Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].C(O)=[O:11].C([O-])=O.Cl>CC#N.CO>[OH:11][CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8]
Reactant: O=CO
Reactant: Cc1oc(=O)oc1CBr
Agent: Cl
Agent: O=C[O-]
Solvent: CO
Solvent: CC#N
Product: Cc1oc(=O)oc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
4,5-dimethyl-2-oxo-1,3-dioxole (5 g, 43.82 mmol), NBS (8.19 g, 46.01 mmol), and benzoyl peroxide (20 mg) were dissolved in CCl4 (30 mL) and heated to 80° C. for 1.5 h. The reaction mixture was cooled to r.t and the solid was filtered off. The filtrate was concentrated. The residue was purified by silica gel column to give 8.29 g of 4-bromomethyl-5-methyl-2-oxo-1,3-dioxole as a yellow oil. TEA (12 mL, 86.1 mmol) was added dropwise to a solution of 4-bromomethyl-5-methyl-2-oxo-1,3-dioxole (6 g, 31.09 mmol) and formic acid (3.36 mL) in CH3CN (96 mL) while keeping the temperature under 20° C. The mixture was stirred at r.t. for 2 h and concentrated. The product was partitioned between H2O and EtOAc (3×). The organic layer was dried with Na2SO4, concentrated and dried in vacuo to give crude formate. The resulting formate was dissolved in MeOH (40 mL) and 0.5 mL of concentrated HCl was added. The mixture was stirred at r.t. for 5 h, concentrated, and co-evaporated with toluene. The crude product was purified by silica gel column to give 2.8 g of 4-hydroxymethyl-5-methyl-2-oxo-1,3-dioxole in 69% yield. 1H NMR (300 MHz, CDCl3): d 4.40 (s, 2H), 2.60 (broad, s, 1H), 2.20 (s, 3H).
Reaction SMILES: [H-].[Li+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([NH:8][C:9]2[S:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)=[CH:6][CH:5]=1.Br[CH2:23][CH2:24][OH:25]>CN(C=O)C>[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([N:8]=[C:9]2[N:14]([CH2:23][CH2:24][OH:25])[C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[N:19][C:11]=3[S:10]2)=[CH:6][CH:5]=1
Reactant: OCCBr
Reactant: O=c1nc(Nc2ccc(Cl)cc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c2cccnc2sc(=Nc2ccc(Cl)cc2)n1CCO
Reaction time: 0.08 h
Yield: 80.6 %

Procedure:
In an atmosphere of argon, a mixture of 60 mg (7.6 mmol) of lithium hydride and 10 ml of DMF was put in a 100 ml flask. To the flask was then connected a dropping funnel which contained 1,600 mg (5.5 mmol) of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one and 10 ml of DMF. The solution of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one was then added dropwise to the aforementioned mixture with stirring in 5 minutes. The mixture was further stirred for 2 hours. To the mixture was then added a mixture of 1,034 mg of 2-bromoethanol and 4 ml of DMF. The mixture was then stirred for 22 hours. After the termination of reaction, the mixture was concentrated under reduced pressure. The resulting residue was then extracted with water and ethyl acetate. The resulting organic phase was separated, washed with water and saturated brine, and then dried over sodium sulfate. The drying agent was then removed by filtration. The filtrate was then concentrated under reduced pressure. The resulting residue was then purified through silica gel column chromatography (eluant: 1/1 mixture of ethyl acetate and normal hexane). As a result, 1.48 g of 2,3-dihydro-2-[(4-chlorophenyl)imino]-3-(2-hydroxyethyl)-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a low polarity substance, and 220 mg of 2-[N-(4-chlorophenyl)-N-(2-hydroxyethyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a high polarity substance.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[CH3:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[NH:22][NH2:23]>CO.C(O)(=O)C>[CH3:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[NH:22][N:23]=[C:1]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: COc1cccnc1C(C)=O
Reactant: Cn1c(NN)nc2ccccc21
Solvent: CO
Solvent: CC(=O)O
Product: COc1cccnc1C(C)=NNc1nc2ccccc2n1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2-acetyl-3-methoxypyridine (0.50 g, 3.31 mmol) and 1-methyl-2-hydrazinobenzimidazole (0.54 g, 3.31 mmol) in 10 ml of methanol is stirred at room temperature for 3 days after the addition of 6 drops of glacial acetic acid. The reaction is monitored by means of thin layer chromatography (Polygram Sil G/UV254 prefabricated foils; eluting agent: CH2Cl2:MeOH (12:1)). Subsequently, the reaction mixture is diluted with distilled water until a precipitate forms and stored for 24 hours in the refrigerator at approximately 5° C. The precipitate is filtered, washed several times with water, and dried. The product is recrystallized from a mixture of 20 ml of methanol and 10 ml of water. Yield: 0.87 g (89% of theory).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[N:8][CH:9]=1)([O-:3])=[O:2].[Br:11]Br>O>[Br:11][C:6]1[C:7]([OH:10])=[N:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: BrBr
Solvent: O
Product: O=[N+]([O-])c1cnc(O)c(Br)c1
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
To a solution of 5-nitropyridin-2-ol (0.06 mol, 8.6 g) in 400 ml of water at 40°, 3.7 ml of Br2 was added. The mixture was stirred at 40° C. for 2.5 h and then it was stirred at room temperature overnight. The solid formed was filtered off, washed with water and dried under vacuum overnight affording 12.5 g (93% of yield) of the expected product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:13]#[N:14])[NH:6][C:7](=O)[CH2:8][CH2:9][O:10][CH3:11])[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:25]2)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[N:6]=[C:7]([CH2:8][CH2:9][O:10][CH3:11])[S:25][C:13]=1[NH2:14])=[O:15])[CH3:2]
Reactant: CCOC(=O)C(C#N)NC(=O)CCOC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(CCOC)sc1N
Temperature: 110 °C
Yield: 82.2 %

Procedure:
A suspension of cyano-(3-methoxy-propionylamino)-acetic acid ethyl ester (0.95 g, 4.44 mmol) in toluene (11.00 ml) was flushed with argon. 2,4-bis(4-Methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (Lawesson's reagent) (0.90 g, 2.22 mmol) was added at once and the mixture was warmed at 110° C. for 2 h. Toluene was evaporated and the residue purified by flash chromatography (heptane/ethyl acetate) to yield 5-amino-2-(2-methoxy-ethyl)-thiazole-4-carboxylic acid ethyl ester (0.42 g, 40%), MS (ISP): m/e=231.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:19]O)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][C:11]1([CH2:16][CH2:17][CH3:18])[O:15][CH2:14][CH2:13][O:12]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[SH:33][C:34]1[NH:35][C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:1][C:2]1[C:3]([CH2:19][S:33][C:34]2[NH:38][C:37]3[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=3[N:35]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][C:11]1([CH2:16][CH2:17][CH3:18])[O:12][CH2:13][CH2:14][O:15]1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CCCC1(CCOc2ccnc(CO)c2C)OCCO1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC1(CCOc2ccnc(CSc3nc4ccccc4[nH]3)c2C)OCCO1
Reaction time: 0.83 h
Yield: 79.8 %

Procedure:
The (3-methyl-4-(2-(2-propyl-1,3-dioxolan-2-yl)ethoxy)pyridin-2-yl) methanol (450 mg, 1.6 mmol) obtained in the step (3e) was mixed with tetrahydrofuran (10 ml). The mixture was cooled on ice in a nitrogen atmosphere. To this, triethylamine (0.446 ml, 3.2 mmol), and methanesulfonyl chloride (0.186 ml, 2.4 mmol) were added and stirred for 50 minutes under ice-cooling. To the reaction mixture, 2-mercaptobenzimidazole (240 mg, 1.6 mmol) was added and stirred at room temperature overnight. To the reaction mixture, an aqueous solution of sodium hydrogen carbonate was added and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate. After silica gel was added to the solution, the solution was concentrated. The dried residue was subjected to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=1/1→0/1) to obtain the title compound (528 mg, 79.8%) as a colorless viscous oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][C:8]1[C:17]2[C:16](=[N:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:15][C:14]([CH:25]([O:27][C:28](=[O:30])[CH3:29])[CH3:26])=[N:13][C:12]=2[CH:11]=[CH:10][CH:9]=1>CCOC(C)=O>[CH3:26][CH:25]([O:27][C:28](=[O:30])[CH3:29])[CH:14]([NH:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:7])[C:17]=1[C:16](=[O:15])[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)c1nc2cccc(C)c2c(=Nc2ccccc2)o1
Reactant: C1CCNCC1
Solvent: CCOC(C)=O
Product: CC(=O)OC(C)C(Nc1cccc(C)c1C(=O)Nc1ccccc1)N1CCCCC1
Reaction time: 19.5 h

Procedure:
Piperidine (1 mL) was added to compound 178 (0.161 g, 0.5 mmol) and the reaction mixture was stirred for 19.5 h. The reaction mixture was then concentrated under reduced pressure to give a yellow gum. Trituration with 1:4 EtOAc:hexanes gave a small amount of compound 179 (0.041 g). Flash chromatography (1:4 EtOAc:hexanes) of the filtrate gave only a partially separable mixture of the expected products, the acetoxyquinazolinone compound 179 and the hydroxyquinazolinone (total mass 0.122 g). ESI-MS m/z=408 (MH+). The reaction described above and compound 179 are shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.[CH3:13][NH:14][C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([O:30]CCC)=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([N:14]([CH3:13])[C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([OH:30])=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:12]
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(O)Cc1ccc(F)cc1Cl
Product: CN(C(=O)Cc1ccc(F)cc1Cl)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from (2-chloro-4-fluorophenyl)acetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 429.
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[C:9]1(=[O:19])[CH:18]2[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11][CH2:10]1.Cl>O1CCCC1.CCOCC>[O:19]=[C:9]1[CH:18]2[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11][CH:10]1[C:3]([O:6][CH3:7])=[O:8]
Reactant: COC(=O)OC
Reactant: O=C1CCCC2CCCCC12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C1CCC2CCCCC2C1=O

Procedure:
A suspension of sodium hydride (4.60 g, 115 mmol) in tetrahydrofuran (20 mL) was treated with dimethyl carbonate (8.29 mL, 99 mmol), heated to reflux under nitrogen, treated dropwise with a solution of octahydronaphthalen-1(2H)-one (Aldrich cat#115063, mixture of trans (major) and cis (minor), 5 g, 32.8 mmol) in tetrahydrofuran (20 mL) over 5 minutes, and heated to reflux overnight. The mixture was cooled, diluted with ether (300 mL) and treated with 1 M hydrochloric acid (150 mL). The layers were separated and the aqueous layer was extracted with ether (2×100 mL). The combined ether layers were washed with brine, dried (magnesium sulfate), filtered and concentrated to provide the desired product that was not purified, but used as is in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12](C(O)=O)[CH2:11][S:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1C[O:20][CH2:19]C1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH2:19][OH:20])[S:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CSCC1C(=O)O
Reactant: C1CCOC1
Agent: B
Product: CC(C)(C)OC(=O)N1CSC(CO)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To a stirred solution of 3-tert-butoxycarbonylthiazolidine4-carboxylic acid (2.3 g, 10.0 mmol) in THF (30 ml) was added BH3.THF(1.0 M solution in THF, 20.0 ml, 20.0 mmol) at 0° C. After stirred at room temperature for 1.0 h, the reaction mixture was heated under reflux for 1.0 hr. After cooled, the mixture was concentrated in vacuo. Water was added thereto at 0° C., and extracted with EtOAc. The extract was washed with water, then dried over Na2SO4, and concentrated in vacuo to give 3-tert-butoxycarbonyl-5-hydroxymethylthiazolidine (2.0 g , quant) as a a colorless oil. 1H-NMR (CDCl3) δ 1.48 (s, 9H), 2.80–2.85 (m, 1H), 3.13–3.17 (m, 1H), 3.20–3.30 (m, 1H), 3.64–3.70 (m, 2H), 4.34 (br s, 1H), 4.60 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:41]=[CH:40][C:32]([C:33]([NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:31][CH:30]=1>>[C:36]([NH:35][C:33]([C:32]1[CH:31]=[CH:30][C:29]([CH2:28][NH:27][C:3]2[C:4]3[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6][C:5]=3[CH:17]=[CH:18][C:2]=2[Cl:1])=[CH:41][CH:40]=1)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)NC(=O)c1ccc(CN)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: CC(C)(C)NC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1

Procedure:
Use a method similar to the General Procedure 5-2, using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.2 g, 0.35 mmol) and 4-aminomethyl-N-tert-butyl-benzamide (0.2 g, 1.06 mmol), to give 6-(4-tert-butylcarbamoyl-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14](N2[C@@H](CC3C=CC=CC=3)COC2=O)=[O:15])[N:9]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-:37]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:37])=[O:15])[N:9]1[C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)N1C(=O)OC(C)(C)C
Reactant: [OH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-3-((S)-4-benzyl-2-oxo-oxazolidine-3-carbonyl)-tetrahydro-pyridazine-1,2-dicarboxylic acid di-tert-butyl ester (1.22 g, 2.5 mmol) in THF (15 mL) at 0° C., is added a solution of LiOH (7 mL, 5% in H2O). After stirring at 0° C. for 2 hours, the reaction mixture is diluted with 15 mL of water and extracted with 20 mL of ether. The ether layer is extracted with 10 mL of saturated NaHCO3. The combined aqueous layers is acidified with saturated NaHSO4 to Ph=2, and extracted with CH2Cl2 (3×20 mL). The combined organic layers is dried over Na2SO4 and concentrated to give clued product (0.83 g) as a pale gum without further purification for next step reaction. (NMR and MS data confirmed, U-3133-56-22).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[CH2:16][NH:17][O:18][CH3:19]>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:17]([CH2:16][C:15]2[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=2[F:13])[O:18][CH3:19])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCc1ccccc1F
Product: CON(Cc1ccccc1F)C(=O)C=C1OC(C)(C)OC1=O
Yield: 84 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(2-fluorobenzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as a white solid (84% yield): mp 109-111° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 3.72 (3H, s, OCH3), 4.92 (2H, s, NCH2), 6.40 (1H, s, CH), 7.03-7.12 (2H, m, aromatics), 7.24-7.30 (1H, m, aromatic), 7.4 (1H, m, aromatic). Anal. calcd. for C15H16FNO5: C, 58.25; H, 5.21; N, 4.52. Found: C, 58.47; H, 5.16; N, 4.66.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Oc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-Chloro-3-nitrophenol (2.0 g, 0.012 mol), phenylboronic acid (3.5 g, 0.029 mol), TEA (9.6 mL, 0.069 mol), cupric acetate (3.3 g, 0.018 mol) and DCM (100 mL, 2 mol) were added to a 100 mL oven dried flask and the reaction was stirred at rt for 48 h. The solvent was then removed under reduced pressure and the resulting residue was purified by flash chromatography (5% EtOAc in Hexane).
Reaction SMILES: [C:1]1([C:7]2[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C([BH3-])#N.[Na+].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=O>CO>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH:13][C:12]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Nc1cccnc1-c1ccccc1
Reactant: COc1ccccc1C=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1CNc1cccnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
Under a nitrogen atmosphere, in a round-bottom flask were placed 500 mg (2.9 mmol) of 2-phenyl-3-aminopyridine, 10 mL of methanol and 1 g of 3A molecular sieves. The pH of the system was adjusted to ca. 4.5, using methanol saturated with HCl , and 190 mg (2.9 mmol) of sodium cyanoborohydride was added to the system. The pH of the system was adjusted to 4.5, 474 mg (3.5 mmol) of 2-methoxybenzaldehyde was added and the mixture was stirred at room temperature overnight. The mixture was filtered through (Celite®) and the filtrate was concentrated. The residue was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate, the layers were separated and the aqueous phase was extracted with three portions of CH2Cl2. The combined organic fractions were dried (Na2SO4) and concentrated with a rotary evaporator. The crude material was purified by flash column chromatography to obtain 475 mg of 3-(2-methoxybenzylamino)-2-phenylpyridine. Mp. 128°-129° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.[OH:21][CH2:22][C:23]([NH:25][NH2:26])=O>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:23]([CH2:22][OH:21])=[N:25][N:26]=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1
Reactant: NNC(=O)CO
Reactant: Fc1ccc2c(c1)C(c1ccccc1Cl)=NCC(=S)N2
Solvent: CCCCO
Product: OCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Preparation 1, a solution of 1,3-dihydro-7-fluoro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione and hydroxyacetic acid hydrazide in n-butyl alcohol is refluxed to give 8-fluoro-1-(hydroxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 7 8-Chloro-1-[(diethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [CH:1]([N:4]1[C:9]2=[N:10][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][CH2:29][N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[N:12][CH:13]=[C:8]2[CH2:7][NH:6][C:5]1=[O:36])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>O1CCCC1.C(OCC)C>[CH:1]([N:4]1[C:9]2=[N:10][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:22][CH2:23][CH:24]([CH2:27][CH2:28][CH2:29][N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[CH2:25][CH2:26]4)=[CH:17][CH:16]=3)=[N:12][CH:13]=[C:8]2[CH:7]=[N:6][C:5]1=[O:36])([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=O)NCc2cnc(Nc3ccc(N4CCC(CCCN5CCOCC5)CC4)cc3)nc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)n1c(=O)ncc2cnc(Nc3ccc(N4CCC(CCCN5CCOCC5)CC4)cc3)nc21
Reaction time: 8 h
Yield: 88.5 %

Procedure:
Prepared from 100 mg (0.20 mmol) of 1-isopropyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 88.5 mg (0.79 mmol) of potassium tert-butoxide in 10 mL of tetrahydrofuran. The reaction mixture is stirred overnight, 88.5 mg (0.79 mmol) of potassium tert-butoxide is added, and the reaction is continued for 48 hours. After the workup, the semi-solid is five times suspended in diethyl ether and rotovapped to dryness to give 87 mg (85%) of the title compound: mp>95° C. (dec).
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].[P:5](Cl)(=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8]>C1(C)C=CC=CC=1>[CH2:7]([O:6][P:5]([N:3]=[C:2]=[S:1])([O:9][CH2:10][CH3:11])=[O:12])[CH3:8]
Reactant: CCOP(=O)(Cl)OCC
Reactant: N#C[S-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOP(=O)(N=C=S)OCC
Temperature: 25 °C

Procedure:
To a mixture of 8.02 g of dry sodium thiocyanate in 100 ml of dry toluene at 0° C., under a nitrogen atmosphere is added 13.1 ml (16.6 g) of diethyl phosphorchloridate dropwise with stirring. The mixture is warmed to ambient temperature and stirred 20 hours. The mixture is filtered through a pad of Celite and the pad is washed with two 50 ml portions of toluene. The filtrate is washed with 50 ml of ice cold 10% sodium bicarbonate solution, 50 ml of ice water and dried over anhydrous magnesium sulfate. The mixture is filtered and the filtrate used without further purification is subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1Cl
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(Cl)c2)CC1

Procedure:
2-chloro-4-fluoronitrobenzene (1.0 eq, 1 g, 5.7 mmol), N-methyl piperazine (1.2 eq, 1.18 g, 6.84 mmol), potassium carbonate (2.0 eq, 1.6 g, 11.6 mmol) were stirred at 100° C. in DMF for 3 hours. The mixture was cooled down and diluted with water. The material was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and the solvent evaporated in vacuo. After trituration in diethylether and filtration, 1-(3-chloro-4-nitrophenyl)-4-methylpiperazine was isolated as a solid (0.9 g, 62%). LCMS (ES): m/z 256 [M+1]+. This material was suspended in MeOH (20 ml) with Raney Nickel (0.2 g) and stirred under hydrogen atmosphere overnight. The catalyst was filtered off through celite. Evaporation of the solvents provided 2-chloro-4-(4-methylpiperazin-1-yl)aniline as a dark brown oil (0.68 g, 86%). LCMS (ES): m/z 226 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>ClCCl>[CH3:17][S:18]([O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])(=[O:20])=[O:19]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1COS(C)(=O)=O
Reaction time: 2 h
Yield: 103.1 %

Procedure:
tert-butyl [(1S,2S)-2-(hydroxymethyl)cyclohexyl]carbamate (1.3 g, 5.68 mmol) was dissolved in dichloromethane (10 mL) and MsCl (0.52 mL, 6.75 mmol) was added drop wise at 0° C. Triethylamine (1 mL) was then added and the mixture stirred for 2 hours. The reaction mixture was quenched with ice and diluted in dichloromethane. Washed with a saturated solution of NaHCO3 and brine, dried and concentrated in vacuo to provide the tile compound as brown solid (1.8 g). MS (M+1): 308.16