)c(OCC2CC2)nc1C(F)(F)F
Temperature: 0 °C
Reaction time: 16 h

Procedure:
5-Bromo-1,6-dihydro-6-oxo-2-(trifluoromethyl)-3-pyridinecarboxylic acid ethyl ester (CAN 862111-61-3) (1.3 g, 3.6 mmol) was dissolved in THF (15 mL). To the solution were added hydroxymethylcyclopropane (0.35 mL, 4.3 mmol), triphenylphosphine (1.1 g, 4.3 mmol) and diethyl azodicarboxylate (0.69 mL, 4.3 mmol) at 0° C. The mixture was stirred for 30 min at 0° C. and for 16 h at room temperature. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel with dichloromethane: methanol 4:1 to yield the product as yellowish oil, MS (ISP) 368.0, 370.0 (M+H)+.
Reaction SMILES: C[N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][C:12]([C:14]3[N:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:13][C:4]=2[CH2:3]1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1O>C1COCC1.ClCCl>[CH:28]1[C:29]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:27]=1[O:9][CH:6]1[CH2:7][CH2:8][NH:2][CH2:3][C:4]2[CH:13]=[C:12]([C:14]3[N:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:11]=[CH:10][C:5]1=2
Reactant: CN1CCC(O)c2ccc(-c3cccnn3)cc2C1
Reactant: Oc1ccc2ccccc2c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: c1cnnc(-c2ccc3c(c2)CNCCC3Oc2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.1 %

Procedure:
To a solution of (−)-2-methyl-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-ol (80 mg, 0.31) from Step H above in THF (5 mL) was added napthalen-2-ol (67 mg, 0.47 mmol), tributylphosophine (95 mg, 0.47 mmol) and 1,1′-(azodicarboyl)dipiperidine (118 mg, 0.47 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with dichloromethane and washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography (98:2 to 95:5 ethyl acetate/methanol), followed by HPLC to give the (+)-5-(naphthalen-2-yloxy)-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine (60 mg, 48%) as a gum-like solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][C@H:13]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)[C:14]1=[O:33]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][C@H:13]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:14]1=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCC[C@H](Nc3ccc(S(C)(=O)=O)cc3F)C2=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(N[C@H]2CCCCN(C3CCNCC3)C2=O)c(F)c1
Yield: 50 %

Procedure:
A solution of (S)-tert-butyl 4-(3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxoazepan-1-yl)piperidine-1-carboxylate (1.0 g, 2.0 mmol) in 50% TFA/DCM was stirred a ambient temperature for 1 hour. The mixture was concentrated in vacuo. 1N NaOH (100 mL) was added to the residue and the product was extracted into DCM (2×50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give (S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1-(piperidin-4-yl)azepan-2-one (0.4 g, 1 mmol, 50%).
Reaction SMILES: Cl[CH2:2][CH2:3][C@@H:4]([O:11][C:12]1[CH:13]=[C:14]([C:18](=[O:20])[CH3:19])[CH:15]=[CH:16][CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24].[Na+].[I-].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:18]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][C@@H:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:2][N:35]1[CH2:36][CH2:37][CH:32]([C:28]2[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=2)[CH2:33][CH2:34]1)(=[O:20])[CH3:19]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: CC(=O)c1cccc(O[C@H](CCCl)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cccc(O[C@H](CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
A mixture of 1-(3-{[(1R)-3-chloro-1-phenylpropyl]oxy}phenyl)ethanone (58.5 mg, 0.200 mmol), 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (56.8 mg, 0.200 mmol), NaI (34.0 mg, 0.200 mmol) and K2CO3 (55.5 mg, 0.400 mmol) in DMF (1.00 mL) was stirred at 100° C. for 3 h. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica using 5% of NH3 (2.0 M in methanol) in CH2Cl2 to give the desired product (98.0 mg, 98.0%): 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.49–7.21 (m, 11H), 7.09–7.03 (m, 1H) 6.96 (d, 1H, J=7.9 Hz), 5.32 (dd, 1H, J=5.0, 7.9 Hz), 3.08–2.98 (m, 2H), 2.57–2.43 (m, 6H), 2.11–1.72 (m, 9H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 499.4 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:19])[CH2:8][O:7][C:6](=[N:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[NH:5]1.I[CH3:21]>C1COCC1>[N+:16]([C:13]1[CH:12]=[CH:11][C:10]([N:9]=[C:6]2[N:5]([CH3:21])[C:4]([CH3:19])([CH3:3])[CH2:8][O:7]2)=[CH:15][CH:14]=1)([O-:18])=[O:17]
Reactant: CI
Reactant: CC1(C)COC(=Nc2ccc([N+](=O)[O-])cc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=Nc2ccc([N+](=O)[O-])cc2)OCC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To a stirred suspension of sodium hydride (0.2 g of 50% in mineral oil, 4.2 mmol) in THF was added (4,4-dimethyl-oxazolidin-2-ylidene)-(4-nitro-phenyl)-amine (1 g, 4.25 mmol), stirred for 30 min at r.t., followed by addition of iodomethane (0.71 g, 5.0 mmol). After a further 6 hours at r.t. the reaction was quenched with water and extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue which was purified by column chromatography over silica gel (60-120 mesh) using 15% ethyl acetate/petroleum ether as eluent to give (4-nitro phenyl)-(3,4,4-trimethyl-oxazolidin-2-ylidene)-amine (0.7 g, 66%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19](=[O:29])[C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)=[N:2]1.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([C:19]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2/[CH:11]=[CH:10]/[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:29])=[CH:25][CH:24]=1
Reactant: O=C(Nc1ccccc1/C=C/c1n[nH]c2ccccc12)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(C(=O)Nc2ccccc2/C=C/c2n[nH]c3ccccc23)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 32.6 %

Procedure:
Compound 65 (60 mg, 0.13 mmol), iron powder (436 mg, 7.80 mmol) and ammonium chloride (42 mg, 0.78 mmol) were added with ethanol (1.0 mL) and water (1.0 mL) at room temperature, stirred at 50° C. for 1 hour and then the reaction mixture was filtered through Celite. The filtrate was extracted with ethyl acetate and the organic layer was sequentially washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated in ethanol to obtain Compound 70 (15 mg, 28%).
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)O1.C([O-])([O-])=O.[K+].[K+]>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.COCCOC.O>[F:19][C:14]([F:20])([O:13][C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH:5]=[N:6][C:2]([C:29]3[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=3)=[N:3]2)=[CH:8][CH:9]=1)[C:15]([F:18])([F:17])[F:16]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: FC(F)(F)C(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Temperature: 120 °C
Yield: 72.7 %

Procedure:
3-Bromo-1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazole (1.5 g, 4.2 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.12 g, 5.12 mmol), Pd(PPh3)4 (0.49 g, 0.424 mmol) and K2CO3 (1.17 g, 8.52 mmol) were combined in a round bottom flask in 5:1 DME/water (22 mL), and the solution was degassed with nitrogen for 15 min. The reaction was then heated for 18 h at 120° C. The reaction mixture was cooled and diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc (2×50 ml). The combined organic extracts were dried over anhydrous MgSO4 and concentrated onto 8 g of Celite®. The Celite® was loaded onto a silica column and the target molecule was eluted using 0-100% EtOAc/hexanes to afford the title compound as a tan solid (1.13 g, 68%): 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.99 (d, J=8.7 Hz, 2H), 7.78 (d, J=9.1 Hz, 2H), 7.36 (d, J=9.1 Hz, 2H), 6.76 (d, J=8.7 Hz, 2H), 3.90 (s, 2H); ESIMS m/z 371.2 ([M+H]+).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.O>COCCOC.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>[NH2:12][C:13]1[CH:18]=[C:17]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Cc1ccn2c(Br)cnc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Product: Cc1ccn2c(-c3cccc(N)c3)cnc2c1
Yield: 100.8 %

Procedure:
3-Bromo-7-methylimidazo[1,2-α]pyridine (4.2 g, 20.0 mmol) and 3-aminophenylboronic acid (4.0 g, 25.8 mmol) were suspended in 1,2-dimethoxyethane (80 ml) and sodium carbonate (40 ml of a 2M solution) and the resulting solution degassed for 25 minutes. Tetrakis(triphenylphosphine)palladium(0) (250 mg, 0.2 mmol) was added and the mixture heated at reflux for 17 hours. The cooled reaction mixture was poured into water (150 ml), extracted with ethyl acetate (3×70 ml) and the combined organics dried over anhydrous magnesium sulphate. The solution was filtered and concentrated in vacuo to yield 3-(3-aminophenyl)-7-methylimidazo[1,2-α]pyridine as a colourless oil (4.5 g, 100%) which was used without further purification. 1H NMR (400 MHz, CDCl3) δH 2.38 (3H, s), 3.58 (2H, br s), 6.60 (1H, d, J 7), 6.70 (1H, d, J 8), 6.81 (1H, s), 6.91 (1H, d, J8), 7.24-7.28 (1H, m), 7.39 (1H, s), 7.57 (1H, s), 8.23 (1H, d, J 7); m/z (ES+) 224 (M++H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].C([N:19]=[C:20]=[S:21])(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[O:10]=[C:6]1[CH2:7][CH2:8][CH2:9][N:5]1[CH2:4][CH2:3][CH2:2][NH:1][C:20]([NH2:19])=[S:21]
Reactant: NCCCN1CCCC1=O
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClC(Cl)Cl
Product: NC(=S)NCCCN1CCCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
A mixture of 1-(3-aminopropyl)-2-pyrrolidinone (560 μL, 4 mmol) and benzoyl isothiocyanate (536 μL, 4 mmol) was dissolved in chloroform (3 mL), stirred at room temperature for 30 min, then concentrated in vacuo. The resulting residue was dissolved in concentrated HCl (3 mL), heated at 95° C. for 2 h, then concentrated in vacuo. The resulting residue was dissolved in water and washed with dichloromethane (2×30 mL), then basified with 2 M NaOH and extracted with dichloromethane (2×30 mL). The combined extracts were dried over MgSO4 and concentrated to provide 1-(3-(2-oxopyrrolidin-1-yl)propyl)thiourea (638 mg) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.CO.C(OCC)(=O)C>C1COCC1>[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:4][CH:3]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)Nc2ccc3cccc(N4CCN(C)CC4)c3c2)cc1
Temperature: 25 °C
Yield: 62.5 %

Procedure:
A solution of 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.205 g, 0.85 mmol) and triethylamine (0.124 mL, 0.935 mmol) in dry THF (3 mL) was chilled to 0° C and para toluenesulfonyl chloride (0.178 g, 0.935 mmol) was added all at once. The mixture was allowed to warm to room temperature and stirred overnight (TLC with 40% methanol/ethyl acetate indicated that the reaction was complete.) The solvent was removed at reduced pressure and the residue was taken up in methylene chloride. The organic solution was extracted with saturated sodium bicarbonate and brine, then it was dried over calcium sulfate and concentrated. Flash chromatography on silica gel (1×3 inches) with ethyl acetate/hexane gradient elution of from 50% to 100% gave 0.21 g of a light tan solid. The solid was further purified by two recrystallizations from ethyl acetate to yield 0.07 g (20%) of the title product: mp 180°-1 81.5° C. Analysis calculated for C22H25N3O2S: C, 66.81; H, 6.37; N, 10.62. Found: C, 66.55; H, 6.31; N, 10.20.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:6](Br)[CH:7]=1.BrC1C=C([I:23])C=C(Br)C=1.C1(B(O)O)C=CC=CC=1.C([Li])CCC.ICCI.S([O-])(O)=O.[Na+]>C(Cl)Cl.O.CCCCCC.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:6]([I:23])[CH:7]=1
Reactant: Brc1cc(Br)cc(-c2ccccc2)c1
Reactant: Brc1cc(Br)cc(I)c1
Agent: ICCI
Agent: O=S([O-])O
Agent: OB(O)c1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: Brc1cc(I)cc(-c2ccccc2)c1
Reaction time: 5 h
Yield: 85 %

Procedure:
Under the atmosphere of argon, 20 g of 3,5-dibromobiphenyl synthesized from 3,5-dibromoiodobenzene and phenylboronic acid was dissolved into 200 ml of anhydrous THF, and the resultant solution was cooled at −70° C. To the cooled solution, 42 ml of a 1.6 M hexane solution of normal-butyllithium was added dropwise, and the resultant mixture was stirred for 30 minutes. Then, 19 g of 1,2-diiodoethane was added, and the obtained mixture was stirred for 5 hours. After the mixture was left standing for one night, water and methylene chloride were added. Then, sodium hydrogensulfite was added until dark brown color of the reaction mixture turned to yellow color. The organic layer was obtained by extraction, washed with water and a saturated aqueous solution of sodium chloride and dried with anhydrous sodium sulfate, and the solvent was removed using an evaporator. The obtained residue was purified in accordance with the silica gel column chromatography (the developing solvent: hexane), and 19.5 g of 3-bromo-5-iodobiphenyl was obtained as a colorless oil (the yield: 85%).
Reaction SMILES: [CH:1]([Si:3](Cl)(Cl)Cl)=[CH2:2].[C:7]([OH:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.ClCl>CCCCCC>[CH:1]([Si:3]([O:15][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O:14][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[O:14][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:2]
Reactant: C=C[Si](Cl)(Cl)Cl
Reactant: O=C(O)c1ccccc1
Agent: ClCl
Solvent: CCCCCC
Product: C=C[Si](OC(=O)c1ccccc1)(OC(=O)c1ccccc1)OC(=O)c1ccccc1
Reaction time: 20 h

Procedure:
A six-liter three-necked flask is placed in a mushroom heating hood, and equipped with a stirrer, a reflux condenser and a dropping funnel whose nozzle bore amounts to 1 cm. 808 g (5 moles) of vinyltrichlorosilane and 1000 ml of hexane are introduced into the flask. The outlet from the reflux condenser is shielded with nitrogen. After the liquid has been heated until an intensive refluxing is taking place at the condenser, 1855 g (15.2 mol) of benzoic acid is added in 30-gram portions. The addition is completed in about 20 hours. The reaction is allowed to run, with refluxing and vigorous stirring, until the analytically determined contents of hydrolyzable chlorine amount to less than 100 parts per million.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].C(Cl)(=O)C(Cl)=O.[Cl:33][C:34]1[CH:35]=[C:36]([NH2:41])[CH:37]=[CH:38][C:39]=1[Cl:40].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[Cl:33][C:34]1[CH:35]=[C:36]([NH:41][C:18]([C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:8][O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[CH:22][CH:21]=2)=[O:19])[CH:37]=[CH:38][C:39]=1[Cl:40]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(Cl)c(Cl)c4)cc3)c(C#N)cc21
Reaction time: 0.33 h
Yield: 71.1 %

Procedure:
4-(6-Cyano-4-(methoxycarbonyl)-3,4-dihydro-2H-chromen-7-yloxy)benzoic acid (17 mg, 0.0481 mmol) was diluted with CH2Cl2 (1 mL) followed by the addition of oxalyl chloride in CH2Cl2 (2M in CH2Cl2) (0.0289 mL, 0.0577 mmol) and 1 drop of DMF. The reaction was stirred for 20 minutes, and then 3,4-dichlorobenzenamine (15.6 mg, 0.0962 mmol) and N,N-diisopropylethylamine (0.0210 mL, 0.120 mmol) were added. After stirring for 30 minutes the reaction was loaded directly onto a Biotage 12i eluting with hexane:ethyl acetate (1:1) to yield the title compound (17 mg, 71.0% yield) as a clear oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1)([OH:8])=[O:7].[CH2:21](O)[CH3:22]>>[CH2:21]([O:7][C:6]([CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1)=[O:8])[CH3:22]
Reactant: O=C(O)CCCn1ccc2ccccc21
Reactant: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)CCCn1ccc2ccccc21

Procedure:
Phosphorus oxychloride (10 ml) was added dropwise with cooling to a stirred solution of 1-(3-carboxypropyl)indole (100 g) in ethanol (750 ml). The solution was heated under reflux for 8 hours and then evaporated. The residue was distilled to give 1-(3-ethoxycarbonylpropyl)indole (95.0 g), b.p. 164°-170° C./2 m.m.
Reaction SMILES: [CH2:1]([NH:4][CH:5]([CH3:11])[CH:6]([O:9][CH3:10])[O:7][CH3:8])[CH:2]=[CH2:3].C1(C)C=CC=CC=1.[OH-].[Na+].Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>O>[CH2:1]([N:4]([CH:5]([CH3:11])[CH:6]([O:9][CH3:10])[O:7][CH3:8])[C:22](=[O:23])[O:24][CH2:25][CH3:26])[CH:2]=[CH2:3]
Reactant: C=CCNC(C)C(OC)OC
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCN(C(=O)OCC)C(C)C(OC)OC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
125 g (0.785 mol) of allyl-(1,1-dimethoxyprop-2-yl)amine are initially introduced into 400 ml of toluene, a solution of 40 g of sodium hydroxide in 200 ml of water is added, the mixture is cooled in an ice-bath to 0° C. and 95 g (0.876 mol) of ethyl chloroformate are added dropwise. The mixture is then stirred for 3 hours at room temperature, and the aqueous phase is separated off and extracted twice using 100 ml of toluene each time. The extracts are dried over potassium carbonate and concentrated, and the residue is distilled.