Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH:21]1[CH2:23][O:22]1)[CH2:3][S:4][CH2:5][CH2:6][C:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:9])[CH3:8].[OH-:24].[K+]>CS(C)=O.O.C(OCC)(=O)C>[CH3:9][C:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH2:6][CH2:5][S:4][CH2:3][CH:2]([OH:1])[CH:21]([OH:24])[CH2:23][OH:22])[CH3:8]
Reactant: CC(C)(CCSCC(O)C1CO1)NC(=O)OCc1ccccc1
Reactant: [OH-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(CCSCC(O)C(O)CO)NC(=O)OCc1ccccc1
Temperature: 90 °C
Yield: 14.9 %

Procedure:
To a solution of benzyl 4-(2-hydroxy-2-(oxiran-2-yl)ethylthio)-2-methylbutan-2-ylcarbamate (3.33 g, 9.81 mmol) in dimethylsulfoxide (50 ml) and H2O (10 ml) was added 5.0 M KOH (600 μl, 3.0 mmol). The solution was heated to 90° C. for 5 hour, cooled to room temperature, diluted with 400 ml ethyl acetate, washed with 1×200 ml 5% NaHSO4, 5×200 ml saturated NaCl, dried on MgSO4, and concentrated in vacuo. The residue was purified by preparatory HPLC (H2O/acetonitrile) to give the title compound as a clear oil (159.3 mg, 0.446 mmol, 45%) as a mixture of diastereomers. 1H NMR (400 MHz, CDCl3) δ 1.28 (s, 6H), 1.9-2.1 (m, 2H), 2.50 (m, 2H), 2.6-2.7 (m, 2H), 3.6-3.8 (m, 4H), 3.85 (br s, 3H), 4.93 (s, 1H), 5.04 (s, 2H), 7.3-7.4 (m, 5H); LRMS (ESI/APCI) m/z 358 [M+H]+, 380 [M+Na]+.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9].[C:13]([O:17][C:18](=[O:36])[CH2:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>C(Cl)Cl>[C:13]([O:17][C:18](=[O:36])[CH2:19][N:20]([S:2](=[O:4])(=[O:3])[NH:5][C:6]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7])[C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)O
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)CNc1ccc(I)cc1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN(c1ccc(I)cc1OCc1ccccc1)S(=O)(=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice cooled solution of chlorosulfonyl isocyanate (0.788 mL, 8.94 mmol) in DCM (40 mL) is added dropwise t-butanol (0.855 mL, 8.94 mmol). Then at 0° C., (2-benzyloxy-4-iodophenylamino)-acetic acid tert-butyl ester (2.62 g, 5.96 mmol) and triethylamine (2.08 mL, 14.9 mmol) in DCM-(40 mL) is added dropwise. After stirring for 30 min., DCM (300 mL) is added and the organic layer is washed with 2N HCl solution. It is then dried with NaSO4, and concentrated. The residue is purified by column chromatography to give the title compound as an off-white foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:17])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2.N1C=CC=CC=1.[CH3:24][C:25]1[S:26][CH:27]=[C:28]([C:30](Cl)=[O:31])[N:29]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:17][C:30]([C:28]2[N:29]=[C:25]([CH3:24])[S:26][CH:27]=2)=[O:31])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2
Reactant: Nc1cc(Br)cc2nn(C3CCCCO3)cc12
Reactant: Cc1nc(C(=O)Cl)cs1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc(C(=O)Nc2cc(Br)cc3nn(C4CCCCO4)cc23)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a round bottom flask was introduced 6-bromo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (2.77 g) dissolved in DCM (120 ml) followed by the addition of pyridine (1.135 ml). The reaction mixture was left to stir for a few minutes before the addition of 2-methyl-1,3-thiazole-4-carbonyl chloride (2.267 g). The reaction mixture was left to stir at RT for 1 h. After this time the reaction mixture was extracted between DCM and saturated sodium bicarbonate aq. The extracted organic layer was dried down. The crude was dissolved in DCM and adsorbed onto fluorisil before purification by solid loading on companion using Si Column (40 g) eluting with 40-100% ethyl acetate in cyclohexane. The appropriate fractions were combined and evaporated to dryness to yield the title compound, 2.6 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9](Cl)=[O:10])=[CH:4][CH:3]=1.N1C=CC=CC=1C.[Cl:22][C:23]([Cl:33])=[CH:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=[O:28]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([O:28][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[CH:24]=[C:23]([Cl:22])[Cl:33])=[O:10])=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1C=C(Cl)Cl
Reactant: CC(C)C(C(=O)Cl)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: Cc1ccccn1
Product: CC(C)C(C(=O)OCc1ccccc1C=C(Cl)Cl)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
2.8 g (0.012 mole) of 2-(4-chlorophenyl)-isovaleryl chloride in 50 ml of absolute toluene are introduced into 1.2 g (0.013 mole) of -picoline and 3.2 g (0.015 mole) of 2-(2,2-dichlorovinyl)-benzaldehyde in a conical flask at room temperature, while stirring. After 30 minutes, the mixture is filtered under suction over silica gel, and washing is carried out with toluene.
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.[CH2:16]([OH:21])[C:17]([CH3:20])([CH3:19])[CH3:18].[H-].[Na+]>O>[CH2:16]([O:21][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)CO
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 330.9 %

Procedure:
To dimethylformamide solution (78 ml) containing 4-chloronitrobenzene (15.7 g) and neopentyl alcohol (10.6 g) was added by portions sodium hydride (60% content, 4.8 g) under ice-cooling. The mixture was stirred under ice-cooling for 1 h. The mixture was warmed to room temperature and stirred further for 1 h. The reaction mixture was poured into water and extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The obtained oily substance was distilled under reduced pressure to give 4-neopentyloxynitrobenzene (69 g), boiling point: 120–125° C./0.1 mmHg.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:20]([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)([O:23][CH3:24])(=[O:22])=[O:21]>>[S:20]([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)([O-:23])(=[O:22])=[O:21].[CH3:24][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Product: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 98.7 %

Procedure:
A mixture of 11.8 g (45.0 mmol) of triphenylphosphine and 8.40 g (45.1 mmol) of methyl tosylate was allowed to react for 2 hr at 130° C. A total of 19.9 g (44.4 mmol, 98.6%) of methyltriphenylphosphonium tosylate was obtained. This was further purified by stirring overnight in 95:5 ether-acetonitrile. Analyses: mp 147.0°-149.0° C.
Reaction SMILES: [CH3:1]I.[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[N:17]([Sn](C)(C)C)[N:16]=[N:15][N:14]=3)=[CH:10][CH:11]=2)[C:6]([C:22]2[N:30]([S:31]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[C:25]3=[N:26][CH:27]=[CH:28][CH:29]=[C:24]3[CH:23]=2)=[CH:5]1>O>[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[N:17]([CH3:1])[N:16]=[N:15][N:14]=3)=[CH:10][CH:11]=2)[C:6]([C:22]2[N:30]([S:31]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[C:25]3=[N:26][CH:27]=[CH:28][CH:29]=[C:24]3[CH:23]=2)=[CH:5]1.[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[N:17]=[N:16][N:15]([CH3:1])[N:14]=3)=[CH:10][CH:11]=2)[C:6]([C:22]2[N:30]([S:31]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[C:25]3=[N:26][CH:27]=[CH:28][CH:29]=[C:24]3[CH:23]=2)=[CH:5]1
Reactant: CI
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(-c5nnnn5[Sn](C)(C)C)cc34)cc3cccnc32)cc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(-c5nnn(C)n5)cc34)cc3cccnc32)cc1
Product: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(-c5nnnn5C)cc34)cc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methyl iodide (2.5 mL) was added to a solution of 2-[1-methyl-5-(1-trimethylstannanyl-1H-tetrazol-5-yl)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine [620 mg, Reference Example 20] at ambient temperature. The mixture was then allowed to stir at ambient temperature for 4 hours then was poured into water and then extracted with ethyl acetate. The combined extract was washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and petroleum ether (1:1, v/v) to give 2-[1-methyl-5-(1-methyl-1H-tetrazol-5-yl)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (191 mg) as a colourless solid, [MS: 506(MNa+). 1H NMR [(CD3)2SO]: δ 8.39 (dd, 1H, J=4.8 and 1.6 Hz); 7.97 (m, 1H); 7.96 (d, 1H, J=4.0 Hz); 7.90 (s, 1H); 7.80 (dd, 1H, J=8.7 and 0.6 Hz); 7.70 (dd, 1H, J=8.7 and 1.8 Hz); 7.56 (m, 2H); 7.30 (dd, 1H, J=7.7 and 4.8 Hz); 7.22 (m, 2H); 6.82 (s, 1H); 4.19 (s, 3H); 4.0 (s, 3H); 2.23 (s, 3H)] and 2-[1-Methyl-5-(2-methyl-2H-tetrazol-5-yl)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (77 mg) as a colourless solid, m.p. 215-218° C. [MS: 506(MNa+)].
Reaction SMILES: C1(O)C=CC=CC=1.[OH:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13].[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30]2[O:36][CH2:35][CH2:34][CH:33](Br)[C:32](=[O:38])[C:31]=2[CH:39]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30]2[O:36][CH2:35][CH2:34][CH:33]([O:8][C:9]3[CH:18]=[CH:17][CH:16]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=3)[C:32](=[O:38])[C:31]=2[CH:39]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: O=C1c2cc(OCc3ccccc3)ccc2OCCC1Br
Solvent: Oc1ccccc1
Product: COC(=O)c1cccc(OC2CCOc3ccc(OCc4ccccc4)cc3C2=O)c1

Procedure:
By the method of Example 27, substituting the phenol with a molar equivalent of methyl 3-hydroxybenzoate, 7-benzyloxy-4-bromo-3,4-dihydro-1-benzoxepin-5(2H)-one (17.3 g) was converted to present title product, 10.9 g, m.p. 134-136° C.
Reaction SMILES: Br[C:2]([CH3:4])=[CH2:3].[Li]C(C)(C)C.[CH2:10]([O:17][C:18]([NH:20][C@@H:21]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:31][CH:30]=1)[C:22](N(OC)C)=[O:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCOC(C)=O>C1COCC1>[C:40]([O:39][C:37]([NH:36][CH2:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][C@H:21]([NH:20][C:18](=[O:19])[O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:22](=[O:23])[C:2]([CH3:4])=[CH2:3])=[CH:30][CH:31]=1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CON(C)C(=O)[C@H](Cc1ccc(CNC(=O)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Reactant: C=C(C)Br
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)[C@H](Cc1ccc(CNC(=O)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Temperature: -20 °C

Procedure:
2-Bromopropene (3.5 eq., 14.0 mmol, 1.25 mL) was dissolved in THF (50 mL) and cooled to −78° C. tBuLi (6.5 eq., 26.0 mmol, 16.3 mL; 1.6 M in hexane) was added slowly and the mixture was stirred for 1 hour at −78° C. after which Weinreb amide 11 (1 eq., 4.0 mmol, 1.89 g) was added in THF (5 mL). The mixture was allowed to warm to −20° C. in 6 hours after which TLC analysis indicated complete consumption of the Weinreb amide. A saturated aqueous NH4Cl solution and EtOAc were added and the layers were separated. The organic layer was extracted with brine, dried over MgSO4 and concentrated under reduced pressure. The title compound was obtained after column chromatography (20%→50% EtOAc/PE) as a colourless oil (yield: 1.71 g, 3.77 mmol, 94%). 1H NMR (400 MHz, CDCl3): δ=7.33-7.24 (m, 5H), 7.11 (d, J=7.87 Hz, 2H), 6.97 (d, J=8.00 Hz, 2H), 6.03 (s, 1H), 5.85 (s, 1H), 5.77 (d, J=8.18 Hz, 1H), 5.30 (dd, J=14.10, 6.11 Hz, 1H), 5.12-5.08 (m, 1H), 5.04 (dd, J=26.54, 12.35 Hz, 2H), 4.21 (d, J=5.41 Hz, 2H), 3.09 (dd, J=13.79, 5.88 Hz, 1H), 2.89 (dd, J=13.76, 5.97 Hz, 1H), 1.84 (s, 3H), 1.44 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3): δ=199.28, 155.66, 155.34, 141.99, 137.40, 136.13, 134.60, 129.27, 128.17, 127.80, 127.71, 126.50, 79.01, 66.45, 55.13, 43.96, 38.76, 28.14, 17.44 ppm. HRMS: calcd. for C26H32N2O5 453.23840 [M+H]+. Found 453.23818.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH2:38][CH3:39])=[C:9](\[C:25]2[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:27][CH:26]=2)/[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:14]=[CH:13]3)=[CH:4][CH:3]=1.[N:40]1[CH:45]=[C:44](B(O)O)[CH:43]=[N:42][CH:41]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:40]1[CH:45]=[C:44]([C:2]2[CH:7]=[CH:6][C:5](/[C:8](/[CH2:38][CH3:39])=[C:9](\[C:25]3[CH:26]=[CH:27][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][CH:30]=3)/[C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[N:15]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[N:14]=[CH:13]4)=[CH:4][CH:3]=2)[CH:43]=[N:42][CH:41]=1
Reactant: OB(O)c1cncnc1
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(Br)cc2)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(-c3cncnc3)cc2)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Temperature: 90 °C
Yield: 47.5 %

Procedure:
A mixture of (E)-ethyl 3-(4-((E)-2-(4-bromophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate (212 mg, 0.36 mmol), pyrimidin-5-ylboronic acid (67 mg, 0.54 mmol) and potassium carbonate (100 mg, 0.72 mmol) in toluene/ethanol (4:1, 5 mL) was degassed with nitrogen. Pd(PPh3)4 (41 mg, 0.036 mmol) was added and the mixture was heated to 90° C. overnight. The reaction was not done so additional pyrimidin-5-ylboronic acid (67 mg, 0.54 mmol), potassium carbonate (100 mg, 0.72 mmol) and Pd(PPh3)4 (41 mg, 0.036 mmol) were added, and the mixture was heated to 90° C. for an additional 4 h. The mixture was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with brine (3×), dried over sodium sulfate, and purified by flash chromatography on silica gel eluting with 0 to 100% ethyl acetate/hexanes to afford 100 mg of the title compound as a yellow foam. 1H NMR (400 MHz, DMSO-d6): δ 9.16 (s, 1H), 9.15 (s, 2H), 8.13 (s, 1H), 7.76-7.67 (m, 4H), 7.48 (d, 1H), 7.42 (d, 2H), 7.35 (d, 2H), 7.26 (dd, 1H), 6.95 (d, 2H), 6.48 (d, 1H), 5.86 (dd, 1H), 4.14 (qt, 2H), 3.90 (m, 1H), 3.75 (m, 1H), 2.49-2.42 (m, 3H), 2.01 (m, 2H), 1.78 (m, 1H), 1.59 (m, 2H), 1.21 (t, 3H), 0.92 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].C(=O)(O)[O-].[Na+].[I:15]I>>[F:1][C:2]1[CH:8]=[C:7]([I:15])[CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4]
Reactant: Nc1c(F)cccc1Cl
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1c(F)cc(I)cc1Cl
Temperature: 60 °C
Reaction time: 72 h

Procedure:
2-Fluoro-6-chloroaniline (28.8 g, 0.2 mol) is suspended in a solution of sodium bicarbonate (17.2 g, 0.2 mol in 150 mL water) and warmed to 60° C. Elemental iodine (50.8 g, 0.2 mol) is added portionwise and the resulting mixture stirred at 60° C. for 3 days. After cooling to room temperature, the reaction mixture is partitioned between CH2Cl2 (350 mL) and saturated sodium bisulfite solution (500 mL). The aqueous layer is re-extracted with additional CH2Cl2 (250 mL) and the combined organic layers dried (MgSO4) and concentrated by rotary evaporator. The residual oil is purified by flash chromatography (9:1 hexanes/EtOAc) to give 2-fluoro-4-iodo-6-chloroaniline (m.p. 85–87° C.).
Reaction SMILES: C([O:5][C:6](=[O:23])[CH2:7][N:8]([C:16]([C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1)=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[C:16]([N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][C:6]([OH:23])=[O:5])=[O:17]
Reactant: CC(C)(C)OC(=O)CN(Cc1ccccc1)C(=O)c1ccc[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN(Cc1ccccc1)C(=O)c1ccc[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
To a solution containing 2.85 g (9.01 mmol) of (Pyrrole-2-carbonyl)-N-(benzyl)glycine-t-butyl ester in 50 mL of anhydrous dichloromethane cooled to 0° C. was added 25 mL of TFA dropwise. After 90 minutes an additional 25 mL of TFA was added and allowed to stir for 30 minutes. The mixture was evaporated in vacuo to afford 2.19 g of (Pyrole-2-carbonyl)-N-(benzyl)glycine as a tan solid. FAB MS [M+H] m/z; Calcd. 259, Found 259.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH2:12][N:11](C(OCC3C=CC=CC=3)=O)[CH2:10][CH2:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.Cl[C:24]1[C:25]2CN(C(OCC3C=CC=CC=3)=O)CCC=2N=C(C)N=1.P(Cl)(Cl)(Cl)=O>>[CH2:24]([O:1][C:2]1[C:3]2[CH2:12][NH:11][CH2:10][CH2:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1)[CH3:25]
Reactant: Cc1nc(O)c2c(n1)CCN(C(=O)OCc1ccccc1)C2
Reactant: Cc1nc(Cl)c2c(n1)CCN(C(=O)OCc1ccccc1)C2
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1nc(C)nc2c1CNCC2

Procedure:
Benzyl 4-hydroxy-2-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate, which may be prepared using the general method of E. Kretzschmar and P. Meisel, Pharmazie 1988, 43, 475-476, was converted to benzyl 4-chloro-2-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate via treatment with phosphorus oxychloride. Chloride displacement with sodium ethoxide was followed by hydrogenolytic removal of the protecting group to afford the requisite 4-ethoxy-2-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2[OH:21])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[Br:22]N1C(=O)CCC1=O>ClCCl>[Br:22][C:7]1[N:8]=[C:3]([CH2:1][CH3:2])[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2[OH:21])=[N:5][C:6]=1[CH2:9][CH3:10]
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Temperature: 0 °C
Yield: 90.9 %

Procedure:
A solution of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol (1.94 g, 6.8 mmol) in dichloromethane (35 mL) was purged with nitrogen and cooled to 0° C. This light purple/grey homogenous solution was treated with a single portion of N-bromosuccinimide (1.34 g, 7.5 mmol) instantly becoming a lighter color. The reaction was warmed to room temperature for 15 minutes, transferred to a separatory funnel, diluted with 100 mL additional dichloromethane, washed twice with water (75 mL), and once with brine (75 mL). The organics were dried over MgSO4, filtered, and concentrated to give a golden oil. This material was purified by biotage MPLC (90 g column, 15% ethyl acetate/heptane) to afford 2.24 g (90%) of the title compound as a pale yellow solid. IR (diffuse reflectance) 3416, 3355, 2969, 2941, 1555, 1538, 1482, 1385, 1378, 1295, 1285, 1200, 1181, 1043, 733 cm−1; OAMS supporting ions at: ESI+ 361.9; MS (EI) m/z 361 (M+); [α]25D=−35 (c 0.53, methylene chloride); Anal. Calcd for C17H20BrN3O: C, 56.36; H, 5.56; N, 11.60. Found: C, 56.46; H, 5.59; N, 11.50.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[CH3:20][O:21][C:22]1[CH:23]=[C:24](O)[CH:25]=[CH:26][CH:27]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([O:21][CH3:20])[CH:27]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: COc1cccc(O)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COc1cccc(CCOc2ccc(C[C@H](OC)C(=O)O)cc2)c1

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 3-methoxy-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid. MS (ES) for C19H22O6 [M−H]−: 345.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23](=[O:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[CH3:27][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:25])([CH3:27])[CH3:24])([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: CC(=O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-one (12 g, 28.8 mmol) in anhydrous THF (100 mL) was added dropwise methylmagnesium bromide (48 mL, 144 mmol) at −78° C. under nitrogen. The mixture was stirred at rt for 1 h. The reaction mixture was quenched with aqueous NH4Cl solution (50 mL) in ice water bath. The layers were separated and the aqueous layer was extracted with EtOAc (150 mL). The combined organic phases were washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo to give the crude product, which was purified by preparative HPLC and chiral HPLC to afford (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (6.6 g, 53%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22].C(Cl)(=O)C1C=CC=CC=1>>[CH2:10]([N:5]1[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([F:17])[CH:19]=2)[N:3]=[CH:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Solvent: O=C(Cl)c1ccccc1
Product: NC(=O)c1c(NC(=O)c2cccc(F)c2)ncn1Cc1ccccc1
Yield: 78 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 1, using 2.16 g (9.99 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide which was prepared in the same manner as in Reference Example 2 and 3-fluorobenzoyl chloride, instead of benzoyl chloride, to obtain 2.63 g of 1-benzyl-4-(3-fluorobenzoylamino)-5-imidazolecarboxamide (yield 78%).