Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].C(O)C.C1COCC1.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1)[CH:15]=[O:16]>C(OCC)(=O)C>[Br:11][C:12]1[CH:13]=[C:14]([CH2:15][OH:16])[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1
Reactant: COc1cc(Br)cc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(Br)cc(CO)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
NaBH4 (3.85 g; WAKO) was added to an ethanol (80 mL) and THF (20 mL) mixture solution of 3-bromo-5-methoxybenzaldehyde (22 g) with ice cooling and the resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was poured into ice water (300 mL) and ethyl acetate (300 mL) was added thereto to extract the mixture with and the organic layer was washed with saturated aqueous sodium bicarbonate solution (300 mL) and then dried. The solvent was evaporated under reduced pressure to give the title compound (22.05 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[C:20]1([S:26][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Sc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(Sc2ccccc2)c([N+](=O)[O-])c1
Yield: 56 %

Procedure:
To a stirred mixture of 2,4-dinitrofluorobenzene, 5.69 ml (45 mmol) and potassium carbonate 6.3 g (45 mmol) in acetone was added benzenethiol 4.65 ml (45 mmol). The mixture was heated to reflux for 2 hours, cooled and the solvent removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated potassium carbonate, dried over sodium sulfate, filtered and the solvent removed under reduced pressure to give 7.0 g (56%) of 2,4-dinitrophenyl phenyl sulfide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([O:24][CH:25]([CH3:27])[CH3:26])[CH2:6][C:7]1[CH:12]=[C:11]([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]([OH:22])=[C:9]([Br:23])[CH:8]=1)[CH3:2].IC.[C:31](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([O:24][CH:25]([CH3:27])[CH3:26])[CH2:6][C:7]1[CH:12]=[C:11]([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]([O:22][CH3:31])=[C:9]([Br:23])[CH:8]=1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(Cc1cc(Br)c(O)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CCOC(=O)C(Cc1cc(Br)c(OC)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
944 mg of 3-(3-bromo-5-[(t-butoxycarbonyl)amino]methyl-4-hydroxyphenyl)-2-isopropoxypropionic acid ethyl ester was dissolved in 5 ml of N,N-dimethylformamide, and 0.15 ml of iodomethane and 500 mg of potassium carbonate were successively added, followed by stirring for 2 hours at room temperature. Then, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 876 mg of 3-(3-bromo-5-[(t-butoxycarbonyl)amino]methyl-4-methoxyphenyl)-2-isopropoxypropionic acid ethyl ester from fractions eluted with hexane-ethyl acetate (4:1).
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:37]([O:39]CC)=[O:38])[CH2:5][C:6]1[CH:36]=[CH:35][C:9]([O:10][CH2:11]/[CH:12]=[C:13](/[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23](/[C:27](/[CH3:34])=[CH:28]/[C:29]([O:31]CC)=[O:30])[CH:22]=3)=[CH:17][CH:16]=2)\[CH3:14])=[CH:8][CH:7]=1)[CH3:2].[OH-:42].[Na+]>>[C:37]([CH:4]([O:3][CH2:1][CH3:2])[CH2:5][C:6]1[CH:36]=[CH:35][C:9]([O:10][CH2:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:5](=[CH:6][CH3:7])[C:4]([OH:3])=[O:42])[CH:22]=3)=[CH:19][CH:20]=2)[CH3:14])=[CH:8][CH:7]=1)([OH:39])=[O:38].[C:37]([C@@H:4]([O:3][CH2:1][CH3:2])[CH2:5][C:6]1[CH:36]=[CH:35][C:9]([O:10][CH2:11]/[CH:12]=[C:13](/[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23](/[C:27](/[CH3:34])=[CH:28]/[C:29]([OH:31])=[O:30])[CH:22]=3)=[CH:17][CH:16]=2)\[CH3:14])=[CH:8][CH:7]=1)([OH:39])=[O:38]
Reactant: CCOC(=O)/C=C(\C)c1cccc(-c2ccc(/C(C)=C/COc3ccc(C[C@H](OCC)C(=O)OCC)cc3)cc2)c1
Reactant: [OH-]
Agent: [Na+]
Product: CC=C(C(=O)O)c1cccc(-c2ccc(C(C)=CCOc3ccc(CC(OCC)C(=O)O)cc3)cc2)c1
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cccc(/C(C)=C/C(=O)O)c3)cc2)cc1)C(=O)O
Yield: 238 %

Procedure:
The title compound was prepared from (E,E)-(S)-ethyl 3-(4′-{3-[4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenoxy]-1-methyl-propenyl}-biphenyl-3-yl)-but-2-enoate (example 111) (190 mg, 0.34 mmol) and sodium hydroxide (1M, 1.4 ml, 1.4 mmol) by a procedure analogous to that described in example 51, yielding (E,E)-(S)-3-(4′-{3-[4-(2-carboxy-2-ethoxy-ethyl)-phenoxy]-1-methyl-propenyl}-biphenyl-3-yl)-but-2-enoic acid (135 mg, 79%) as a colourless solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH2:4][OH:5].[C:11]1([CH2:17][CH2:18][CH2:19]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl[C:22]([N:24]1[C@H:29]([CH3:30])[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][C@@H:25]1[CH3:38])=[O:23]>>[CH3:38][C@H:25]1[CH2:26][NH:27][CH2:28][C@@H:29]([CH3:30])[N:24]1[C:22]([O:5][CH2:4][C:3]1[CH:6]=[C:7]([O:10][CH2:19][CH2:18][CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][C:2]=1[F:1])=[O:23]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Reactant: OCc1cc(O)ccc1F
Reactant: BrCCCc1ccccc1
Product: C[C@@H]1CNC[C@H](C)N1C(=O)OCc1cc(OCCCc2ccccc2)ccc1F

Procedure:
2-Fluoro-5-(3-phenyl)propoxybenzyl cis-2,6-dimethylpiperazine-1-carboxylate was prepared from 2-fluoro-5-hydroxybenzyl alcohol, 3-phenylpropyl bromide and 1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazine according to the methods described for Examples 54 and 121 to give the product as a yellow oil (2.3%); HPLC (XTERRA, 50/80, 220 nm) 91.1% (6.29 min); NMR δH (400 MHz, DMSO-d6) 7.32–7.10 (6H, m), 6.95 (1H, q, J 3 Hz), 6.91 (1H, dt, J 9, 4 Hz), 5.08 (2H, s), 3.93 (2H, t, J 6.5 Hz), 3.91 (2H,m), 2.73 (2H, t, J 7 Hz), 2.71 (2H, d, J 8.5 Hz), 2.65 (2H, dd, J 12.5, 4.5 Hz), 2.00 (2H, m) and 1.18 (6H, d, J 7 Hz).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([N:22](CC)C(C)C)(C)[CH3:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(CN)O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[Br:18][C:16]1[CH:17]=[C:9]2[C:10]([C:11](=[O:13])[N:22]3[CH2:19][CH2:20][O:8][C:1]32[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:15]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(Br)cc1C(=O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: NCCO
Product: O=C1c2ccc(Br)cc2C2(c3ccccc3)OCCN12

Procedure:
To a solution of 2-Benzoyl-4-bromo-benzoic acid (100 mg; 0.33 mmol) in N,N-dimethylformamide (1 ml) with N,N-Diisopropylethylamine (127 μl; 0.98 mmol) is added HATU (137 mg; 0.36 mmol). It is stirred at ambient temperature for 5 minutes before ethanolamine (21 μl; 0.33 mmol) is added. After 4 hours the reaction mixture is purified via reversed phase chromatography under basic conditions. The received 5-Bromo-3-hydroxy-2-(2-hydroxy-ethyl)-3-phenyl-2,3-dihydro-isoindol-1-one is taken up in 1 ml toluene and treated with p-Toluenesulfonic acid monohydrate (3 mg; 0.02 mmol) at 120° C. for 2 days. It is purified via reversed phase chromatography under basic conditions.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[CH2:11][NH2:12].F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[CH2:11][NH:12][C:19]1[CH:20]=[N:21][CH:22]=[CH:14][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: NCc1cc2ccccc2o1
Reactant: O=C(O)c1ccncc1F
Agent: Cl
Product: O=C(O)c1ccncc1NCc1cc2ccccc2o1
Yield: 3 %

Procedure:
The title compound was prepared in 3% yield from (1-benzofuran-2-ylmethyl)amine hydrochloride and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ 13.44 (br s, 1H), 8.39 (s, 1H), 7.97 (br s, 1H), 7.87 (d, 1H, J=5.0 Hz), 7.52-7.60 (m, 3H), 7.19-7.29 (m, 2H), 6.81 (s, 1H), 4.79 (s, 2H). [M+H] calc'd for C15H12N2O3, 269; found 269.
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)=S)([CH3:4])([CH3:3])[CH3:2].ClCCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>C(N(CC)CC)C>[C:1]([N:5]=[C:6]=[N:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=S)Nc1cc(F)cc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)N=C=Nc1cc(F)cc(Cl)c1

Procedure:
To a solution of 1.04 g of N-t-butyl-N'-(3-chloro-5-fluorophenyl)thiourea produced in Example A-11 in 25 of dichloromethane were added 4.18 g of triphenylphosphine, 2.53 g of carbon tetrachloride and 1.61 g of triethylamine. The mixture was refluxed for 2 hours and evaporated in vacuo. The residue was chromatographed on a silica gel column using cyclohexane as a solvent to give N-t-butyl-N'-(3-chloro-5-fluorophenyl)carbodiimide as an oil. To a solution of this oil in 1.5 ml of DMF were added 500 mg of cyanamide and 0.1 ml of diisopropylethylamine. The mixture was stirred at 100° C. overnight, cooled to room temperature, poured into ice-water, and extracted with ethyl acetate. The extract was evaporated in vacuo to dryness and the residue recrystallized from isopropyl alcohol to give 0.1 g of the title compound as colorless needles melting at 156.0°-157.0° C.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][CH2:10][CH2:11][C:12](O)=[O:13])[CH2:5][CH2:4]1.[CH3:28][NH:29][CH3:30].CN1CCOCC1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.C1COCC1>[CH3:28][N:29]([CH3:30])[C:12](=[O:13])[CH2:11][CH2:10][O:9][C@H:6]1[CH2:7][CH2:8][C@H:3]([N:2]([CH3:1])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:4][CH2:5]1
Reactant: CNC
Reactant: CN([C@H]1CC[C@H](OCCC(=O)O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)CCO[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 0 °C

Procedure:
g (2.7 mmol) trans-3-{4-[Methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-propionic acid in 30 ml CH2Cl2 were treated with 2 ml (4.0 mmol, 1.5 eq) 2M dimethylamine in THF and 0.44 ml (4.03 mmol, 1.5 eq) NMM. The solution was cooled to 0° C. and 670 mg (3.5 mmol, 1.3 eq) EDCI and 82 mg (5.4 mmol, 0.2 eq) HOBT were added. The mixture was stirred at RT over night, partitioned between CH2Cl2 and a saturated aqueous solution of NaHCO3. The organic phase was washed with KHSO4 and brine, dried over Na2SO4 and evaporated. Column chromatography with EtOAc gave 1.06 g (90%) trans-N,N-Dimethyl-3-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-propionamide as white solid, mp 88° C., MS: 437 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:25]=[C:26]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[N:28][CH:29]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]2[CH:25]=[C:26]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[N:28][CH:29]=2)=[CH:4][CH:5]=1
Reactant: COC(=O)c1cncc(O)c1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cncc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.9 %

Procedure:
To a mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (4.52 g), methyl 5-hydroxy-3-pyridinecarboxylate (2.0 g), and N,N-dimethylformamide (30 mL) was added sodium hydride (60%, oil, 0.58 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration. The crystals were subjected to silica gel column chromatography to give crystals (2.41 g, 0.43%) of methyl 5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridinecarboxylate from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 138-139° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[OH:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[OH:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[C:28]([C:2]2[N:3]=[C:4]3[C:10]([C:11]([C:13]4([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCC1
Reactant: OCCCc1cccc(B(O)O)c1
Product: CC1(C(=O)c2c[nH]c3ncc(-c4cccc(CCCO)c4)nc23)CCCCC1

Procedure:
{2-[3-(3-Hydroxy-propyl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-(1-methyl-cyclohexyl)-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone and 3-(3-hydroxypropyl)phenylboronic acid following general procedures as described in these Examples. MP 80-83° C., M+H=378.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13](=[O:22])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[S:11])[CH:5]=[CH:6][C:7]=1[OH:8].[C:23]([O:29][C:30]1[C:31]([CH3:40])=[C:32]2[N:37]([CH:38]=1)[N:36]=[CH:35][N:34]=[C:33]2Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25].N12CCN(CC1)CC2>CC#N>[C:23]([O:29][C:30]1[C:31]([CH3:40])=[C:32]2[N:37]([CH:38]=1)[N:36]=[CH:35][N:34]=[C:33]2[O:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10]([NH:12][C:13](=[O:22])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)=[S:11])=[CH:3][C:2]=1[F:1])(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1c(OC(=O)C(C)(C)C)cn2ncnc(Cl)c12
Reactant: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(O)c(F)c1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: Cc1c(OC(=O)C(C)(C)C)cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a mixture of 1-(3-fluoro-4-hydroxyphenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea (60 mg, 0.19 mmol, Compound A of Example 3), 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl pivalate (50 mg, 0.19 mmol, Compound D of Example 1) and 1,4-diazabicyclo[2.2.2]octane (DABCO, 21.3 mg, 0.19 mmol) was added MeCN (5 mL). The reaction was stirred at RT for 1 h and concentrated in vacuo. The residue was purified by flash chromatography (eluted with 1–15% MeOH/CH2Cl2) to give the title compound (91 mg, 86%) as a white solid. 1H NMR (CDCl3) δ 12.40 (s, 1H), 8.54 (s, 1H), 7.87 (m, 3H), 7.29 (m, 4H), 7.12 (m, 2H), 3.71 (s, 2H), 2.43 (s, 3H), 1.39 (s, 9H); MS(ESI+) m/z 554 (M+H) +.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[O:6]([CH2:13][C:14](Cl)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[CH2:1]([NH:5][C:14](=[O:15])[CH2:13][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)COc1ccccc1
Reactant: CCCCN
Solvent: ClCCl
Product: CCCCNC(=O)COc1ccccc1
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 104.2 %

Procedure:
A 100 mL 3-neck, round-bottom flask was charged with N-butylamine (8 mL, 80 mmol) and CH2Cl2 (20 mL) under N2 purge. The reaction was cooled to −10° C. Phenoxylacetylchloride (2.8 mL, 20 mmol) was slowly added via syringe, and the reaction was stirred at −10° C. for 5 minutes and warmed to room temperature. After 2 hours, the solvent was removed under vacuum. The reaction was diluted with water and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under vacuum. The pale yellow oil crystallized upon standing to provide 4.32 g of the title compound as a pale yellow crystalline solid. MS (DCI/NH3) m/z 225 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2Cl.[CH3:18][N:19]([CH2:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)[CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2[NH:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:19]([CH3:20])[CH3:18])=[CH:28][CH:27]=1
Reactant: CC(C)C(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CN(C)Cc1ccc(N)cc1
Product: CC(C)C(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN(C)C)cc1
Yield: 27.2 %

Procedure:
Following general procedure B, 1-(6-bromo-4-chloroquinolin-3-yl)-2-methylpropan-1-one (604 mg, 1.93 mmol) was reacted with 4-((dimethylamino)methyl)aniline (882 mg, 3.87 mmol) to afford the desired product (224 mg, 27%) as a yellow solid: ESI MS m/z 432, [C22H30BrN3O+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12](I)=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:14]#[N:15])=[CH:10]2)=[CH:5][CH:4]=1.[CH2:16]([OH:21])/[CH:17]=[CH:18]\[CH2:19][OH:20].C([O-])(O)=O.[Na+]>CN1CCCC1=O.Cl[Pd]Cl>[CH3:1][O:2][C:3]1[C:12]([C:17]([CH2:16][OH:21])=[CH:18][CH2:19][OH:20])=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:14]#[N:15])=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(C#N)cc2c1I
Reactant: OC/C=C\CO
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1ccc2ccc(C#N)cc2c1C(=CCO)CO
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A solution of Example 53B (3.09 g, 10 mmol), PdCl2 (120 mg, 1 mmol), cis-2-butene-1,4-diol (1.23 mL, 15 mmol) and NaHCO3 (1.01 g, 12 mmol) in N-methylpyrrolidinone (10 mL) was stirred at 130° C. for 1 h, cooled to room temperature and chromatographed on silica gel with 30% ethyl acetate/hexanes to provide 2.19 g of the title compound as a mixture of diastereomers.
Reaction SMILES: N1[CH:6]=[CH:5][C:4]([C:7](N)=O)=NC=1.Cl.[C:11]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=2)[N:15]=1)([OH:13])=O.[CH2:33](N(CC)CC)[CH3:34].C(OC(Cl)=O)C(C)C.Cl.CNOC>C(Cl)Cl>[C:11]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=2)[N:15]=1)(=[O:13])[C:4]1[CH:7]=[CH:34][CH:33]=[CH:6][CH:5]=1
Reactant: COc1cc(Nc2nccc(C(=O)O)n2)cc(OC)c1OC
Reactant: CCN(CC)CC
Reactant: NC(=O)c1ccncn1
Agent: CC(C)COC(=O)Cl
Agent: CNOC
Agent: Cl
Solvent: ClCCl
Product: COc1cc(Nc2nccc(C(=O)c3ccccc3)n2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
The pyrimidine-4-carboxamide used as starting material was prepared by treating a solution of 4-carboxy-N-(3,4,5-trimethoxyphenyl)-2-pyrimidineamine hydrochloride (2.0 g, 5.86 mmol) and triethylamine (2.0 ml, 14.0 mmol) in CH2Cl2 (40 ml), cooled to −20° under a nitrogen atmosphere, with isobutylchloroformate (1.1 ml, 7.0 mmol). The resulting mixture was stirred for 20 min. before N,O-dimethylhydroxylamine hydrochloride (683 mg, 7.0 mmol) and triethylamine (1.0 ml, 7.0 mmol) were added and the reaction allowed to warm to room temperature over 3 h. After washing with 2M hydrochloric acid (1×50 ml) and 2M NaOH solution (1×50 ml), the reaction was dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to column chromatography [silica ethyl acetate] to give the desired product (1.02 g), as a yellow oil. δH (CDCl3) 8.51 (1H, d, J 4.9 Hz), 7.21 (1H, br s), 6.92 (3H, br s), 3.86 (6H, s), 3.82 (3H, s), 3.69 (3H, br s) and 3.36 (3H, s). MS m/z 349 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:11][CH2:10][C@@H:9]2[N:4]([C:5](=[O:12])[CH2:6][CH2:7][CH2:8]2)[C@@H:3]1[C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[CH:14]=1.[CH3:22][C:23]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])[CH3:24].N1C=CN=C1.O>CN(C1C=CN=CC=1)C.CN(C=O)C.C(OCC)(=O)C>[Si:26]([O:1][C@H:2]1[CH2:11][CH2:10][C@@H:9]2[N:4]([C:5](=[O:12])[CH2:6][CH2:7][CH2:8]2)[C@@H:3]1[C:13]1[CH:14]=[C:15]([F:21])[C:16]([F:20])=[C:17]([F:19])[CH:18]=1)([C:23]([CH3:25])([CH3:24])[CH3:22])([CH3:28])[CH3:27]
Reactant: O=C1CCC[C@@H]2CC[C@H](O)[C@@H](c3cc(F)c(F)c(F)c3)N12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H]2CCCC(=O)N2[C@@H]1c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
A solution of (6R*,7S*,9aR*)-7-hydroxy-6-(3,4,5-trifluorophenyl)octahydroquinolizin-4-one (164 mg), TBSCl (165 mg), imidazole (149 mg), and DMAP (6.7 mg) in DMF (5.0 mL) was stirred at room temperature overnight. To make the starting material disappear, TBSCl (165 mg) was added to the reaction solution, which was then stirred at room temperature overnight. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 227 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]2[N:22]=[CH:23][S:24][C:20]=2[CH:19]=1>>[S:24]1[C:20]2[CH:19]=[C:18]([NH:17][C:10](=[O:12])/[CH:9]=[CH:8]/[C:7]3[C:2]([CH3:1])=[N:3][C:4]([C:13]([F:16])([F:15])[F:14])=[CH:5][CH:6]=3)[CH:26]=[CH:25][C:21]=2[N:22]=[CH:23]1
Reactant: Nc1ccc2ncsc2c1
Reactant: Cc1nc(C(F)(F)F)ccc1/C=C/C(=O)O
Product: Cc1nc(C(F)(F)F)ccc1/C=C/C(=O)Nc1ccc2ncsc2c1

Procedure:
Analogous to the procedure used to prepare Example 1, (2E)-3-[2-methyl-6-(trifluoromethyl)(3-pyridyl)]prop-2-enoic acid, Example 82(b), (120 mg, 0.50 mmol) and 6-aminobenzothiazole (75 mg, 0.50 mmol, Lancaster) provided, after purification by silica gel chromatography (55:45 hexane:EtOAc), the title compound as a white solid. MP 196° C. MS (ESI, pos. ion) m/z: 364 (M+1).
Reaction SMILES: [N:1]1C=CC=CC=1.[Cl:7][CH2:8][CH2:9][C:10](Cl)=[O:11].Cl.[C:14]([O:19][CH2:20][CH2:21]N)(=[O:18])[C:15]([CH3:17])=[CH2:16]>CN(C)C=O>[C:14]([O:19][CH2:20][CH2:21][CH:9]([CH2:8][Cl:7])[C:10]([NH2:1])=[O:11])(=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: c1ccncc1
Reactant: C=C(C)C(=O)OCCN
Reactant: O=C(Cl)CCCl
Agent: Cl
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCCC(CCl)C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridine (15.8 g, 0.2 mole) was added dropwise to a mixture of 3-chloropropionyl chloride (12.7 g, 0.1 mole) and 2-aminoethyl methacrylate hydrochloride (16.5 g, 0.1 mole) in N,N-dimethylformamide (20 ml) at 0° C. The mixture was left to stir overnight at ambient temperature. The solvent was evaporated in vacuo, and the residue was dissolved in dichloromethane (500 ml). The mixture was then washed with saturated sodium chloride (24,200 ml), dried over anhydrous magnesium sulfate, and the solvent removed. The product was collected by distillation, bp 104°-110° C. at 2μ.