Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]([C:16]([NH2:18])=[O:17])[CH:10]=1)(=[O:3])[NH2:2].[Cl:19][C:20]1[CH:41]=[CH:40][C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)=[C:22]([F:42])[CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>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.Cl[Pd]Cl.[Fe+2]>[C:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[N:14]=[C:13]([C:28]2[CH:27]=[CH:26][C:25]([O:24][C:23]3[CH:40]=[CH:41][C:20]([Cl:19])=[CH:21][C:22]=3[F:42])=[CH:30][CH:29]=2)[N:12]=[C:11]([C:16]([NH2:18])=[O:17])[CH:10]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1cc(N2CCC[C@H]2C(N)=O)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(Oc3ccc(Cl)cc3F)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: NC(=O)c1cc(N2CCC[C@H]2C(N)=O)nc(-c2ccc(Oc3ccc(Cl)cc3F)cc2)n1
Temperature: 100 °C
Yield: 33 %

Procedure:
To a mixture of (S)-6-(2-carbamoylpyrrolidin-1-yl)-2-chloropyrimidine-4-carboxamide (0.272 g, 1.01 mmol) in dioxane (5 mL) was added 2-(4-(4-chloro-2-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.387 g, 1.11 mmol), 2M aqueous Na2CO3 (1.0 mL, 2.0 mmol) and PdCl2(dppf) (0.044 g, 0.054 mmol). The reaction vessel was flushed with argon, sealed, and heated at 100° C. overnight. After cooling, the reaction mixture was evaporated in vacuo and the residue chromatographed over silica gel with 25-100% acetone in hexanes. The product fractions were evaporated in vacuo and the residue further chromatographed using reverse-phase chromatography with a 40-70% acetonitrile in water (+0.1% TFA) gradient. The product fractions were pooled and lyophilized. The residue was triturated with acetonitrile (3 mL). The solid was filtered off, washed with acetonitrile (1×1 mL), and dried under vacuum at 40° C. to give (S)-6-(2-carbamoylpyrrolidin-1-yl)-2-(4-(4-chloro-2-fluorophenoxy)phenyl)pyrimidine-4-carboxamide as an off-white powder (0.152 g, 0.333 mmol, 33% yield). 1H NMR (400 MHz, DMSO-d6): Exists as a ˜70:30 ratio of rotamers: 8.60-8.52 (2H, m), 8.35 (1H, s), 7.80 (1H, s), 7.73-7.67 (1.3H, m), 7.51 (0.7H, s), 7.38-7.28 (2H, m), 7.23 (0.3H, s), 7.09 (0.6H, d, J=8.3 Hz), 7.04 (1.4H, d, J=8.8 Hz), 7.00-6.94 (1.4H, m), 6.77 (0.3H, s), 4.58-4.52 (0.7H, m), 4.33-4.27 (0.3H, m), 3.90-3.81 (0.3H, m), 3.79-3.70 (0.3H, m), 3.70-3.62 (0.7H, m), 3.56-3.47 (0.7H, m), 2.38-2.17 (1H, m), 2.11-1.91 (3H, m). LC/MS: m/z=456.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([Br:32])[N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[CH:8]2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2c(cc(CCc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(CCc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Yield: 82.1 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenethyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (78 mg, 0.19 mmol) and N-bromosuccinimide (37 mg, 0.21 mmol) in CH2Cl2 (0.7 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-20% EtOAc/hexanes+1% AcOH) to give 77 mg of the title compound as a light yellow solid. MS: (+) m/z 493.25, 495.14 (M+1, 79/81Br).
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:3]1.C(N(C)C(C)C)(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:1][C@@H:2]1[C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:3]1[S:20]([CH3:19])(=[O:22])=[O:21]
Reactant: C[C@H]1N[C@@H]1c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: CC(C)N(C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1[C@@H](c2ccccc2)N1S(C)(=O)=O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To (2R,3R)-2-Methyl-3-phenylaziridine (38b, 0.08 g, 0.60 mmol) in CH2Cl2 (3 ml) was is added N,N-Diisopropylmethyamine (0.219 ml, 1.32 mmol) and the reaction mixture was cooled to −10° C. before methansulfonyl chloride (0.051 ml, 0.66 mmol) was added The mixture was stirred for 30 min at −10° C. than at room temperature for 1 h. The crude sample was added to a Chromasil C18 column and was eluted with MeCN/H2O 35-70%, 20 min.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([C@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22]2[C:31]([CH2:32][N:33]([C:49]3[N:50]=[N:51][N:52]([CH3:54])[N:53]=3)[CH2:34][C:35]3[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:36]=3)=[CH:30][C:29]3[C:24](=[CH:25][C:26]([F:56])=[C:27]([F:55])[CH:28]=3)[N:23]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[F:43][C:41]([F:42])([F:44])[C:39]1[CH:40]=[C:35]([CH:36]=[C:37]([C:45]([F:46])([F:47])[F:48])[CH:38]=1)[CH2:34][N:33]([CH2:32][C:31]1[C:22]([N:18]2[CH2:19][CH2:20][CH2:21][C@@H:17]2[C@H:14]2[CH2:13][CH2:12][C@H:11]([CH2:10][CH2:9][OH:8])[CH2:16][CH2:15]2)=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([F:55])=[C:26]([F:56])[CH:25]=2)[C:49]1[N:50]=[N:51][N:52]([CH3:54])[N:53]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc3cc(F)c(F)cc3nc2N2CCC[C@@H]2[C@H]2CC[C@H](CCOCc3ccccc3)CC2)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc3cc(F)c(F)cc3nc2N2CCC[C@@H]2[C@H]2CC[C@H](CCO)CC2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of trans-N-[2-((R)-2-{4-[2-(benzyloxy)ethyl]cyclohexyl}pyrrolidin-1-yl)-6,7-difluoroquinolin-3-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amine (11.0 g, 14.0 mmol) in CH2Cl2 (120 mL) is added dropwise BBr3 (1.0 M CH2Cl2 solution, 18.0 mL, 18.0 mmol) at 0° C. and stirred at room temperature for 10 min. The reaction mixture is quenched by addition of sat. NaHCO3 aq. extracted with ethyl acetate, and the organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by silica gel column chromatography to give trans-2-(4-{(R)-1-[3-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-6,7-difluoroquinolin-2-yl]pyrrolidin-2-yl}cyclohexyl)ethanol.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]2[CH:29]=[C:30](I)[S:31][C:24]=12)[NH2:18].C(=O)([O-])[O-].[Cs+].[Cs+].COCCO>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.[OH-].[Na+]>[NH2:18][C:17]1[CH:19]=[CH:20][C:21]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]3[CH:29]=[C:30]([C:8]4[CH:9]=[CH:10][C:5]([C:3]([OH:2])=[O:4])=[CH:6][CH:7]=4)[S:31][C:24]=23)=[C:15]([F:14])[CH:16]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
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: [Cs+]
Solvent: COCCO
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)O)cc4)sc23)c(F)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A round-bottomed flask was charged with 4-(methoxycarbonyl)phenylboronic acid (4.95 g, 27.5 mmol), 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)aniline (Example 6, Step A, 7.08 g, 18.3 mmol), cesium carbonate (8.96 g, 27.5 mmol) and 2-methoxyethanol (1.40 g, 18.3 mmol) (100 mL). The mixture was purged with nitrogen for 10 minutes and then Pd(PPh3)4 (1.27 g, 1.10 mmol) was added as a solid. The mixture was heated under nitrogen to 90° C. for 48 hours and then cooled to room temperature. NaOH (10 mL, 5N) was added and the mixture was stirred for 2 hours. The mixture was extracted with EtOAc (2×300 mL). The aqueous phase was acidified with HCl (2N) to pH 7. The formed precipitate was collected by filtration and washed with water to get the product (7.6 g, 109%, contains residual water) as a beige solid. LRMS (esi+) 381 m/z (M+1) detected.
Reaction SMILES: [CH2:1]([O-:4])[CH:2]=[CH2:3].[Na+].[Na].[CH3:7][S:8][C:9]1[N:14]=[C:13]([NH:15][CH:16]([CH3:18])[CH3:17])[C:12]([N+:19]([O-:21])=[O:20])=[C:11](Cl)[N:10]=1>C(O)C=C>[CH3:7][S:8][C:9]1[N:14]=[C:13]([NH:15][CH:16]([CH3:18])[CH3:17])[C:12]([N+:19]([O-:21])=[O:20])=[C:11]([O:4][CH2:1][CH:2]=[CH2:3])[N:10]=1
Reactant: C=CC[O-]
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(NC(C)C)n1
Agent: [Na+]
Agent: [Na]
Solvent: C=CCO
Product: C=CCOc1nc(SC)nc(NC(C)C)c1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A solution of sodium allyl alcoholate (prepared from 1.2 g (50 m-moles of sodium in 50 ml of allyl alcohol) is added to 13.2 g (50 m-moles) of 2-methylthio-4-isopropylamino-5-nitro-6-chloro-pyrimidine and the mixture is stirred overnight at 20° C. The allyl alcohol is evaporated off, the residue is suspended in water and extracted with ether. The ethereal extracts are dried over MgSO4 and concentrated to yield 15 g of 2-methylthio-4-isopropylamino-5-nitro-6-allyloxypyrimidine of m.p. 51°-54° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([N:10]2[CH2:15][CH2:14][CH:13](NC(=O)OC(C)(C)C)[CH2:12]C2)[N:3]=1.ClC1N=C(Cl)C=C(OC)N=1.N[C@@H]1CCC[N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36]1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C@@H:15]2[CH2:14][CH2:13][CH2:12][N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36]2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: COc1cc(Cl)nc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Agent: COc1cc(Cl)nc(Cl)n1
Product: COc1cc(Cl)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)n1

Procedure:
The title compound was prepared according to the procedure for compound 276a, using 2,4-dichloro-6-methoxypyrimidine and (R)-tert-butyl 3-aminopiperidine-1-carboxylate.
Reaction SMILES: [C:1](=[N:9][OH:10])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:11]=[C:12]=[O:13]>>[C:12]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:1](=[N:9][OH:10])[NH2:8])(=[O:13])[NH2:11]
Reactant: [N-]=C=O
Reactant: NC(=NO)c1ccccc1
Product: NC(=O)c1ccccc1C(N)=NO

Procedure:
Alternatively, the benzamide oxime in Reaction 1 above is reacted with the isocyanate to produce the carbamyl benzamidoxime shown below: ##STR9##
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH:13]=[CH:14][CH:15]=1)=[N:5]2.[H-].[Na+].[CH3:23]N(C)C=O.CI>O>[CH3:23][N:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:6]2[CH:7]=[CH:8][C:9]3[N:4]([CH:3]=[N:2][N:1]=3)[N:5]=2)[CH:11]=1)[C:17](=[O:20])[CH2:18][CH3:19]
Reactant: CCC(=O)Nc1cccc(-c2ccc3nncn3n2)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCC(=O)N(C)c1cccc(-c2ccc3nncn3n2)c1
Reaction time: 1 h

Procedure:
A mixture of 3.58 g of N-[3-(1,2,4-triazolo(4,3-b]pyridazin-6-yl)phenyl]propanamide, 0.71 g of sodium hydride (50% in oil) and 200 ml of dimethylformamide was stirred under argon, for 1 hour. A 0.92 ml portion of methyl iodide was added and the mixture was stirred overnight. A 0.355 g portion of sodium hydride (50% in oil) and 0.46 ml of methyl iodide were added and stirring was continued overnight. The mixture was poured into 200 ml of water and extracted with 150 ml portions of dichloromethane. The extracts were combined dried and evaporated in vacuo. The residue was crystallized from ehtyl acetate-hexane, giving 1.60 g of the desired product as light orange crystals, mp 140°-150° C.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:35]=[CH:36][C:37](=[O:40])[N:38]([CH3:39])[C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CO.C(OCC)C>O1CCOCC1>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([N:22]5[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]5)=[CH:20][N:21]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:35]=[CH:36][C:37](=[O:40])[N:38]([CH3:39])[C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cn1c(=O)ccc2c3cnc(Nc4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cn4)nc3n(C3CCCC3)c21
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: C1COCCO1
Product: Cn1c(=O)ccc2c3cnc(Nc4ccc(N5CCNCC5)cn4)nc3n(C3CCCC3)c21
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 62.5 %

Procedure:
Compound 274 (51 mg) was dissolved in 2 mL dioxane. Dioxane (1 mL) saturated at room temperature with HCl was added, followed by 1 mL methanol to aid solution. The reaction was stirred at room temperature for 80 min. The solution was then added dropwise to diethyl ether (8 mL) and the resulting precipitate was collected and dried in vacuo to give compound 271 as a yellow solid (26 mg, 62%). 1H NMR (500 MHz, DMSO-d6) δ 11.75 (br. s., 1 H) 9.36 (br. s., 2 H) 9.20 (s, 1 H) 8.53 (d, J=8.31 Hz, 1 H) 7.91-8.01 (m, 2 H) 7.49 (d, J=9.29 Hz, 1 H) 6.83 (d, J=8.56 Hz, 1 H) 5.37 (quin, J=8.56 Hz, 1 H) 3.35-3.43 (m, 5 H) 1.94-2.13 (m, 4 H) 1.64-1.79 (m, 2 H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.C(O)(=O)CCCCCCCCCCCCC.N1C(C)=CC=CC=1C.[NH2:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[N:41]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]([C:52]([O:54]CC)=[O:53])=[C:39]2[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1.O.[OH-].[Li+]>C(OCC)(=O)C.C1COCC1.CO.O.CC([O-])=O.CC([O-])=O.[Cu+2].C1(C)C=CC=CC=1>[CH2:45]([N:41]1[C:42]2[C:38](=[CH:37][C:36]([NH:35][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[CH:7]=3)=[CH:44][CH:43]=2)[C:39]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)=[C:40]1[C:52]([OH:54])=[O:53])[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1Cc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CCCCCCCCCCCCCC(=O)O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cccc(Nc2ccc3c(c2)c(-c2ccccc2)c(C(=O)O)n3Cc2ccccc2)c1
Reaction time: 24 h
Yield: 50.9 %

Procedure:
3-Methylphenylboronic acid (0.20 g, 1.5 mmol), Cu(OAc)2 (0.036 g, 0.2 mmol), and myristic acid (0.046 g, 0.2 mmol) were combined in a 100-mL round-bottom flask with a large stir bar. A rubber septum was attached, and dry toluene (2 mL), 2,6-lutidine (0.116 mL, 1.0 mmol), and ethyl 5-amino-1-benzyl-3-phenyl-1H-indole-2-carboxylate (0.19 g, 0.5 mmol) were successively added. The resulting mixture was stirred at a high rate for 24 h, diluted with ethyl acetate (10 mL), filtered through a plug of silica gel, and then purified by column chromatography (5 to 25% EtOAc/hexanes) to give a gummy solid. To a stirred solution of the gummy solid in 15 mL of 2:1:1 THF/MeOH/water was added lithium hydroxide monohydrate (0.2 g, 4.8 mmol). The reaction was stirred at 40° C. for 5 h. Most of the organic solvents was removed and the reaction mixture was made acidic (pH 6) with glacial acetic acid, and the solid was collected and purified by semi-preparative HPLC (Column: Phenomenex C18 Luna 21.6 mm×60 mm, 5 μM; Solvent A: Water (0.1% TFA buffer); Solvent B: Acetonitrile (0.1% TFA buffer); Solvent Gradient: Time 0: 0% B; 10 min: 100% B; Hold 100% B 5 min. Flow Rate: 22.5 mL/min) The product was collected based on UV absorption and concentrated to give the title compound as a brown solid (0.11 g, 50%): 1H NMR (DMSO-d6) δ 2.18 (s, 3 H), 5.81 (s, 2 H), 6.51-6.53 (m, 1 H), 6.70-6.72 (m, 1 H), 6.75-6.80 (m, 1 H), 7.00-7.60 (m, 13 H), 7.88 (s,1 H), 12.86 (s, 1 H); MS (ESI) m/z 433 (MH+); MS (ESI) m/z 431 ([M-H]=); Anal. calcd. for C29H24N2O2.0.1H2O: C, 80.20; H, 5.62; N, 6.45. Found: C, 80.03; H, 5.61; N, 6.61.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1C=C[NH+]=CC=1.[Br:20][Br-]Br>C1COCC1>[Br:20][CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:11](=[O:13])[CH3:12]
Reactant: CC(=O)Cc1cccc([N+](=O)[O-])c1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: CC(=O)C(Br)c1cccc([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
A stirred solution of 3-nitrophenylacetone (2.5 g, 14.0 mmol) in dry THF (50 ml) at room temperature is treated with polymer supported pyridine hydrobromide perbromide (7.0 g, 14.0 mmol) and left to stir overnight. The reaction mixture is then filtered and the solvent removed in vacuo. The residue is purified by chromatography on silica eluting with 1:4 ethyl acetate-hexane to give the titled compound
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].O>C(OCC)(=O)C.C(OCC)(=O)C.CCCCCC>[CH3:17][S:18]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(Br)cc1
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCc1ccc(Br)cc1
Yield: 95.7 %

Procedure:
To a solution of 4-bromobenzylalcohol (9.98 g) and triethylamine (11.2 μL) in ethyl acetate (100 mL) was added dropwise methanesulfonyl chloride (7.35 g) under nitrogen gas atmosphere and ice-cooling and the mixture was stirred under ice-cooling for 1 hour. To the reaction mixture was added water and the mixture was extracted with ethyl acetate (×2). After washing successively with water and a saturated brine, the organic layer was dried over anhydrous magnesium sulfate. After evaporation to remove solvent, the resultant crude product was triturated in ethyl acetate/hexane to 4-bromobenzyl methanesulfonate (13.54 g, yield: 91%) as crystals.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:19][C@H:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH2:34][CH2:35][CH2:36][O:37][CH3:38])[CH:26]=1)[CH:21]([CH3:23])[CH3:22])[CH2:17][OH:18])=[O:14])([CH3:11])([CH3:10])[CH3:9]>S(OC)(OC)(=O)=O.ClCCl>[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:19][C@H:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH2:34][CH2:35][CH2:36][O:37][CH3:38])[CH:26]=1)[CH:21]([CH3:23])[CH3:22])[CH:17]=[O:18])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: COCCCOc1cc(C[C@@H](C[C@@H](CO)NC(=O)OC(C)(C)C)C(C)C)ccc1OC
Solvent: COS(=O)(=O)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1cc(C[C@@H](C[C@@H](C=O)NC(=O)OC(C)(C)C)C(C)C)ccc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C., first triethylamine (175.6 ml) and then a solution of pyridine/sulfur trioxide complex (221 g) in dimethyl sulfate (0.84 liters) are added dropwise over a period of 45 minutes, with stirring, to a solution of 2(S)-(tert-butoxycarbonyl)amino-4(S)-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-5-methyl-hexanol (184.8 g) in dichloromethane (1.34 liters). When the addition is complete, the batch is stirred for a further 30 minutes at 0° C. and then ice-water (1.6 liters) is added. The mixture is extracted with dichloromethane (3×1.6 liters), and the combined organic phases are washed with saturated sodium hydrogen carbonate solution (2×1.6 liters), water (1.6 liters) and saturated sodium chloride solution and filtered through cotton wool and the solvent is removed in vacuo. The residue is dried under a high vacuum, yielding the crude title compound in the form of an oil (190 g): Rf (ethyl acetate/hexane 1:1)=0.44. IR (CH2Cl2) 3430, 2960, 1710, 1589, 1515 cm-. 1H-NMR (CDCl3): δ 0.86 (m, 6H), 1.44 (s, 9H), 1.55-1.8 (m, 4H), 2.09 (m, 2H), 2.4-2.7 (m, 2H), 3.35 (s, 3H), 3.57 (t, J=6.4 Hz, 2H), 3.83 (s, 3H), 4.10 (t, J=6.4 Hz, 2H), 4.05-4.20 (m, 1H), 4.89 (d, br., 1), 6.7-6.8 (m, 3H), 9.50 (s, 1H).
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][O:2]1.[N+:7]([C:10]1[CH:18]=[CH:17][C:13](C(O)=O)=[CH:12][CH:11]=1)([O-:9])=[O:8].C(=O)=O>[Cl-].C([N+](CC)(CC)CC)C.C(OCC)(=O)C>[OH:5][CH2:4][CH2:3][O:2][C:1](=[O:6])[C:13]1[CH:17]=[CH:18][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=1
Reactant: O=C1OCCO1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC[N+](CC)(CC)CC
Agent: O=C=O
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: O=C(OCCO)c1ccc([N+](=O)[O-])cc1
Temperature: 140 °C

Procedure:
Ethylene carbonate (20 g., 0.22 mole), 4-Nitrobenzoic acid (38 g., 0.2 mole), and tetraethylammonium chloride (2.0 g., 0.04 mole) were placed in a one liter round bottom flask and heated at 140° C. with stirring until evolution of CO2 stopped. The reaction was cooled to room temperature and dissolved in one liter of ethyl acetate. The solution was washed with water and dried over MgSO4. The drying agent was removed by filtration. The volume was reduced in-vacuo and the 2-hydroxyethyl-4-nitrobenzoate obtained as a pale yellow solid. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:18][CH3:19])(=[O:17])[CH:14]([CH3:16])[CH3:15].Br[C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][N:22]=1>C1COCC1>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([C:14]([CH3:16])([CH3:15])[C:13]([O:18][CH3:19])=[O:17])=[N:22][CH:23]=1
Reactant: Brc1ccc(Br)nc1
Reactant: COC(=O)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C)(C)c1ccc(Br)cn1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
Diisopropylamine (0.45 ml, 3.17 mmol) was dissolved in THF (10 ml) under a nitrogen atmosphere and cooled to −10° C. n-BuLi (2.64 ml, 3.17 mmol, 1.2M solution in THF) was added dropwise over 5 minutes. The reaction mixture was stirred at −10° C. for 30 minutes, after which time the reaction mixture was cooled to −78° C. Methyl isobutyrate (0.36 ml, 3.17 mmol) was added dropwise over 5 minutes. Stirring was continued at −78° C. for 45 minutes. 2,5-Dibromopyridine (0.5 g, 2.11 mmol) in THF (10 ml) was added and the mixture allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched by addition of saturated aqueous ammonium chloride solution, extracted into DCM (3×20 ml), the combined organics dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by FCC on silica gel [19:1 heptane/EtOAc as eluent] to provide the title compound as colourless oil (195 mg, 36%).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[C:16]3[C:11](=[C:12]([CH3:17])[CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccccc1CCNC(=O)c1ccc(Br)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1C
Product: Cc1cccc2c1CCN=C2c1ccc(Br)cc1

Procedure:
Forty-four (44) grams of 1-(4-bromobenzoylamino)-2-(2-methylphenyl)ethane was heated with stirring at 140° C. for 4 hours together with 300 ml of xylene, 100 ml of phosphorus oxychloride and 100 g of phosphorus pentoxide. The reaction mixture was decanted to remove the solvent. The residue was carefully decomposed with ice water, and made weakly alkaline with an aqueous solution of sodium hydroxide. The crystals precipitated were extracted with benzene, and dried, followed by distilling off the solvent. Recrystallization of the residue from hexane afforded 35 g of 1-(4-bromophenyl)-5-methyl-3,4-dihydroisoquinoline as colorless needles having a melting point of 60.0° to 61.5° C.