Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:10]=[CH:9][C:8]=1[CH2:26][C:27]([NH2:29])=[O:28].[C:33](OC(=O)C)(=[O:35])[CH3:34].O>N1C=CC=CC=1>[C:33]([NH:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[N:10]=[CH:9][C:8]=1[CH2:26][C:27]([NH2:29])=[O:28])(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCOCC3)cc2)cc1NCc1cccc(N)c1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1cccc(CNc2cc(Nc3ccc(N4CCOCC4)cc3)ncc2CC(N)=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.8 %

Procedure:
22 mg of 4-[(3-aminobenzyl)amino]-6-[(4-morpholinophenyl)amino]pyridine-3-carboxyamide (the compound of Example 103) was dissolved in 0.5 mL of pyridine, to which 5.4 mg of acetic anhydride was added, and stirred at room temperature for 4 hours. To the reaction mixture, water was added, stirred, and the solvent was evaporated. The residue was purified by silica gel thin layer chromatography (chloroform: methanol=10:1) to obtain 2.6 mg (11%) of 4-{[3-(acetylamino)benzyl]amino}-6-[(4-morpholinophenyl)amino]pyridine-3-carboxyamide (Example 104-1) as a white solid. Furthermore, 11.6 mg (44%) of 4-{[3-(acetylamino)benzyl]amino}-6-[acetyl(4-morpholinophenyl)amino]pyridine-3-carboxyamide (Example 104-2) was obtained as a yellowish brown oil.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7][CH3:8])[C:4]=1[OH:5].[OH-].[K+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(Cl)Cl>O>[C:14]1([S:20]([OH:22])(=[O:1])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH:5][C:4]1[C:6]([O:7][CH3:8])=[CH:9][CH:10]=[CH:11][C:3]=1[CH:2]=[O:1]
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: COc1cccc(C=O)c1O
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(O)c1ccccc1
Reaction time: 8 h

Procedure:
A solution of o-vanillin (537.5 g, 3.54 mole) in water (3.6 L) containing potassium hydroxide (215 g, 3.77 mole) was treated with benzenesulfonyl chloride (360 mL, 2.83 mole) dropwise over a period of one hour. Methylene chloride (75 ml) was added and the mixture was stirred overnight. The resultant solid was collected by filtration and washed with 500 mL of 5% aqueous potassium hydroxide and 1 L of water. The solid was dried in vacuo at 70°-90° C. to give the title compound, 750 g, mp 115°-119° C.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[C:1]1([CH2:7][C:8]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(Cc1ccccc1)Nc1ccccc1
Temperature: 0 °C
Yield: 65.6 %

Procedure:
A mixture of 5.84 g (37.81 mmol) phenylacetyl chloride and 50 mL benzene was stirred at 0° C. A solution of 3.52 g (2.0 equivs.) aniline and 50 mL benzene was added dropwise. After addition was complete, the mixture was allowed to warm to room temperature and stirred for 3 hrs. The mixture was poured into 100 mL water and was extracted with 3×100 mL ethyl acetate. The organic layers were combined and washed sequentially with 100 mL portions of 5% aqueous hydrochloric acid, water, saturated sodium carbonate and water. The organic layer was dried, filtered and solvent was removed from the filtrate to provide 5.24 g (24.80 mmol, 65%) phenylacetanilide as a tan solid, mp=114°-116° C. NMR (CDCl3 /TMS): 3.73 (s, 2H), 7.08 (t, 1H), 7.18 (bs, 1H), 7.25-7.43 (m, 9H). Mass spectrum
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[S:24][CH:25]=[C:26]([CH2:27]O)[C:21]=4[S:20](=[O:30])(=[O:29])[N:19]=3)=[C:14]([OH:31])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:32][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.C1(P([N:60]=[N+:61]=[N-:62])(C2C=CC=CC=2)=O)C=CC=CC=1>ClCCl>[N:60]([CH2:27][C:26]1[C:21]2[S:20](=[O:29])(=[O:30])[N:19]=[C:18]([C:15]3[C:16](=[O:17])[N:7]([CH2:6][C:5]4[CH:33]=[CH:34][C:2]([F:1])=[CH:3][CH:4]=4)[C@@H:8]4[C@H:13]([C:14]=3[OH:31])[C@@H:12]3[CH2:32][C@H:9]4[CH2:10][CH2:11]3)[NH:23][C:22]=2[S:24][CH:25]=1)=[N+:61]=[N-:62]
Reactant: O=C1C(C2=NS(=O)(=O)c3c(CO)csc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: [N-]=[N+]=NCc1csc2c1S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
To a solution of (1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-5-(7-hydroxymethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.38 g, 0.76 mmol) in dichloromethane (9 mL) at 0° C. was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.60 mL, 4.03 mmol) and diphenylphosphoryl azide (0.84 mL, 3.88 mmol). The reaction was stirred at 25° C. overnight. The reaction was quenched with 1.0 M aqueous hydrochloric acid solution (10 mL). The resulting mixture was extracted with dichloromethane (3×10 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified via flash column chromatography (Teledyne Isco RediSep column; 0-1% methanol in dichloromethane) to afford the desired product, (1R,2S,7R,8S)-5-(7-azidomethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.21 g, 0.40 mmol, 52%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 1.18-1.78 (6H, m), 2.56-2.57 (1H, m), 2.82-2.87 (2H, m), 3.47 (1H, d, J=9.6 Hz), 4.21 (1H, d, J=14.8 Hz), 4.67 (2H, s), 5.15 (1H, d, J=14.4 Hz), 7.00-7.07 (2H, m), 7.19-7.23 (2H, m), 7.32-7.36 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.C(O)(=O)C.[N-:24]=[C:25]=[O:26].[K+]>O>[N+:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:25]([NH2:24])=[O:26])=[CH:19][C:6]=2[C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: [N-]=C=O
Reactant: Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.75 g. of 5-amino-2-nitro-3-phenylbenzofuran in 5 ml. of glacial acetic acid and 3 ml. of water is added an equimolar amount of potassium isocyanate dissolved in 5 ml. of warm water. The reaction is stirred at about 20° C. for 30 minutes then filtered to separate the solid product. The solid is recrystallized from aqueous methanol to provide yellow crystals of 2-nitro-3-phenyl-5-ureidobenzofuran, m.p. 230°-232° C.
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].O=[CH:12][C:13]([Cl:16])([Cl:15])[Cl:14]>>[CH3:10][C:9]1[C:2]2[NH:1][CH:12]([C:13]([Cl:16])([Cl:15])[Cl:14])[O:5][CH2:4][C:3]=2[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccc(CO)c1N
Reactant: O=CC(Cl)(Cl)Cl
Product: Cc1cccc2c1NC(C(Cl)(Cl)Cl)OC2
Reaction time: 0.5 h

Procedure:
2-Amino-3-methylbenzyl alcohol (1.7 g.) and anhydrous chloral (2.4 ml.) were mixed for 10 minutes with external ice-cooling, and the mixture was left to stand for 1/2 hour. The mixture was then chromatographed on silica, and elution with diethyl ether/petroleum ether (b.p. 60°-80° C.), 7:3 by volume, gave 1,2-dihydro-8-methyl-2-trichloromethyl-4H-benzo[d]-[1,3]-oxazine, which was crystallised from aqueous ethanol, m.p. 69°-70° C.
Reaction SMILES: CO.[CH3:3][S:4][C:5]([C:11]1[S:12][C:13]([C:16](OC)([O:23]C)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][CH:15]=1)([CH3:10])[C:6]([O:8][CH3:9])=[O:7].Cl>O>[CH3:3][S:4][C:5]([C:11]1[S:12][C:13]([C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][CH:15]=1)([CH3:10])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C(C)(SC)c1ccc(C(OC)(OC)c2ccccc2)s1
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)C(C)(SC)c1ccc(C(=O)c2ccccc2)s1
Yield: 97.2 %

Procedure:
Methanol (5 ml) and 1 ml of water were added to 887 mg of methyl α-methylthio-α-[5-(α,α-dimethoxybenzyl)-2-thienyl]propionate, and 0.2 ml of conc. hydrochloric acid was added. The mixture was heated under reflux for 1 hour. After cooling, the mixture was concentrated under reduced pressure. The residue was chromatographed on a silica gel column using benzene as an eluent to afford 754 mg of methyl α-methylthio-α-(5-benzoyl-2-thienyl)propionate as an oil in a yield of 97%.
Reaction SMILES: [Na].C(O)C.[NH2:5][C:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[N:12]=2)[N:7]=1.[Cl:18][C:19]1[CH:28]=[CH:27][C:22](C=CC#N)=[CH:21][CH:20]=1>ClCCl>[NH2:5][C:6]1[CH2:10][CH:9]([C:22]2[CH:27]=[CH:28][C:19]([Cl:18])=[CH:20][CH:21]=2)[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[N:12]=2)[N:7]=1
Reactant: N#CC=Cc1ccc(Cl)cc1
Reactant: NC1=NN(c2cccc(Cl)n2)CC1
Agent: [Na]
Solvent: CCO
Solvent: ClCCl
Product: NC1=NN(c2cccc(Cl)n2)C(c2ccc(Cl)cc2)C1

Procedure:
An 0.3 g. amount of sodium metal is dissolved in 100 ml. of absolute ethanol, then 7.2 g. of 2-chloro-6-hydrazinopyridine (Example 2) is added, followed by 8.2 g. of 4-chlorocinnamonitrile. The reaction mixture is refluxed for 18 hours, then is evaporated in vacuo to a gum. Water is added to give a solid. The solid is collected and dissolved in dichloromethane, dried over magnesium sulfate and filtered. The filtrate is concentrated while adding hexane to separate yellow crystals on cooling. The product is collected and washed with ether-hexane to give 10.3 g. of tan solid. The solid is dissolved in dichloromethane, filtered through absorbent magnesium silicate, then is concentrated while adding hexane to give the product of the Example as white crystals, m.p. 157°-158°.
Reaction SMILES: Br[C:2]1[N:3]=[N:4][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:6][C:7]=1[O:8][CH3:9].[CH3:20][Sn](C)(C)C>CN(C=O)C.[CH2-]C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd+]>[CH3:9][O:8][C:7]1[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:4]=[N:3][C:2]=1[CH3:20]
Reactant: COc1cc(-c2cccc(C(F)(F)F)c2)nnc1Br
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd+]
Agent: [CH2-]c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(-c2cccc(C(F)(F)F)c2)nnc1C
Yield: 63 %

Procedure:
3-Bromo-4-methoxy-6-[3-(trifluoromethyl)phenyl]pyridazine (1.0 g, 0.003 mole, Compound No. 65), tetramethyltin (1.28 g, 0.0072 mole) and trans-benzyl(chloro)bis-(triphenylphosphine)palladium(II) (20 mg) were heated to 100° C. in DMF under N2 for 18 h. The reaction was then cooled and partitioned between aqueous KF solution and ethyl acetate. The KF solution was extracted with additional ethyl acetate. The organic layers were washed with brine, dried (MgSO4), filtered through silica gel and then evaporated in vacuo. The crude oil was then chromatographed on a Prep-500 to give 4-methoxy-3-methyl-6-[3-(trifluoromethyl)phenyl]pyridazine (0.51 g, 63% yield, Compound No. 66) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]([F:17])[C:10]([F:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=O)=[O:5].[Br:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1>CN(C=O)C>[F:17][C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:18]=[C:19]([CH2:22][NH:23][C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[CH:20]=[CH:21][C:2]=2[Cl:1])[CH:15]=[C:11]([C:12]([NH:35][C:34]2[CH:36]=[CH:37][C:31]([Br:30])=[CH:32][CH:33]=2)=[O:14])[C:10]=1[F:16]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cc(F)c(F)c(C(=O)O)c2)c1
Reactant: Nc1ccc(Br)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cc(F)c(F)c(C(=O)Nc3ccc(Br)cc3)c2)c1

Procedure:
Prepared analogously to example 2f with 5-{2-Chloro-5-[(tert-butylcarbonylamino)-methyl]-benzoylamino}-2,3-difluoro-benzoic acid (0.29 g; 0.68 mmol); 4-bromoaniline (0.117 g; 0.68 mmol); PPA (0.523 mL; 0.89 mmol; 50% solution in DMF) and TEA (0.237 mL; 1.71 mmol).
Reaction SMILES: OS([O-])=O.[Na+].O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:17](=[O:19])[CH3:18])[CH:11]=[CH:10]2.[CH3:20][NH:21][CH2:22][CH2:23][OH:24]>O.C(OCC)(=O)C>[OH:24][CH2:23][CH2:22][N:21]([CH3:20])[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:17](=[O:19])[CH3:18])[CH:11]=[CH:10]2
Reactant: CNCCO
Reactant: CC(=O)c1ccc2cc(O)ccc2c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1ccc2cc(N(C)CCO)ccc2c1
Yield: 73 %

Procedure:
A mixture of 4.15 g (55.5 mmol) NaHSO3, 8 m L of water, 0.78 g (4.19 mmol) of 1-(6-hydroxy-2-naphthyl)-1-ethanone (prepared as described in Example 1(b)), and 8 mL of 2-methylaminoethanol was heated and stirred in a steel bomb at 140° C. for 28 hours. After cooling, the mixture was distributed between ethyl acetate and water (500 mL and 200 mL, respectively). The organic layer was dried and evaporated to leave raw 1-(6-(2-hydroxyethyl-methylamino)-2-naphthyl)-1-ethanone (0.749 g, 73%) of which was further purified by radial chromatography (4 mm SiO2, CH2Cl2).
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C:6]1[C:14]([N:15]=[N:16][C:17]2[NH:18][C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:21]=2)=[CH:13][C:9]([C:10](O)=[O:11])=[C:8]([N+:34]([O-:36])=[O:35])[CH:7]=1>O1CCCC1>[OH:5][C:6]1[C:14]([N:15]=[N:16][C:17]2[NH:18][C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:21]=2)=[CH:13][C:9]([C:10]([Cl:3])=[O:11])=[C:8]([N+:34]([O-:36])=[O:35])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(N=Nc2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)c(O)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: O=C(Cl)c1cc(N=Nc2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)c(O)cc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
Thionyl chloride (120 ml) was added with stirring to a suspension of VI (11.1 g, 0.026 mole) in dry tetrahydrofuran (120 ml) at 20° C. The mixture became warm and the suspension dissolved, giving a dark-red solution. After a few minutes, a bright-red solid precipitated. The mixture was stirred for a further 15 minutes, cooled to 5° C. and the product filtered off and dried at 50° C. for one hour. TLC analysis showed the product to be pure.
Reaction SMILES: [C:1]([CH:3]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)#[N:2].N.[H][H].[ClH:22]>[Ni].C(OCC)(=O)C.CO>[ClH:22].[NH2:2][CH2:1][CH:3]([C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1
Reactant: [H][H]
Reactant: COc1ccc(C(C#N)C2(O)CCCCC2)cc1
Agent: [Ni]
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(C(CN)C2(O)CCCCC2)cc1

Procedure:
A 5 liter autoclave is charged with 180 g of 1-[cyano(4-methoxyphenyl)methyl]cyclohexanol, 2400 ml of methanol, 600 ml of aqueous ammonia (25% by volume) and 135 g of Raney nickel (pretreated as given under 1a)) and the mixture is subjected to hydrogenation at 27 to 30° C. and 120 psi pressure of hydrogen for 9 to 10 hours. The reaction mixture is filtered through 100 g of the celite and the catalyst bed is washed with 700 ml of methanol. The filtrate is concentrated to get 167.1 g of the crude product as an oily residue. 1.1 g of the crude product is dissolved in 2 ml of dry ethyl acetate and about 2 ml of isopropanolic HCl are added (the pH of the solution is about 2). The solvent is removed at high vacuum to give 1.14 g of 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([N:19]=[N+]=[N-])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(P(CCCC)CCCC)CCC.C1C([N+]([O-])=O)=CC=C(O)C=1>C(#N)C>[CH2:11]([NH:19][C:8](=[O:10])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: [N-]=[N+]=NCCc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=[N+]([O-])c1ccc(O)cc1
Solvent: CC#N
Product: O=C(Cc1ccccc1)NCCc1ccccc1
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To an argon-blanketed solution of phenylacetic acid (69 mg, 0.51 mmol) in acetonitrile (3 mL) was added bis(trimethylsilyltrifluoroacetamide) (BSTFA, 400 μL, 1.51 mmol) via syringe. The mixture was stirred for 30 min. after which time solvent, unreacted starting material and the reaction by-products were removed at high vacuum. The colorless residue was redissolved in toluene (5 mL) and phenethyl azide (58 mg, 0.39 mmol) then freshly-distilled tri-n-butylphosphine (98 μL, 0.39 mmol) were added via syringe. While nitrogen evolution was still progressing, p-nitrophenol (55 mg, 0.40 mmol) was added in one portion, imparting a bright yellow color to the solution. The reaction was stirred at 65° C. for 48 h. The reaction mixture was partitioned between satd Na2CO3 solution and ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow oil that was purified by flash chromatography (1:1 EtOAc/hexane) to yield 91 mg (98%) of the title compound as a white powder (mp 91-92° C., lit. mp 91-93° C.). Spectral data were identical to those reported in the literature.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-:2].C(N(CC)CC)C.[F:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[F:25])[C:19](Cl)=[O:20]>C1COCC1>[F:15][C:16]1[CH:17]=[C:18]([C:19]2[O:20][CH:2]=[N:1][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: [C-]#[N+]CC(=O)OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ncoc1-c1ccc(F)c(F)c1
Reaction time: 0.25 h
Yield: 78.7 %

Procedure:
To a well stirred solution of the methyl isocyanoacetate (2 g, 20.2 mmol) in THF (3 mL), triethyl amine (8.4 mL, 6.06 mmol) was added and the reaction mixture was stirred for 15 minutes. Then 3,4-difluorobenzoylchloride (2.5 mL, 20.20 mmol) was added neat over a period of five minutes and the reaction mixture was allowed to stir at room temperature for 48 hours. It was then concentrated, partitioned between ethyl acetate (50 mL) and water. The organic layer was washed with 10% NaOH solution (20 mL), dried over sodium sulfate, filtered and concentrated to yield 3.8 g (79%) of a brown solid which was recrystallized from hexanes: 1H-NMR (CDCl3) δ3.74(s, 3H), 7.47-7.50 (m, 1 H), 7.92 (s, 2 H), 8.01-8.10 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C@@H:9]([NH2:11])[CH3:10].C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C@@H:9]([NH:11][C:41]([C:37]1[CH:36]=[C:35]2[C:40](=[CH:39][CH:38]=1)[N:32]([CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C:20]3[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:30][CH:29]=1)[C:33]([CH3:45])=[C:34]2[CH3:44])=[O:42])[CH3:10]
Reactant: C[C@H](N)c1c(Cl)cccc1Cl
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3c(Cl)cccc3Cl)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using (S)-1-(2,6-dichlorophenyl)ethanamine and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 571 [M+H]+.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[N:15]=[C:14]([NH:16][CH3:17])[CH2:13][N:12]=[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:10]=2[CH:24]=1.C(O)(=O)C>O>[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[N:15]=[C:14]([NH:16][CH2:17][N:1]=[O:3])[CH2:13][N:12]=[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:10]=2[CH:24]=1
Reactant: CNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=NCNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4.3 g. (0.0625 mol) of sodium nitrite was added in small portions to a stirred solution of 16.4 g. (0.05 mol) of 7-bromo-2-methylamino-5-(2-pyridyl)-3H-1,4-benzodiazepine in 200 ml. of glacial acetic acid. After addition (15 minutes), the mixture was stirred for 30 minutes at room temperature, diluted with water and extracted with ether. The extracts were washed with saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated, giving crude 7-bromo-2-(N-nitrosomethylamino)-5-(2-pyridyl)-3H-1,4-benzodiazepine as an oil. 2 g. of the remaining oil was chromatographed over 60 g. of silica gel using 10 percent ethanol in methylene chloride. The clean fractions were combined and evaporated. The residue was stirred in isopropanol overnight, whereupon crystalline 7-bromo-2-(N-nitrosomethylamino)-5-(2-pyridyl)-3H-1,4-benzodiazepine separated, m.p. 102°-106°.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7](Cl)=[O:8])(=[O:3])[CH3:2].[CH3:14][S:15][C:16]1[S:20][C:19]([NH2:21])=[N:18][CH:17]=1.C(N(CC)CC)C>C1COCC1>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](=[O:8])[NH:21][C:19]1[S:20][C:16]([S:15][CH3:14])=[CH:17][N:18]=1)(=[O:3])[CH3:2]
Reactant: CSc1cnc(N)s1
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1cnc(NC(=O)c2ccccc2OC(C)=O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
Under nitrogen a solution of acetylsalicyloyl chloride (1.24 g, 6.20 mmol, 1.3 eq) in THF (40 mL) was added to a stirred solution of 5-(methylthio)thiazol-2-amine 514 (700.0 mg, 4.79 mmol, 1.0 eq) in dry THF (5 mL). This was followed by the addition of triethylamine (0.67 mL, 4.79 mmol, 1.0 eq). The reaction mixture was stirred at room temperature and monitored by TLC. After two hours, reaction was filtered through sintered funnel and solvent removed in vacuo. The crude product was dissolved in EtOAc (150 mL) and washed twice each with 1M HCl and saturated aq. sodium hydrogen carbonate solutions. The organic fraction was dried over MgSO4 followed the removal of solvent. Flash column chromatography yielded the pure product 518 (1.450 g, 98%) as a solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH3:12])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1)=[O:4].CO.[BH4-].[Na+]>O>[CH3:12][NH:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([CH:2]([CH3:16])[CH3:1])[OH:4])=[CH:6][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: CNc1ccc(C(=O)C(C)C)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNc1ccc(C(O)C(C)C)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred solution of 30 parts of intermediate 45, namely 2-methyl-1-[4-(methylamino)-3-nitrophenyl]-1-propanone in 320 parts of methanol were added dropwise 15 parts of sodium tetrahydroborate (the temperature was kept at 20° C.). Upon complete addition, stirring was continued for 30 minutes at room temperature. The reaction mixture was poured into water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated to dry, yielding 30 parts (100%) of 4-(methylamino)-α-(1-methylethyl)-3-nitrobenzenemethanol as an oily residue (interm. 46).