Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:11]=[CH:12][C:13]=1Cl.OC(C(O)(C)C)(C)C.[OH:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([OH:33])=[O:32]>CS(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:11]=[CH:12][C:13]=1[O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([OH:33])=[O:32]
Reactant: O=C(O)c1cccc(O)c1
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Agent: CC(C)(O)C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)c1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Temperature: 25 °C

Procedure:
To a 300 ml, 3-necked flask equipped with a condenser, stirrer, drying tube and thermometer is charged dimethylsulfoxide (100 ml), anhydrous potassium carbonate (30 g. >0.20 mole), 3,4-dichlorobenzotrifluoride (21.5 g., 0.10 mole), pinacol (10 g.) and 3-hydroxybenzoic acid (13.8 g., 0.10 mole). The reaction temperature is then taken slowly to 140°-5° C. while stirring vigorously and maintained as such for 4 days. The reaction mixture is then cooled to room temperature and the inorganic solids removed by filtration prior to pouring the filtrate into water (1200 ml). The aqueous solution is then triturated with CCl4 (2 × 200 ml), decanted and then acidified to pH1 (conc. HCl) to give a tan colored solid, 25,6 g., mp 114°-17° C. This solid is further purified by dissolving in CCl4 (500 ml) and drying with anhydrous MgSO4. The CCl4 solution is reduced in vacuo to give 19.6 g. (62%) of a yellow solid, mp 116°-19° C. Recrystallization of the yellow solid from hexane gives a tan colored solid, 3-(2-chloro-4-trifluoromethylphenoxy)-benzoic acid, mp 122°-3° C.
Reaction SMILES: [CH2:1]([C:4]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[NH:7][C:6](=[O:15])[N:5]1[CH2:16][C:17]([F:20])([F:19])[F:18])[CH:2]=[CH2:3]>C(OCC)(=O)C.[Pd]>[Cl:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:15])[N:5]([CH2:16][C:17]([F:19])([F:18])[F:20])[C:4]2([C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[CH2:1][CH2:2][CH3:3]
Reactant: C=CCC1(c2ccc(F)cc2)c2cc(Cl)ccc2NC(=O)N1CC(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC1(c2ccc(F)cc2)c2cc(Cl)ccc2NC(=O)N1CC(F)(F)F
Yield: 100.4 %

Procedure:
To a solution of 4-allyl-6-chloro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (22.1 g, 55.4 mmol) in ethyl acetate (450 mL) and under a nitrogen atmosphere was added 10% palladium on carbon (224 mg). A balloon of hydrogen was bubbled into the stirring mixture. The reaction was then stirred over night under an atmosphere of hydrogen. The reaction was purged with nitrogen, filtered through a pad of celite and the filtrate concentrated in vacuo to give 22.3 gm (100%) of (±)-6-chloro-4-(4-fluorophenyl)-4-propyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one as a white solid. Further purification by chiral chromatography (ChiralPak AD packing, 30% iPrOH/heptane with DEA modifier at 1.0 mL/L) followed by crystallization from hexanes provided individual enantiomers of 6-chloro-4-(4-fluorophenyl)-4-propyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (Peak 1 and Peak 2). Data for Peak 2: 1H NMR (d6-DMSO, 400 MHz) δ 10.02 (s, 1H); 7.43 (m, 2H); 7.20 (m, 3H); 6.84 (d, J=8.61 Hz, 1H); 6.59 (d, J=2.19 Hz, 1H); 3.80 (q, J=9.34 Hz, 2H); 2.33 (m, 2H); 1.24 (m, 1H); 0.94 (m, 1H); 0.89 (t, J=6.87 Hz, 3H). Exact Mass (Electrospray, M+H): Calc'd, 401.1039; Found, 401.1040. [α]D=−6.7° (c0.0045, MeOH). Optical rotation for Peak 1: [α]D=+5.2° (c0.0062, MeOH).
Reaction SMILES: C1(CC([N:10]2[CH2:14][CH2:13][CH:12]([NH:15][C:16]3[CH:25]=[CH:24][N:23]=[C:22]4[C:17]=3[C:18]3[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=3[C:20](=[O:26])[NH:21]4)[CH2:11]2)=O)C=CC=CC=1.Cl[CH2:32][C:33]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:34]>>[O:26]=[C:20]1[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[C:17]2[C:22](=[N:23][CH:24]=[CH:25][C:16]=2[NH:15][CH:12]2[CH2:13][CH2:14][N:10]([CH2:32][C:33]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:34])[CH2:11]2)[NH:21]1
Reactant: O=C(CCl)Nc1ccccc1
Reactant: O=C(Cc1ccccc1)N1CCC(Nc2ccnc3[nH]c(=O)c4ccccc4c23)C1
Product: O=C(CN1CCC(Nc2ccnc3[nH]c(=O)c4ccccc4c23)C1)Nc1ccccc1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 370 using the amine intermediate from example 369 and 2-chloro-N-phenylacetamide to provide 371. LC-MS (M+H=414, obsd.=414).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:18])=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[C:19](=[O:26])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[NH2:20].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:18][C:10]1[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:20][C:19](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:7]=2)=[CH:14][CH:13]=[C:12]([N+:15]([O-:17])=[O:16])[N:11]=1
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Reactant: CC(C)(C)OC(N)=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(NC(=O)OC(C)(C)C)c1
Temperature: 100 °C
Yield: 29.1 %

Procedure:
A mixture of Example A3 (1.2 g, 4.52 mmol), t-butyl carbamate (1.058 g, 9.03 mmol), Cs2CO3 (2.94 g, 9.03 mmol) and DPPF (0.351 g, 0.632 mmol) in dioxane (25 mL) was sparged with Ar, treated with Pd2(dba)3 (0.290 g, 0.316 mmol), sparged again with Ar and heated at 100° C. for 3 days. The mixture was cooled to RT, diluted with EtOAc, the solids removed via filtration through diatomaceous earth and the filtrate concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford tert-butyl (4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)carbamate (456 mg, 29%). MS (ESI) m/z: 347.2 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[Cl:10][C:11]([Cl:16])([Cl:15])[C:12](Cl)=[O:13]>ClCCCl>[Cl:10][C:11]([Cl:16])([Cl:15])[C:12]([C:2]1[NH:1][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1)=[O:13]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: c1cc2c([nH]1)CCCC2
Solvent: ClCCCl
Product: O=C(c1cc2c([nH]1)CCCC2)C(Cl)(Cl)Cl
Temperature: 85 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer, condenser and nitrogen inlet was purged with nitrogen and charged with 4,5,6,7-tetrahydro-1H-indole (3.00 g, 24.8 mmol), trichloroacetyl chloride (13.5 g, 74.4 mmol) and 1,2-dichloroethane (50 mL). The solution was stirred at 85° C. for 2 h. After that time, the reaction mixture was concentrated under reduced pressure to afford a 100% yield (6.50 g) of 104f as a black semi-solid: 1H NMR (500 MHz, DMSO-d6) δ 11.94 (s, 1H), 7.05 (s, 1H), 2.62 (t, 2H, J=6.0 Hz), 2.47 (t, 2H, J=6.0 Hz), 1.80 (m, 2H), 1.65 (m, 2H); MS (ESI+) m/z 266.0 (M+H)
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[CH:4][N:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.I[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:23][CH2:24][O:25][CH3:26])[CH:14]=1.C([O-])(=O)C.[K+].O>CN1CCCC1=O>[Br:1][C:2]1[C:3]([F:11])=[C:4]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:23][CH2:24][O:25][CH3:26])[CH:14]=2)[N:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COCOc1cc(I)ccc1C(=O)OC
Reactant: Fc1cn2ccccc2c1Br
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COCOc1cc(-c2c(F)c(Br)c3ccccn23)ccc1C(=O)OC
Temperature: 100 °C
Reaction time: 5 h
Yield: 68.2 %

Procedure:
To a solution of 1-bromo-2-fluoroindolizine (0.30 g) in N-methylpyrrolidone (6.0 mL) were added methyl 4-iodo-2-methoxymethoxybenzoate (0.54 g), dichlorobis (triphenylphosphine) palladium (II) (0.05 g), potassium acetate (0.27 g) and water (0.05 mL), and the mixture was stirred at 100° C. for 5 hours. After cooling to room temperature, to the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give methyl 4-(1-bromo-2-fluoroindolizine-3-yl)-2-methoxymethoxybenzoate (0.39 g). To a solution of the obtained compound (0.39 g) in N-methylpyrrolidone (3 mL) were added zinc cyanide (0.44 g) and tetrakis (triphenylphosphine) palladium (0.22 g), and stirred at 150° C. for 1 hour using microwave reactor. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give methyl 4-(1-cyano-2-fluoroindolizine-3-yl)-2-methoxymethoxybenzoate (0.07 g). To a mixed solution of the obtained compound (0.07 g) in tetrahydrofuran (3.0 mL), ethanol (1.0 mL) and water (1.0 mL) was added lithium hydroxide monohydrate (0.04 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 2 mol/L hydrochloric acid (1.0 mL), and the mixture was stirred at 50° C. overnight. After cooling to room temperature, to the reaction mixture was added water. The precipitated solid was collected by filtration, washed with water and methanol, and dried under reduced pressure at 50° C. to give the title compound (0.05 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:30](OC)(OC)([O:33]C)[O:31][CH3:32].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH2:16][OH:17])[CH2:14][O:15][C:30]([O:31][CH3:32])=[O:33])=[CH:4][N:3]=1
Reactant: COC(OC)(OC)OC
Reactant: Nc1ncc2ncn(CCC(CO)CO)c2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)OCC(CO)CCn1cnc2cnc(N)nc21
Reaction time: 1.67 h

Procedure:
To a suspension of 2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine (237 mg, 1.0 mmol) in dry tetrahydrofuran (3 ml) were added p-toluene-sulphonic acid monohydrate (0.21 g, 1.1 mmol) and tetramethyl orthocarbonate (0.53 ml, 4.0 mmol) and the mixture was stirred for 100 minutes. Water (0.8 ml) was added and after a further 15 minutes the solution was neutralised by addition of aqueous sodium bicarbonate. The solvent was removed and the residue was extracted with chloroform-methanol (3:1). The solvent was removed and the residue was purified by column chromatography on silica gel eluting with chloroform-methanol (10:1) to afford 2-amino-9-(3-hydroxymethyl-4-methoxycarbonyloxybut-1-yl)purine which was obtained as a white crystalline solid after trituration with ethyl acetate (65 mg, 22%), m.p. 129°-132°; νmax (KBr) 3440, 3220, 1745, 1650, 1615, and 1580 cm-1 ; &H [(CD3)2SO] 1.73 (1 H, m, 3'-H), 1.81 (2H, m, 2'-H), 3.41 (2H, t, J 5.1Hz, D2O exchange gives d, CH2OH) 3.68 (3H, s, CH3), 4.0-4.2 (4H, m, CH2OCO and 1'-H), 4.65 (1H, t, J 5.2Hz, D2O exchangeable, OH), 6.44 (2H, s, D2O exchangeable, 2-NH2), 8.06 (1H, s, 8-H), and 8.55 (1H, s, 6-H); (Observed M+, 295.1286, C12H17N5O4 requires 295.1280).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:18][C:19]([C:21]2[C:29]3[CH:28]=[C:27]([C:30]4[C:35](C)=[CH:34][N:33]=[C:32]([Cl:37])[N:31]=4)[S:26][C:25]=3[CH:24]=[CH:23][CH:22]=2)=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[Br:38]C1C(C2SC3C=CC=C(C(O)=O)C=3C=2)=NC(Cl)=NC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:18][C:19]([C:21]2[C:29]3[CH:28]=[C:27]([C:30]4[C:35]([Br:38])=[CH:34][N:33]=[C:32]([Cl:37])[N:31]=4)[S:26][C:25]=3[CH:24]=[CH:23][CH:22]=2)=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1cccc2sc(-c3nc(Cl)ncc3Br)cc12
Reactant: COc1ccc(C(NC(=O)c2cccc3sc(-c4nc(Cl)ncc4C)cc23)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(NC(=O)c2cccc3sc(-c4nc(Cl)ncc4Br)cc23)c2ccc(OC)cc2)cc1

Procedure:
Using the method of 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid [bis-(4-methoxyphenyl)-methyl]-amide, the title compound is synthesized from 2-(5-bromo-2-chloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid as a tan solid.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:10].[CH3:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18](Cl)=[O:19])[CH2:14][CH2:13]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH3:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([N:3]2[C:4]3=[N:5][CH:6]=[CH:7][CH:8]=[C:9]3[O:1][C:2]2=[O:10])=[O:19])[CH2:14][CH2:13]1
Reactant: O=c1[nH]c2ncccc2o1
Reactant: CC1CCN(C(=O)Cl)CC1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC1CCN(C(=O)n2c(=O)oc3cccnc32)CC1

Procedure:
100 mg (0.735 mmol) of 3H-oxazolo[4,5-b]pyridin-2-one, 235 mg (1.45 mmol) of 4-methylpiperidine-1-carbonyl chloride and 101 μl (2.18 mmol) of triethylamine were stirred in 5 ml of pyridine at room temperature for 3 h. The reaction mixture was concentrated, and the residue was dissolved in water and extracted with ethyl acetate. The organic phase was concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 6 mg (3%), M+H+: 262.12.
Reaction SMILES: [C:1]([CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[C:5]1=O)(=O)[CH3:2].Cl.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][NH2:33])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C.O>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]2[C:5]3[C:6]4[CH:7]=[C:8]([O:14][CH3:15])[CH:9]=[CH:10][C:11]=4[CH2:12][CH2:13][C:4]=3[C:1]([CH3:2])=[N:33]2)=[CH:30][CH:31]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc2c(c1)C(=O)C(C(C)=O)CC2
Reactant: NNc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)-c1c(c(C)nn1-c1ccc(OCc3ccccc3)cc1)CC2
Yield: 32.1 %

Procedure:
2-Acetyl-7-methoxy-3,4-dihydro-2H-naphthalen-1-one (72.5 mg, 0.33 mmol) and 4-benzyloxyphenylhydrazine hydrochloride (90 mg, 0.36 mmol) were heated in ethanol at 70° C. for 2.5 days. The reaction was diluted with water and extracted with ethyl acetate. The organic extracts were washed with 1 N HCl, saturated sodium bicarbonate solution, and brine, dried over MgSO4, and concentrated. SiO2 chromatography with 5-20% ethyl acetate/hexanes gave 42 mg of the desired product. LC-MS (C26H24N2O2 calculated 396) m/z 397 (M+H).
Reaction SMILES: [NH:1]([C:20]([O:22]C(C)(C)C)=O)[C@H:2]([C:6]([NH:8][CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].Cl.O1CCOCC1.N[C@H](C(NCC(OCC1C=CC=CC=1)=O)=O)C(C)C.Cl.[NH:54]([C:71]([O:73][CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)=[O:72])[C@H:55]([C:61]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:62])[CH2:56][CH2:57]C(=O)O.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[NH:54]([C:71]([O:73][CH2:74][C:75]1[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=1)=[O:72])[C@H:55]([C:61]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:62])[CH2:56][CH2:57][C:20]([NH:1][C@H:2]([C:6]([NH:8][CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])=[O:7])[CH:3]([CH3:4])[CH3:5])=[O:22]
Reactant: O=C(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Agent: CC(C)[C@H](N)C(=O)NCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 70 %

Procedure:
Boc-Val-Gly-OBzl (5.47 g, 15.0 mmol) was added to 4 N HCl/dioxane solution (40 ml), and the mixture was stirred at room temperature for 50 minutes. Dioxane was removed by concentration under reduced pressure, n-hexane (30 ml) was added to the residue, and the mixture was concentrated under reduced pressure. This procedure was repeated 3 times to quantitatively obtain H-Val-Gly-OBzl.HCl. Then, H-Val-Gly-OBzl.HCl and Z-Glu-OBzl (5.57 g, 15.0 mmol) were dissolved in methylene chloride (50 ml), and the solution was kept at 0° C. Triethylamine (2.30 ml, 16.5 mmol), HOBt (1-hydroxybenzotriazole, 2.53 g, 16.5 mmol), and WSC.HCl (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 3.16 g, 16.5 mmol) were added to the solution, and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in heated ethyl acetate (1500 ml). The solution was washed with water (200 ml), 5% citric acid aqueous solution (200 ml×twice), saturated brine (150 ml), 5% sodium hydrogencarbonate aqueous solution (200 ml×twice), and saturated brine (150 ml). The organic layer was dried over anhydrous magnesium sulfate, then the magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The deposited crystals were collected by filtration, and dried under reduced pressure to obtain white crystals of Z-Glu(Val-Gly-OBzl)-OBzl (6.51 g, 10.5 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([O:17][CH2:18][CH2:19][O:20][C:21]2[N:26]=[CH:25][C:24]([Br:27])=[CH:23][N:22]=2)[N:5]=[C:4]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[N:3]=1.[H-].[Na+].[S:36]1[CH:40]=[CH:39][CH:38]=[C:37]1[S:41](Cl)(=[O:43])=[O:42].[Cl-].[NH4+]>O1CCCC1>[Br:27][C:24]1[CH:23]=[N:22][C:21]([O:20][CH2:19][CH2:18][O:17][C:6]2[N:5]=[C:4]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:3]=[C:2]([NH:1][S:41]([C:37]3[S:36][CH:40]=[CH:39][CH:38]=3)(=[O:43])=[O:42])[C:7]=2[O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[N:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1ccccc1Oc1c(N)nc(N2CCOCC2)nc1OCCOc1ncc(Br)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2cccs2)nc(N2CCOCC2)nc1OCCOc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17.9 %

Procedure:
A mixture of 4-amino-6-[2-(5-bromopyrimidin-2-yloxy)ethoxy]-5-(2-methoxyphenoxy)-2-morpholinopyrimidine (200 mg), sodium hydride (60% dispersion, 46.2 mg) and tetrahydrofuran (6 ml) is stirred at room temperature for 20 minutes. To the mixture is added 2-thiophenesulfonyl chloride (211 mg), and the mixture is stirred for 20 hours. The reaction solution is treated with a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated under reduced pressure to remove the solvent. The residue is recrystallized from ether-hexane to give the title compound (46 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11](CC2C=CC=CC=2)[CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(Cl)(Cl)Cl)=O>CC#N>[C:1]([O:5][C:6](=[O:29])[N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][NH:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC#N
Product: CN(C(=O)OC(C)(C)C)C1CNCC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
To a stirred solution of [(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (928 mg, 2.13 mmol) in CH3CN (10 ml) at RT, was added 2,2,2-trichloroethyl chloroformate (0.45 ml, 2.13 mmol). The reaction mixture was stirred at RT for 3 hours, concentrated under vacuo. The residue was dissolved in AcOH (5 ml) and zinc dust (400 mg) was added portion wise over 1 hours. The solvent was evaporated, the residue diluted in EtOAc and the organic phase was washed with an aqueous solution of NaHCO3. The organic phase was dried over Na2SO4 and concentrated under vacuo to afford 415 mg (98%) of the tile compound as a light yellow oil. ES-MS m/e: 345.2 (m+H+),
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[CH2:16][CH2:15][NH:14][CH2:13][C:10]3=[N:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[I-].C([O-])([O-])=O.[K+].[K+].Cl[CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([CH:35]2[CH2:38][CH2:37][CH2:36]2)[CH2:31][CH2:30]1)=[O:28]>C(#N)C.C(Cl)Cl>[CH:35]1([N:32]2[CH2:33][CH2:34][N:29]([C:27](=[O:28])[CH2:26][N:14]3[CH2:15][CH2:16][C:9]4[C:10](=[N:11][CH:12]=[C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)[N:8]=4)[CH2:13]3)[CH2:30][CH2:31]2)[CH2:38][CH2:37][CH2:36]1
Reactant: O=C(CCl)N1CCN(C2CCC2)CC1
Reactant: c1nc2c(nc1N1CCOCC1)CCNC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: O=C(CN1CCc2nc(N3CCOCC3)cnc2C1)N1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-morpholin-4-yl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine (60 mg, 0.27 mmol) in acetonitrile (5 mL) is added NaI (50 mg, 0.333 mmol), K2CO3 (200 mg, 1.45 mmol) and 2-chloro-1-(4-cyclobutyl-piperazin-1-yl)-ethanone (100 mg, 0.463 mmol). The mixture is stirred overnight at rt. The mixture is diluted with DCM (25 mL) and filtered through Celite. The filtrate is concentrated and the residue is purified by PTLC eluting with EtOAc/MeOH/NEt3 (90:10:10) to yield the title compound. 1H NMR (300 MHz, CDCl3) δ 7.90 (1H, s), 3.85 (2H, m), 3.72 (4H, m), 3.63-3.60 (4H, m), 3.50 (2H, t), 3.40 (2H, s), 2.92-2.87 (3H, m), 2.74-2.69 (2H, m), 2.51 (2H, t), 2.34-2.26 (4H, m), 2.09-1.67 (m, 6H); MS (+VE) m/z 401.26 (M++1).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](Cl)=[O:15])[CH:5]=[CH:4][C:3]1=2.[OH:18][CH2:19][C:20]1[S:24][C:23]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:22][CH:21]=1>>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([O:18][CH2:19][C:20]3[S:24][C:23]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:22][CH:21]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Cl)ccc21
Reactant: C=CCOC(=O)c1ccc(CO)s1
Product: C=CCOC(=O)c1ccc(COC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)s1

Procedure:
In a manner similar to Example l(d), by reaction of 2.5 g (10 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl -2-naphthoyl chloride with 1.98 g (10 mmol) of allyl 5-hydroxymethyl-2-thiophene carboxylate, 3.7 g (90%) of allyl ester are obtained in the form of a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[O:10][CH:11]([CH3:14])[C:12]#[N:13])([O-:3])=[O:2].[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[N+:1]([C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[O:10][CH:11]([C:12]1[NH:24][N:23]=[N:22][N:13]=1)[CH3:14])([O-:3])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C#N)Oc1cccc(Oc2ccccc2[N+](=O)[O-])c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(Oc1cccc(Oc2ccccc2[N+](=O)[O-])c1)c1nnn[nH]1
Temperature: 115 °C
Reaction time: 1.33 h
Yield: 104.2 %

Procedure:
In 25 ml of N,N-dimethylformamide was dissolved 2.0 g of the 2-[3-(2-nitrophenoxy)phenoxy]propionitrile followed by addition of 0.92 g of sodium azide and 0.76 g of ammonium chloride, and the mixture was stirred at 115° C. for 80 minutes. The reaction mixture was then poured into ice-water containing 3 ml of concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried and concentrated to give 2.4 g of the title compound as a light brown oil.