Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]([CH2:8][OH:9])[CH2:4][C@H:3]1[CH2:10][O:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[H-].[Na+].[CH3:20]I.[I-]>C1COCC1>[CH3:20][O:9][CH2:8][CH:5]1[C:6](=[O:7])[N:2]([CH3:1])[C@H:3]([CH2:10][O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:4]1
Reactant: CN1C(=O)C(CO)C[C@H]1COc1cccnc1
Reactant: CI
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1C[C@@H](COc2cccnc2)N(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 327 mg (139 mmmol) sample of 3-(1-methyl-4hydroxymethyl-5-oxo-2(S)-pyrrolidinylmethoxy)pyridine, prepared as in Example 48a above, was dissolved in 13 mL of anhydrous THF, 111 mg (2.77 mmol) of NaH was added, and the mixture was stirred for 30 minutes at room temperature. To this solution was added 258 mL (4.17 mmol) of methyl iodide and 256 mg of tetrabutylammomnum iodide, and the reaction was stirred at room temperature for 2 hours. The reaction was quenched by the addition of water, and the mixture was extracted with chloroform. The extract was dried over MgSO4, filtered and concentrated. The solvent was removed, and the residue was purified by column chromatography on silica gel, eluting with 10: 1 chloroform:methanol to give 314 mg of the title compound. MS (DCI/NH3) m/e: 251 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.37-8.25 (m, 2H), 7.35-7.25 (m, 2H), 4.18-4.0 (m, 2H), 3.99-3.84 (m, 1H), 3.73-3.58 (m, 2H), 3.37 (s, 2H), 3.36 (s, 1H), 3.05 (s, 1H), 2.95 (s, 1H), 2.94 (s, 1H), 2.90-2.63 (m, 1H), 2.49-2.24 (m, 2H).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]2[CH:18]=[N:19][N:20](C3CCCCO3)[CH:21]=2)[CH:16]=1.[CH2:29]([OH:31])[CH3:30]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]2[CH:18]=[N:19][N:20]([CH2:11][CH2:3][N:4]3[CH2:5][CH2:6][O:31][CH2:29][CH2:30]3)[CH:21]=2)[CH:16]=1.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]2[CH:21]=[N:20][NH:19][CH:18]=2)[CH:16]=1
Reactant: CCO
Reactant: Nc1ncc(-c2cnn(C3CCCCO3)c2)cc1-c1nc2ccccc2o1
Agent: Cl
Product: Nc1ncc(-c2cn[nH]c2)cc1-c1nc2ccccc2o1
Product: Nc1ncc(-c2cnn(CCN3CCOCC3)c2)cc1-c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The 3-(1,3-benzoxazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine was prepared as follows: Hydrogen chloride (16.26 ml, 4N in dioxane) was added to a stirred suspension 3-(1,3-benzoxazol-2-yl)-5-(1-tetrahydropyran-2-ylpyrazol-4-yl)pyridin-2-amine (4.7 g) dissolved in ethanol (30 ml). The resulting mixture was stirred at 25° C. for 2 hours. The reaction was evaporated under reduce pressure, adsorbed on silica gel and purified by flash chromatography on silica gel eluting with 20 to 80% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford 3-(1,3-benzoxazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine (3.35 g). NMR Spectrum: (CDCl3) 7.39-7.50 (m, 2H), 7.65 (bs, 2H), 7.80 (dd, 1H), 7.84 (dd, 1H), 7.98 (bs, 1H), 8.24 (bs, 1H), 8.45 (d, 1H), 8.55 (d, 1H); Mass spectrum: M+H+ 278
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1([F:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[O:21]1[CH2:24][C:23](=O)[CH2:22]1.C([BH3-])#N>O1CCCC1.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:17]([NH2:20])(=[O:18])=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1([F:16])[CH2:15][CH2:14][N:13]([CH:23]2[CH2:24][O:21][CH2:22]2)[CH2:12][CH2:11]1
Reactant: NS(=O)(=O)c1ccc(OCC2(F)CCNCC2)c(Cl)c1
Reactant: O=C1COC1
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccc(OCC2(F)CCN(C3COC3)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 322C (830 mg) in tetrahydrofuran (15 mL) and acetic acid (5 mL) was added oxetan-3-one (163 mg) and MP-cyanoborohydride (2.38 mmol/g, 1.9 g). The mixture was stirred at room temperature overnight. The reaction was then filtered and the filtrate was concentrated under vacuum. The residue was slurried in ether and the solid product was collected by filtration.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([P:21](=[O:28])([O:25]CC)[O:22]CC)[P:13](=[O:20])([O:17]CC)[O:14]CC)=[CH:3][CH:2]=1>Cl>[OH2:14].[N:1]1[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([P:21](=[O:22])([OH:25])[OH:28])[P:13](=[O:14])([OH:17])[OH:20])=[CH:3][CH:2]=1.[N:1]1[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([P:21](=[O:22])([OH:25])[OH:28])[P:13](=[O:14])([OH:17])[OH:20])=[CH:3][CH:2]=1
Reactant: CCOP(=O)(OCC)C(NCCCSc1ccncc1)P(=O)(OCC)OCC
Agent: Cl
Product: O
Product: O=P(O)(O)C(NCCCSc1ccncc1)P(=O)(O)O
Yield: 112.8 %

Procedure:
A mixture of tetraethyl 3-(4-pyridylthio)propylaminomethylenebisphosphonate (7.4 g) and concentrated hydrochloric acid (50 ml) was heated under reflux for 2 hours, and then concentrated under reduced pressure. The residual crystals were collected by filtration to obtain 3-(4-pyridylthio)propylaminomethylenebisphosphonic acid hemihydrate (4.3 g, 77%), and recrystallized from water.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](CN)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:17][CH2:18][C:19]([N:21]([O:23][CH3:24])[CH3:22])=[O:20].[C:25](#[N:27])C>>[CH2:7]([N:27]([CH3:25])[CH2:17][CH2:18][C:19]([N:21]([O:23][CH3:24])[CH3:22])=[O:20])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NCCc1ccccc1
Reactant: CON(C)C(=O)CCBr
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CON(C)C(=O)CCN(C)Cc1ccccc1
Yield: 82 %

Procedure:
Add potassium carbonate (63.50 g, 459 mmol) to a stirred solution of N-benzylmethylamine (14.8 mL, 115 mmol), 3-bromo-N-methoxy-N-methyl-propionamide (22.47 g, 115 mmol, prepared according to Jacobi, P. A.; Blum, C. A.; DeSimone, R. W.; Udodong, U. E. S. J. Am. Chem. Soc. 1991, 113, 5384-5392), and anhydrous acetonitrile (460 mL). Heat the reaction to reflux under nitrogen for 3 hours. Cool the reaction to room temperature and filter the reaction through Celite®. Wash the Celite® with ethyl acetate and concentrate on a rotary evaporator to give the crude product. Purify the crude product by flash chromatography on silica gel eluting with 0.5% concentrated ammonium hydroxide/5% ethanol/chloroform to yield 22.31 g (82%) of 3-(benzyl-methyl-amino)-N-methoxy-N-methyl-propionamide: mass spectrum (ion spray) m/z=237.1(M+1); 1H NMR (CDCl3) δ 7.31-7.21 (m, 5H), 3.65 (s, 3H), 3.53 (s, 2H), 3.17 (s, 3H), 2.80-2.76 (m, 2H), 2.67-2.63 (m, 2H), 2.23 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)OC(C)(C)C)=[C:13]([O:25][CH3:26])[CH:12]=3)=[CH:9][O:10][C:6]=2[C:5]([I:27])=[CH:4][N:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([I:27])[C:6]=3[O:10][CH:9]=2)=[CH:12][C:13]=1[O:25][CH3:26]
Reactant: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1N
Reaction time: 2 h
Yield: 80.3 %

Procedure:
Tert-butyl 4-(4-amino-7-iodofuro[3,2-c]pyridin-3-yl)-2-methoxyphenylcarbamate (3.98 g, 8.28 mmol) was added to a 20% solution of trifluoroacetic acid in dichloro-methane (150 mL). The mixture was stirred for two hours and then the solvent was removed in vacuo. To the residue was added water (15 mL) and dichloromethane (25 mL). The mixture was adjusted to pH 12 with 1 N aqueous sodium hydroxide and the layers were separated. The aqueous layer was extracted with dichloromethane (2×10 mL) and the combined organic layers were dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give the title compound (2.534 g, 80%). 1H NMR (DMSO-d6, 400 MHz) □ 8.03 (s, 1H), 7.94 (s, 1H), 6.91 (d, 1H), 6.82 (dd, 1H), 6.75 (d, 1H), 5.69–5.77 (bs, 2H), 4.96–5.05(bs, 2H), 3.81 (s, 3H); RP-HPLC (Conditions f) Rt 11.22 min.; MS: MH+ 382.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:13]([F:12])[CH:14]=1
Reactant: Clc1cc(Br)c2cn[nH]c2c1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Fc1cc(-n2ncc3c(Br)cc(Cl)cc32)ccc1OCc1ccccc1
Yield: 53.4 %

Procedure:
4-Bromo-6-chloro-1H-indazole (413 mg, 1.78 mmol), {3-fluoro-4-[(phenylmethyl)oxy]phenyl}boronic acid (876 mg, 3.56 mmol), copper (II) acetate (483 mg, 2.67 mmol) and pyridine (0.29 mL, 3.56 mmol) in DCM (30 mL) were stirred in the presence of molecular sieves (4A, 790 mg) in air. After 40 hours the mixture was filtered through a pad of celite and concentrated to afford 1.24 g of crude material. This was purified by flash chromatography (Biotage SP4, 40+M silica column) with a gradient of Et2O (0 to 30%) in hexane to afford 410 mg of desired compound (D10) containing a small amount of the N2-aryl regioisomer.
Reaction SMILES: [CH:1]1[CH:6]=CC=CC=1.[Cl:7][C:8]1[C:13]([CH:14]=[O:15])=[C:12]([Cl:16])[N:11]=[CH:10][N:9]=1.O.C1(C)C=CC(S(O)(=O)=[O:25])=CC=1.C([O-])(O)=O.[Na+]>O.C(O)CO>[Cl:7][C:8]1[C:13]([CH:14]2[O:25][CH2:1][CH2:6][O:15]2)=[C:12]([Cl:16])[N:11]=[CH:10][N:9]=1
Reactant: c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=Cc1c(Cl)ncnc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCCO
Solvent: O
Product: Clc1ncnc(Cl)c1C1OCCO1

Procedure:
A mixture of 300 ml benzene and 8.2 ml ethylene glycol was heated to reflux and 100 ml solution was distilled off. To the hot solution was added 4,6-dichloro-5-pyrimidinecarbaldehyde (Bionet, 8.6 g, 48.6 mmol) and p-toluenesulfonic acid monohydrate (Aldrich, 150 mg, 0.8 mmol). The mixture was returned to reflux and water was removed via Dean-Stark trap over 3 h. After cooling, the solvents were removed under vacuum to yield a dry, yellow solid. The solids were slurried in H2O (30 ml)/saturated NaHCO3 solution (30 ml). White solid 107 was filtered off and dried under vacuum (8.8 g, 82%). Compound 107: mp 108-110° C.; MS (ES+ calculated: 221.04; found: 221/223 M+H). 1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 6.26 (s, 1H), 4.23 (m, 2H), 4.05 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]#[N:17])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.[BH4-].[Na+]>C1COCC1.CO.[Co](Cl)Cl>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][NH2:17])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CC#N)c1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1cccc(CCN)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.2 %

Procedure:
To a solution of 1 g of tert-butyl[3-(cyanomethyl)phenoxy]acetate in 20 ml of THF and 10 ml of methanol was added dropwise a suspension of 1.31 g of cobalt chloride and 20 ml of water, and then 459 mg of sodium borohydride was portionwise added thereto at room temperature. After stirring at room temperature for 10 minutes, the insoluble material was separated by filtration over Celite, washed with methanol, and then concentrated. The obtained residue was extracted with chloroform, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated. The obtained residue was purified by silica gel column chromatography (eluent:chloroform-methanol-saturated aqueous ammonia) to obtain 632 mg of tert-butyl[3-(2-aminoethyl)phenoxy]acetate as a pale yellow oily substance.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([F:14])=[CH:9][C:8]=1I.CN(C)[CH:18]=[O:19].C(OC)(C)(C)C>O1CCCC1.O>[Br:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([F:14])=[CH:9][C:8]=1[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: Fc1cc(I)c(Br)cc1Cl
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(F)c(Cl)cc1Br
Temperature: -78 °C

Procedure:
A solution of 1 mmol of n-butyllithium (1N in hexane) is added dropwise to a solution of 1 mmol of 1-bromo-5-chloro-4-fluoro-2-iodo-benzene in 20 ml of tetrahydrofuran cooled to −78° C. After the addition, 1.1 mmol of N,N-dimethylformamide is added and the mixture is allowed to warm to room temperature. 100 ml of tert-butylmethyl ether then 20 ml of water are added. The organic phase is separated, washed with 20 ml of brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (SiO2 60 F) to afford the title compound which is identified based on the Rf value.
Reaction SMILES: Cl.N1C=C[CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([OH:12])=O.[NH2:13][CH2:14][C:15]([OH:17])=O.N1C=CC=CC=1NCC(O)=[O:27].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:44]([O:46][C:47](=[O:50])[CH2:48][NH2:49])[CH3:45]>ClCCl>[NH:8]1[C:3](=[O:27])[CH2:4][CH2:5][C@H:9]1[C:10]([NH:13][CH2:14][C:15]([NH:49][CH2:48][C:47]([O:46][CH2:44][CH3:45])=[O:50])=[O:17])=[O:12]
Reactant: O=C(O)CNc1ccccn1
Reactant: NCC(=O)O
Reactant: CCOC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)CNC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C

Procedure:
The synthesis of peptide bond reaction from the 2-pyridylglycine.hydrochloride and glycine can be carried out, for example, as follows: To N-2-pyridylglycine, are added dichloromethane, N,N'-dicyclohexylcarbodiimide and glycine ethyl ester. After stirring at room temperature for several hours, the reaction solution is filtered. The filtrate is purified by using, for example, high performance liquid chromatography to give Pyr-Gly-Gly-OEt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[CH:9])[CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20]2[NH:23][C:24]([C:26]3[CH:31]=[CH:30][N:29]=[C:28](I)[N:27]=3)=[CH:25][C:19]=2[C:18]1=[O:33])=[O:16])([CH3:13])([CH3:12])[CH3:11].[CH2:34](N(CC)CC)C>C(#N)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20]2[N:23]([CH3:34])[C:24]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([C:9]#[C:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:27]=3)=[CH:25][C:19]=2[C:18]1=[O:33])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c(-c3ccnc(I)n3)cc2C1=O
Reactant: CCN(CC)CC
Reactant: C#Cc1cccc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC#N
Product: Cn1c(-c2ccnc(C#Cc3cccc(Cl)c3)n2)cc2c1CCN(C(=O)OC(C)(C)C)C2=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
1-Chloro-3-ethynyl-benzene (0.018 g, 0.132 mmol), copper iodide (0.0012 g, 0.006 mmol) and PdCl2(PPh3)2 (0.0023 g, 0.003 mmol) were added under argon to a solution of 2-(2-iodo-pyrimidin-4-yl)-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.030 g, 0.066 mmol) and triethylamine (0.170 ml) in dry ACN (0.500 ml). The reaction mixture was stirred at 80° C. for 3 h in argon atmosphere. The solvent was removed under vacuum and the crude residue was purified by flash chromatography, over silica gel, using DCM/MeOH (9.8:0.2) as eluent, to afford 2-[2-(3-chloro-phenylethynyl)-pyrimidin-4-yl]-1-methyl-4-oxo-1,4,6,7-tetra-hydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.018 g, 0.04 mmol, 60%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][O-:16].[Na+].O.Cl>CO>[CH3:15][O:16][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C[O-]
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(C(F)(F)F)ccc1C(=O)O
Temperature: 25 °C
Yield: 55.9 %

Procedure:
A mixture of 2-chloro-6-(trifluoromethyl)nicotinic acid (2 g, 8.9 mmol) and sodium methoxide (1.9 g, 36 mmol) in methanol (20 mL) was heated at reflux for 48 hours. The mixture was allowed to cool to room temperature then poured into water (50 mL). This was cooled in an ice-bath and acidified with hydrochloric acid (2 N, aq). The resulting precipitate was filtered and dried to give 2-methoxy-6-(trifluoromethyl)nicotinic acid as a white solid (1.1 g): 1H NMR (400 MHz, CDCl3): δ 8.61 (1H, d, J 7.7), 7.48 (1H, d, J 7.7), 4.25 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH:17]1([C:20](=[O:25])[CH2:21][C:22](=O)[CH3:23])[CH2:19][CH2:18]1.C(O)(C)C>CCCCCCC.C(OCC)(=O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:22]([CH3:23])[C:21]([C:20]([CH:17]1[CH2:19][CH2:18]1)=[O:25])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Reactant: CC(=O)CC(=O)C1CC1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C1CC1
Reaction time: 16 h
Yield: 75 %

Procedure:
The title compound was prepared from (2-amino-5-bromo-phenyl)-phenyl-methanone [example A16] and 1-cyclopropyl-1,3-butanedione according to the procedure of example 1, except that the solvent was isopropanol, the reaction time was of 16 h and heptane/ethyl acetate (1:2) was used. Yield: 75%; MS: m/z=366 (M).
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[CH2:3][CH2:4][CH:5]([NH:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[OH:7].[H-].[Na+].S(C1C=CC(C)=CC=1)(O[CH3:31])(=O)=O.[ClH:39]>C1(C)C=CC=CC=1.CC(C)=O>[ClH:39].[ClH:39].[CH3:31][O:7][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:5]([NH:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)[CH2:4][CH2:3][CH:2]([CH3:24])[CH3:1]
Reactant: CC(C)CCC(NCCCN1CCCCC1)C(O)c1ccccc1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: COC(c1ccccc1)C(CCC(C)C)NCCCN1CCCCC1
Yield: 21 %

Procedure:
To a solution of (1RS,2SR)-5-methyl-1-phenyl-2-(3-piperidinopropylamino)hexan-1-ol (1.66 g, 5 mmol) in toluene (25 ml) was added sodium hydride (0.14 g, 6 mmol) and the mixture was refluxed for 1 hour. To the reaction mixture was added methyl tosylate (1.12 g, 6 mmol) and the resulting mixture was refluxed for further 1 hour. After being cooled, the mixture was washed twice with water and once with brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by neutral alumina column chromatography (alumina: 40 g, eluent: chloroform) to give 1.1 g of oily matter. To a solution of the matter in acetone (20 ml) was added concentrated hydrochloric acid (0.1 ml) and the mixture was concentrated under reduced pressure. The residue was recrystallized from acetone (10 ml)-ethanol (0.2 ml) to obtain 0.45 g of the title compound as white crystals (yield: 21%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:37])[CH2:16][N:17]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18]2([CH3:29])[CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH3:28])=[C:23]([CH3:27])[CH:24]=3)[CH2:19]2)=[CH:11][C:10]=1[N+:38]([O-:40])=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:37][C:41](=[O:43])[CH3:42])[CH2:16][N:17]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18]2([CH3:29])[CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH3:28])=[C:23]([CH3:27])[CH:24]=3)[CH2:19]2)=[CH:11][C:10]=1[N+:38]([O-:40])=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(cc1C)CC(C)(N(Cc1ccccc1)C[C@H](O)c1ccc(OCc3ccccc3)c([N+](=O)[O-])c1)C2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@@H](CN(Cc1ccccc1)C1(C)Cc2cc(C)c(C)cc2C1)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reaction time: 18 h

Procedure:
To a solution of (R)-1-(4-Benzyloxy-3-nitro-phenyl)-2-[benzyl-(2,5,6-trimethyl-indan-2-yl)-amino]-ethanol in pyridine is added acetic anhydride and the mixture stirred for 18 hours. The reaction mixture is quenched with water and after addition of ethyl acetate washed twice with aqueous KHSO4 solution, twice with aqueous NaHCO3 and once with brine. The product is purified by chromatography (silica, ethyl acetate/hexane 1:4). ES+ MS m/e 579 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH2:8][O:9]C(=O)C)=[C:4]([CH:15]=O)[CH:3]=1.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1.N1CCCC1>CO>[Cl:17][C:18]1[CH:26]=[C:25]2[C:21](/[C:22](=[CH:15]/[C:4]3[CH:3]=[C:2]([Cl:1])[CH:14]=[CH:13][C:5]=3[O:6][CH2:7][CH2:8][OH:9])/[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CC(=O)OCCOc1ccc(Cl)cc1C=O
Solvent: CO
Solvent: C1CCNC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cc(Cl)ccc1OCCO
Temperature: 70 °C
Yield: 43 %

Procedure:
Acetic acid 2-(4-chloro-2-formyl-phenoxy)-ethyl ester (1.5 g, 9.3 mmol) and 6-chlorooxindole (2.7 g, 11.2 mmol) were mixed in anhydrous methanol (20 mL) at room temperature. Then Pyrrolidine (0.8 g, 11.2 mmol) was added slowly. The reaction mixture was heated at 70° C. for 3 h, then cooled to r.t and the precipitation was collected by filtration to obtain title compound as a yellow solid (1.4 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH:6]1[C:18]2[CH:17]([CH2:19][O:20][C:21](Cl)=[O:22])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.O>O1CCOCC1>[NH:1]([C:21]([O:20][CH2:19][CH:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[C:18]1=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:22])[CH2:2][C:3]([OH:5])=[O:4]
Reactant: NCC(=O)O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
Glycine (Gly) (0.5 g, 6.66 mmole) was dissolved in 10% NaCO3 (14 ml) under stirring in a 50-ml flask. To the resulting solution, which had been put into an ice bath, 9-fluorenylmethoxycarbonyl chloride (Fmoc-Cl) (1.72 g, 6.66 mmol) in dioxane (12 ml) was gradually added. The reaction mixture was stirred at room temperature for 4 hours, and water (150 ml) was then added. The aqueous phase layer was separated from the reaction mixture and stripped with ether three times (75 ml×3). The stripped aqueous layer was acidified with 2N HCl aqueous solution to a pH value of 2, followed by extraction with ethyl acetate three times (75 ml×3). The organic phase layer was recovered and concentrated to obtain crude product of 1.70 g. The crude product was recrystallized in a mixed solvent of ethyl acetate hexane=1:2 (30 ml), and white solid denoted as Fmoc-Gly was obtained after filtration at a reduced pressure. Yield: 1.69 g (85%).
Reaction SMILES: [CH3:1][C:2]12[O:9][CH2:8][C:5]([CH2:10][OH:11])([CH2:6][O:7]1)[CH2:4][O:3]2.CS(C)=O.[OH-].[K+].[CH2:18](Br)[C:19]#[CH:20]>C(Cl)(Cl)Cl>[CH3:1][C:2]12[O:3][CH2:4][C:5]([CH2:10][O:11][CH2:20][C:19]#[CH:18])([CH2:6][O:7]1)[CH2:8][O:9]2
Reactant: C#CCBr
Reactant: CC12OCC(CO)(CO1)CO2
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: C#CCOCC12COC(C)(OC1)OC2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
Compound 6 (5.434 g, 33.9 mmol) was added to a stirring solution of anhydrous DMSO (30 mL) and powdered KOH (7.6 g, 135.7 mmol). After stirring for 10 minutes, the reaction mixture was cooled in an ice bath (0° C.). Propargyl bromide (4.04 g, 3.02 mL, 33.93 mmol) was added drop-wise, the reaction became dark brown rapidly. The reaction was stirred at room temperature for 95 minutes and poured into ice-cold water (200 mL). The product, an off-white solid, was collected by vacuum filtration, and washed with water, dried in vacuo to obtain the analytically pure product. X-ray quality crystals were obtained by slow evaporation from chloroform. Yield: 81%, 5.44 g. 1H NMR (CDCl3; 500 MHz) δ ppm: 1.456 (s, 3H, CH3), 2.442 (t, 1H, CCH), 3.286 (s, 2H, CCH2O), 4.006 (s, 6H, (CH2)3C), and 4.094 (d, 2H, OCH2CCH). 13C NMR (CDCl3; 125.8 MHz) δ ppm: 23.56 (CH3), 34.85 (CH2CCH2), 58.88 (OCH2CCH), 68.12 (CCH2O), 69.55 (OCH2C), 75.34 (CH), 78.97 (CH2CCH), 108.72 (OCCH3). ESI-MS (m/z): 199.10 (199.09 calc'd for C10H14O4 [M+H]+). Elemental analysis calc'd (found) for C7H12O4: C, 60.59 (59.06); H, 7.12 (7.23).