Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](OC)([O:4][CH3:5])[O:2][CH3:3].[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13](C=O)=[CH:12][CH:11]=1>ClCCl>[CH3:3][O:2][CH:1]([O:4][CH3:5])[C:13]1[CH:16]=[CH:17][C:10]([S:9][CH3:8])=[CH:11][CH:12]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: COC(OC)OC
Solvent: ClCCl
Product: COC(OC)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96.9 %

Procedure:
A suspension of K-10 (32 g) in trimethyl orthoformate (115 ml, 1.05 mol) was added to a solution of 4-(methylthio)benzaldehyde (31.0 g, 0.203 mol) in dichloromethane (300 ml) at 0° C. The obtained mixture was stirred at room temperature for 20 minutes and filtered to remove the K-10. The filter cake was washed with dichloromethane. The filtrate and washings were together washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of common salt, dried over magnesium sulfate and concentrated in a vacuum to give the title compound as a pale-yellow oil (39.0 g, 96%).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[H-].[Na+].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].Cl>CN(C=O)C>[C:1]([CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C#N)c1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
6.3 A solution of 180 ml of methyl cyanoacetate in 300 ml of DMF is added dropwise at 0-50° with stirring and under a nitrogen atmosphere to a solution of 88 g of NaH suspension in 2 litres of DMF. The mixture is stirred for a further 30 minutes without cooling. A solution of 106 ml of o-fluoronitrobenzene in 100 ml of DMF is subsequently added dropwise, and the mixture is stirred at room temperature for a further 14 hours. The mixture is acidified using 10% HCl and subjected to conventional work-up, giving 165 g of methyl cyano(2-nitrophenyl)acetate (“FC”), m.p. 58-60°.
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[CH:10]2.N1C=CN=C1.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22]>O>[Si:25]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[CH:10]2)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27]
Reactant: Oc1ccc2[nH]ncc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ncc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Charge a 10 L reaction vessel with N,N-dimethylformamide (DMF, 2.50 L), 5-hydroxyindazole (150.20 g, 1.12 mol) and 1H-imidazole (114.35 g, 1.68 mol). Cool the mixture to 0° C. and add tert-butyldimethylchlorosilane (253.16 g, 1.68 mol) over 0.5 hours. Stir the mixture at 18° C. for 3 hours. Add water (2.5 L) to the reaction slowly with an ice bath at 5° C. to maintain an internal temperature at around 20° C. Transfer the mixture to a separating funnel and extract with EA (2×2.5 L). Combine the extracts and wash with water (3×2.5 L) and brine. Dry the organic solutions over anhydrous sodium sulfate, filter, and evaporate to a red oil. Pass the oil through a silica gel pad and elute with eluent (0% to 30% EA in hexane) to afford the title compound as an orange oil which crystallizes. Yield: 300 g (100%). MS (ES) m/z 249 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([CH3:13])=[O:12])[CH:5]=1)=[O:3].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>C(OCC)(=O)C.CCOCC>[CH3:16][N:17]([CH3:19])[CH:18]=[CH:1][C:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:12])[CH3:13])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)Nc1cccc(C(C)=O)c1
Reactant: COC(OC)N(C)C
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(=O)Nc1cccc(C(=O)C=CN(C)C)c1

Procedure:
A mixture of 3-acetamidoacetophenone 7 (20 g, 112.9 mmol), dimethylformamide dimethyl acetal (40.3 g, 338.6 mmol) was refluxed under nitrogen for 1 hour. The reaction mixture was cooled, diluted with ethyl acetate (150 mL) and ether (150 mL). The solid was collected by filtration, triturated with a solution of ethyl acetate and hexane (1:1, 200 mL). Compound 8 was obtained as a red-orange solid (23.6 g, 101.6 mmol, 90%). GC/MS, m/z=232 at tR=15.11 min (100%). LC/MS, [M+H]′=233.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.[CH2:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:16]#[CH:17]>>[CH2:15]([N:18]1[CH2:23][CH2:22][N:21]([CH2:3][C:4]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]3[C:5]=2[CH:6]=[CH:7][CH:8]=[N:9]3)[CH2:20][CH2:19]1)[C:16]#[CH:17]
Reactant: Oc1ccc(CCl)c2cccnc12
Reactant: C#CCN1CCNCC1
Agent: Cl
Product: C#CCN1CCN(Cc2ccc(O)c3ncccc23)CC1

Procedure:
The title compound was prepared by reaction of 5-chloromethyl-8-hydroxyquinolinoline (A2) with N-propargyl piperazine as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(COC)OC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: COCCOC
Product: O=Cc1ccc(-c2ccc(Cl)cc2)cc1
Yield: 94 %

Procedure:
A mixture of 4-chlorobenzeneboronic acid (19.4 g, 1 equiv), 4-bromobenzaldehyde (22.9 g, 1 equiv), palladium(II) acetate (1.4 g, 0.05 equiv) aqueous sodium carbonate (30.3 g in 144 ml solution, 2 equiv) and dimethoxyethane (500 ml) was stirred at reflux under argon for 2.5 h, then evaporated to low volume and diluted with dichloromethane. Workup continued as in (a) above to give identical material (25.2 g, 94%). 1H-NMR (CDCl3) δ10.05 (1H, s), 7.96 (2H, d), 7.73 (2H,d), 7.57 (2H, d), 7.46 (2H, d); MS (AP+) found (M+1)=217, C13H935ClO requires 216.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][CH2:13][S:14](Cl)(=[O:16])=[O:15].Cl>N1C=CC=CC=1>[Cl:12][CH2:13][S:14]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)CCl
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(NS(=O)(=O)CCl)ccc1F
Reaction time: 4 h

Procedure:
To a solution of 4-fluoro-3-nitroaniline (23.4 g, 0.15 mol) in anhydrous pyridine (120 mL) was added dropwise a solution of chloromethylsulfonyl chloride (22.35 g, 0.15 mol) at 0° C. under a nitrogen atmosphere. The mixture was then stirred at 0°-5° C. for 4 h and then the mixture was poured onto ice (1500 g) containing concentrated aqueous hydrochloric acid (300 mL). The mixture was filtered, and the residue was dissolved in methylene chloride (1200 mL). After drying (MgSO4) and concentration under reduced pressure, the crude product was dissolved in 1-chlorobutane:ether 9:1 v/v and passed through silica gel. The eluent was concentrated under reduced pressure to give the title compound of Step A.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Br)ccc1CO
Yield: 98.1 %

Procedure:
Borane tetrahydrofuran complex solution (1 M in tetrahydrofuran, 13 mL, 13 mmol) was added over 5 min to a solution of 4-bromo-2-nitrobenzoic acid (2.00 g, 8.13 mmol) at room temperature, then after 72 h the reaction mixture was carefully poured upon sat. aq. sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was dried (MgSO4) and evaporated to produce (4-bromo-2-nitro-phenyl)-methanol (1.85 g, 96%). White solid, 1H-NMR (300 MHz, CDCl3): 8.25 (d, J=1.8, 1H), 7.80 (dd, J=8.1, 1.8, 1H), 7.67 (d, J=8.1, 1H), 4.96 (d, J=6.3, 2H), 2.37 (t, J=6.3, 1H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:10][CH:11]=[CH:12][C:5]=12.Cl[CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:11]=[CH:12][C:5]=12
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1ccnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)ccnc21
Yield: 53 %

Procedure:
To a suspension of NaH (88 mg, 60% in mineral oil, 2.2 mmol) in DMF (1 mL) was added 4-chloro-1H-pyrrolo[2,3-b]pyridine (305 mg, 2 mmol, prepared according to Thibault, C. et al. Org. Lett. 2003, 5, 5023) at room temperature with stirring. The mixture was stirred for 5 min and trimethylsilylethyl chloromethyl ether (350 mg, 2.1 mmol, Aldrich) was added. The mixture was stirred at room temperature for 1 h, poured onto ice, and extracted with ethyl acetate (3×10 mL). The combined extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure to give the crude product, which was purified by flash chromatograph (5% ethyl acetate in hexanes) to afford the title compound (300 mg, 1.06 mmol, 53%) as a liquid. 1H NMR (CDCl3) δ 8.28 (d, 1H, J=5.5 Hz), 7.45 (d, 1H, J=3.6 Hz), 7.18 (d, 1H, J=5.5 Hz), 6.69 (d, 1H, J=3.6 Hz), 5.74 (s, 2H), 3.60 (t, 2H, J=6.8 Hz), 0.96 (t, 2H, J=6.8 Hz), 0.07 (s, 9H); MS(ESI+) m/z 283 and 285 (M+H, 1 Cl)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=O)[C:5]=2[S:4][CH:3]=1.O=P(Cl)(Cl)[Cl:14]>CN(C=O)C>[Cl:14][C:10]1[C:5]2[S:4][CH:3]=[C:2]([CH3:1])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1csc2c(=O)[nH]cnc12
Solvent: CN(C)C=O
Product: Cc1csc2c(Cl)ncnc12
Temperature: 110 °C
Yield: 81 %

Procedure:
7-methyl-3H-thieno[3,2-d]pyrimidin-4-one (9 g, 54.2 mmol), DMF (1 mL), POCl3 (80 mL) were mixed and refluxed for 4 hours at 110° C. The reaction solution was cooled to room temperature, and the reaction mixture was concentrated under reduced pressure. The reaction mixture was added with toluene, and further concentrated under reduced pressure. The resulting residue was neutralized with sodium bicarbonate, subjected to extraction with ethyl acetate, dried, and filtered to obtain the title compound (8.1 g, 81%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([NH2:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([NH2:14])(=[O:12])=[O:13])=[CH:6][CH:5]=1
Reactant: NS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccc(CS(N)(=O)=O)cc1
Yield: 100 %

Procedure:
5.0 g (23.1 mmol) of 4-nitrophenylmethanesulfonamide was suspended in 90% acetic acid, which was then hydrogenated at normal temperature under normal pressure in the presence of palladium-carbon. After filtering off the catalyst, the filtrate was concentrated to dryness, to give 4.3 g of 4-aminophenylmethanesulfonamide. The obtained compound was added to a mixed solution of 40 ml of water and 4.1 ml of concentrated hydrochloric acid, followed by stirring. An aqueous saturated solution containing 1.63 g (23.6 mmol) of sodium nitrite was added dropwise there into at 0° C. or less. The reaction solution was added to an acetic acid solution saturated with sulfur dioxide (solution obtained by saturating 30 ml of acetic acid with sulfur dioxide and then adding 0.97 g of cupric chloride.dihydrate thereto) under ice-cooling with stirring. After stirring at room temperature for 40 minutes, the reaction solution was poured into ice-water and the mixture was saturated with sodium chloride. The mixture was extracted with ethyl acetate, and the extract was dried over magnesium sulfate and then concentrated to dryness, to give 1.7 g of the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[O-]CC.[Na+].CN(C)[CH:12]=[CH:13][C:14](=O)[C:15]([O:19][CH3:20])([O:17][CH3:18])[CH3:16]>CCO>[CH3:18][O:17][C:15]([C:14]1[CH:13]=[CH:12][N:2]=[C:3]([NH2:5])[N:4]=1)([O:19][CH3:20])[CH3:16]
Reactant: COC(C)(OC)C(=O)C=CN(C)C
Reactant: N=C(N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COC(C)(OC)c1ccnc(N)n1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
To guanidine hydrochloride salt (15 g, 156.68 mmol) was added sodium ethoxide, 21% wt in EtOH (59 mL, 156.68 mmol). After stirring for 5 min, 1-dimethylamino-4,4-dimethoxy-pent-1-en-3-one (Lipinski; J. Het. Chem., 22:1723 (1995)) (29.30 g, 156.68 mmol) in EtOH (50 mL) was added. The mixture was heated at 80° C. under N2 for 20 h, then cooled to RT. Solvent was evaporated in vacuo and the residue was re-dissolved in hot EtOAc (200 mL). The undissolved solid was separated by filtration and the solvent was evaporated in vacuo to give a pale yellow solid. MS m/z:184.3(M+H). Calc'd for C8H14N3O2: 184.21.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]([C:16]1[Se:20][C:19]([C:21]([NH2:23])=[O:22])=[C:18]([NH2:24])[CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>C(O)(C)C>[C:12]([C:16]1[Se:20][C:19]([C:21]([NH2:23])=[O:22])=[C:18]([NH:24][C:2]2[C:3]3[CH:11]=[CH:10][CH:9]=[N:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Reactant: Clc1ncnc2ncccc12
Solvent: CC(C)O
Product: CC(C)(C)c1cc(Nc2ncnc3ncccc23)c(C(N)=O)[se]1

Procedure:
As shown in scheme G, 4-chloropyrido[2,3-d]pyrimidine (Robins, R. K. et. al., J. Am. Chem. Soc., 1955, 77, 2256-2260) is reacted with 5-tert-butyl-3-aminoselenophene-2-carboxamide in a protic solvent such as isopropyl alcohol to yield 5-(tert-butyl)-3-(pyridino[3,2-e]pyrimidin-4-ylamino)selenophene-2-carboxamide.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C(=O)N2CCCc3ccccc32)cc1
Yield: 97.8 %

Procedure:
To a solution of 10% Pd-C (5 g) in ethanol (500 ml) is added 1-(4-nitrobenzoyl)-1,2,3,4-tetrahydroquinoline (53.4 g) and the mixture is subjected to catalytic reduction at ordinary temperature under atmospheric pressure of hydrogen. After the reduction, 10% Pd-C is removed by filtration, and the filtrate is concentrated under reduced pressure to give 1-(4-aminobenzoyl)-1,2,3,4-tetrahydroquinoline (46.7 g) as yellow powder, m.p. 185°-188° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([O:16]C)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].CO>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1-c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2ccccc2C(=O)O)cc1
Reaction time: 5 h
Yield: 92.8 %

Procedure:
Methyl 4'-methylbiphenyl-2-carboxylate (10.0 g, 44.2 mmol, 1 eq), 0.5 N KOH in methanol (265.5 mL, 133 mmol, 3 eq), and water (50 mL) were mixed and refluxed under N2. After 5 hours, the solvent was removed in vacuo and water (200 mL) and ethyl acetate (200 mL) added. The aqueous layer was acidified with concentrated hydrochloric acid to a pH of 3 and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×200 mL), the organic layers collected, dried (MgSO4) and the solvent removed in vacuo to yield 8.71 g of a white solid; m.p. 140.0°-145.0°. NMR (200 MHz, DMSO-d6) δ 7.72 (d, 1H, J=7 Hz); 7.56 (t, 1H, J=7 Hz); 7.45 (d, 1H, J=7 Hz); 7.40 (t, 1H, J=7 Hz); 7.25 (s, 4H); 2.36 (s, 3H). Anal Calcd. for C14H12O2 ; C, 79.23; H, 5.70. Found: C, 79.22; H, 5.47.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:20][C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)=O.[CH3:31][O:32][C:33](=[O:43])[C@H:34]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[NH2:35].O>O1CCCC1>[CH3:31][O:32][C:33](=[O:43])[C@H:34]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[NH:35][C:25](=[O:27])[CH2:24][NH:23][C:21]([O:20][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:22]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
Solid carbonyldiimidazole (79.10 g, 0.488 mol) was added to a room temperature solution of N-benzyloxycarbonyl-glycine (117.11 g, 0.560 mol) in anhydrous tetrahydrofuran (THF, 600 mL). The resulting solution was stirred for 45 minutes until CO2 evolution had ceased. A solution of L-phenylalanine methyl ester (79.65 g, 0.444 mol) in anhydrous THF (~200 mL) was then added. The reaction temperature was maintained below 40° C. by application of a water bath to the exterior of the reaction vessel. After two hours, a small portion of water (1.5 mL, ~0.08 mol) was added to the reaction mixture to hydrolyze any remaining acylimidazolides and the resulting solution was left to stir overnight. The reaction mixture was concentrated in vacuo and the residual oil was dissolved in ethyl acetate (~1 L). This ethyl acetate solution was extracted with 1 N HCI (2×300 mL--the first aqueous extract was acidified a pH of 1 by addition of 6 N HCl), water (300 mL), saturated aqueous sodium carbonate (300 mL), half-saturated aqueous sodium carbonate (250 mL), and brine (250 mL). The organic phase was dried by filtration through magnesium sulfate and sodium sulfate and concentrated in vacuo to constant weight. Field desorption mass spectrometry (FDMS) of the resulting oil (160.88 g, ~0.434 mol, 98%) indicated the presence of a single component (M+=370). This material was not further purified, but was instead converted directly into cyclo-glycyl-L-phenylalanine (8) by catalytic hydrogenation (vide infra).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CCCCCC.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][Br:10]
Reactant: Cc1cc(Cl)ccc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: Clc1ccc(Br)c(CBr)c1
Temperature: 25 °C
Yield: 79.8 %

Procedure:
20.5 g (100 mmol) of 2-bromo-5-chlorotoluene was dissolved in 200 ml of carbon tetrachloride, 0.2 g (1 mmol) of AIBN and 19.6 g (110 mmol) of N-bromosuccinimide were added thereto, the resulting mixture was refluxed for 2 hours and cooled to room temperature. The reaction mixture was washed with 50 ml of water twice and with 50 ml of a brine solution, dried over anhydrous MgSO4, and distilled under a reduced pressure to obtain an oil containing a small amount of the starting material. The oil was dissolved in 20 ml of hexane, and recrystallized at room temperature to obtain 22.7 g (yield 80%) of 2-bromo-1-bromomethyl-5-chlorobenzene.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([NH:8][NH:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])=[O:7].N1C=CC=CC=1.ClCl>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([N:8]=[N:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])=[O:7]
Reactant: COCCOC(=O)NNC(=O)OCCOC
Agent: ClCl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COCCOC(=O)N=NC(=O)OCCOC
Yield: 59.6 %

Procedure:
To a solution obtained by adding 1,2-hydrazinedicarboxylic acid bis(2-methoxyethyl) ester (1 g, 4.23 mmol), pyridine (0.34 g, 4.23 mmol), and toluene (10 ml) to a 30 ml flask, followed by cooling with an ice bath, chlorine gas was blown for 30 minutes. After the reaction, the solution was washed with water (1 mL, ×2), and dehumidified with anhydrous magnesium sulfate, followed by concentration to dryness. The solid was recrystallized with toluene (1.5 mL) and hexane (7.5 mL), to give azodicarboxylic acid bis(2-methoxyethyl) ester as a pale yellow crystal (0.59 g, yield: 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1.Br[CH2:18][CH2:19][CH2:20][Cl:21]>>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[N:9]([CH2:18][CH2:19][CH2:20][Cl:21])[CH:10]=[CH:11][C:5]=2[CH:4]=1
Reactant: ClCCCBr
Reactant: COc1cc2c(cc1OC)CC(=O)NC=C2
Product: COc1cc2c(cc1OC)CC(=O)N(CCCCl)C=C2

Procedure:
This compound was prepared analogous to Example 111(a) by reacting 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one with 1-bromo-3-chloro-propane.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23](OC)=[O:24])=[N:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(OC)C=CC=CC=1>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]([NH:34][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:24])=[N:20][CH:21]=3)=[CH:14][CH:15]=2)[CH2:5][CH2:6]1
Reactant: NCc1ccccc1
Reactant: COC(=O)Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Solvent: COc1ccccc1
Product: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1

Procedure:
The resulting methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate (7) and benzyl amine were coupled in anisole at high temperature to afford 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide (KX2-391). An HCl solution formed by adding acetyl chloride to absolute ethanol was added to KX2-391 to form the bis-HCl salt, 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide dihydrochloride, (KX2-di-HCl).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[CH:9]=[O:10])=[CH:3][CH:2]=1.[CH:11]([O:13][CH2:14][CH3:15])=[CH2:12].C1(C=CC(O)=CC=1)O>>[CH2:11]([O:13][CH:14]1[CH2:15][CH:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:8]=[CH:9][O:10]1)[CH3:12]
Reactant: O=C/C=C/c1ccccc1
Reactant: C=COCC
Agent: Oc1ccc(O)cc1
Product: CCOC1CC(c2ccccc2)C=CO1
Yield: 87.2 %

Procedure:
313 g (2.37 Mole) of cinnamic aldehyde, 290 g (4.03 Mole) of ethyl vinyl ether and 45 g of hydroquinone were heated at 200° for 16 hours in a 1 l stainless steel autoclave (pressure about 20 atm.). After fractional distillation of the crude material thus obtained, there were isolated 422 g (87% yield) of 2-ethoxy-4-phenyl-3,4-dihydro-2H-pyran, b.p. 89°/0.02 Torr;
Reaction SMILES: [O:1]([CH2:8][CH2:9]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:20])=O>N1C=CC=CC=1>[Cl:20][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCOc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: ClCCOc1ccccc1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a flask was added 41.5 grams (g.) (0.3 mole) of 2-phenoxyethanol, 50 ml of toluene and 3.93 g. of pyridine, then 39.3 g. (0.33 mole) of thionyl chloride dropwise while stirring at room temperature. The exothermic reaction was heated at 50°-60° C. for two hours. After cooling to room temperature, the resulting salt was filtered and washed with methylene chloride. The filtrate was washed several times with aqueous sodium bicarbonate, dried using sodium sulfate, and then concentrated to obtain 39 g. of the 1-chloro-2-phenoxyethane as a yellow oil (83% yield).