Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][S:10][C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[I:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:18])/[C:9](/[S:10][C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:24]\[C:23]2[CH:26]=[CH:27][C:20]([I:19])=[CH:21][CH:22]=2)=[CH:6][CH:7]=1
Reactant: O=C(CSc1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: O=Cc1ccc(I)cc1
Product: O=C(/C(=C\c1ccc(I)cc1)Sc1ccc(Br)cc1)c1ccc(Br)cc1

Procedure:
The title compound is prepared by the methods described in Synthesis Example 1. A solution of 1-(4-bromophenyl)-2-(4-bromophenylthio)ethanone (10 mmol) and 4-iodobenzaldehyde (10 mmol) was subjected to the procedure described as Method B in part C of Synthesis Example 1 and the product obtained was purified by column chromatography. m.p. 128-130° C.
Reaction SMILES: C([NH:8][C@H:9]([C:13](O)=[O:14])[CH:10]([CH3:12])[CH3:11])(OC(C)(C)C)=O.[ClH:16].[NH2:17][N:18]1[C:24](=[O:25])[CH:23]([CH3:26])[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[C:20]2[CH:31]=[CH:32][CH:33]=[CH:34][C:19]1=2>>[ClH:16].[NH2:8][C@H:9]([C:13]([NH:17][N:18]1[C:24](=[O:25])[CH:23]([CH3:26])[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[C:20]2[CH:31]=[CH:32][CH:33]=[CH:34][C:19]1=2)=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: CC1C(=O)N(N)c2ccccc2-c2ccccc21
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: CC1C(=O)N(NC(=O)[C@@H](N)C(C)C)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using N-Boc-L-valine (Aldrich) and 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 1), the title compound was prepared.
Reaction SMILES: CC([CH2:5][N:6]([CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27](=[O:29])[CH3:28])[C@@H:22]([CH3:30])[CH2:21][C@H:20]3[NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[N:33]=2)[CH:14]=[N:13]1)C(=O)[O-])(C)C.FC(F)(F)C(O)=O.[ClH:46].CCOCC>ClCCl>[ClH:46].[C:27]([N:23]1[C:24]2[C:19](=[CH:18][C:17]([C:15]3[CH:14]=[N:13][N:12]([CH2:11][CH2:10][NH:6][CH3:5])[CH:16]=3)=[CH:26][CH:25]=2)[C@H:20]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[N:33]=2)[CH2:21][C@@H:22]1[CH3:30])(=[O:29])[CH3:28]
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN(CC(C)(C)C)C(=O)[O-])c3)cc2[C@H](Nc2cccc(F)n2)C[C@@H]1C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCn1cc(-c2ccc3c(c2)[C@H](Nc2cccc(F)n2)C[C@H](C)N3C(C)=O)cn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 40.4 %

Procedure:
A solution of 1,1-dimethylethyl[2-(4-{(2S,4R)-1-acetyl-4-[(6-fluoro-2-pyridinyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}-1H-pyrazol-1-yl)ethyl]methylcarbamate (for a preparation see intermediate 73) (260.2 mg, 0.498 mmol) in dichloromethane (DCM) (4 mL) was treated with trifluoroacetic acid (TFA) (1 mL, 12.98 mmol) and the resulting mixture was stirred at room temperature for 45 min then concentrated in vacuo. The residue was loaded on a 5 g SCX cartridge then eluted with MeOH (20 mL) followed by 2M NH3 in MeOH (20 mL). The ammonia fractions were combined to give a residue which was purified by MDAP (modifier: formic acid) to give a second residue which was dissolved in DCM (5 mL). The resulting solution was treated with HCl (1M in Et2O, 0.24 mL, 0.24 mmol) then concentrated in vacuo. Trituration of the residue with Et2O gave (2S,4R)-1-acetyl-N-(6-fluoro-2-pyridinyl)-2-methyl-6-{1-[2-(methylamino)ethyl]-1H-pyrazol-4-yl}-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (100.6 mg, 0.201 mmol, 40.4% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)=[C:6]([NH:26][C@H:27]([C:29]2[N:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:33](=[O:41])[C:32]3=[C:42]([CH3:45])[CH:43]=[CH:44][N:31]3[N:30]=2)[CH3:28])[N:5]=[CH:4][N:3]=1.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([NH:14][S:15]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)=[C:6]([NH:26][C@H:27]([C:29]2[N:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:33](=[O:41])[C:32]3=[C:42]([CH3:45])[CH:43]=[CH:44][N:31]3[N:30]=2)[CH3:28])[N:5]=[CH:4][N:3]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cccc(-c3c(N)ncnc3N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cccc(NS(=O)(=O)c4ccc(O)cc4)c3)n(-c3ccccc3)c(=O)c12
Yield: 28 %

Procedure:
(S)—N-(3-(4-Amino-6-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidin-5-yl)phenyl)-4-methoxybenzenesulfonamide (145 mg, 0.23 mmol) was treated with boron tribromide (1M in dichloromethane, 0.7 ml, 0.7 mmol) IN dichloromethane (5 ml) according to the method described in Example 23. The residue was purified by reverse phase using SP1® Purification System to give 40 mg (28% yield) as a solid. Purity 99%.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][CH2:4][CH3:5].C(N(CC)C(C)C)(C)C.[CH3:17][C:18]1[CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:21]=[C:20]([CH3:30])[C:19]=1[NH2:31].C(OCC)(=O)C>CN(C)C=O>[CH3:17][C:18]1[CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:21]=[C:20]([CH3:30])[C:19]=1[NH:31][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Cc1cc(N2CCOCC2)cc(C)c1N
Reactant: CCCCC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCCC(=O)Nc1c(C)cc(N2CCOCC2)cc1C
Reaction time: 0.03 h
Yield: 39.8 %

Procedure:
Pentanoic acid (0.37 g), N,N-diisopropyl-ethylamine (1.51 mL) and N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-yl-methylene]-N-methyl-methanaminium hexafluoro-phosphate N-oxide (1.66 g) were mixed in dry N,N-dimethylformamide (3 mL) and stirred under argon for 2 minutes. 2,6-Dimethyl-4-morpholin-4-yl-phenylamine (0.50 g) dissolved in dry N,N-dimethylformamide (2 mL) was added to the reaction mixture, which was stirred at 25° C. under argon for 16 hours. Ethyl acetate (20 mL) was added and the organic phase was washed with saturated aqueous ammonium chloride/water (1:1, 20 mL), water (20 mL), brine/water (1:1, 20 mL), dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography to furnish 0.28 g (40% yield) of the title compound as a white solid. LC-MS (m/z) 291 (MH+); tR=1.61, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, DMSO-d6): 0.91 (t, 3H), 1.34 (m, 2H), 1.58 (qui, 2H), 2.06 (s, 6H), 2.27 (t, 2H), 3.04 (t, 4H), 3.71 (t, 4H), 6.62 (s, 2H), 8.94 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:14]([C:15](=[O:17])[CH3:16])=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>CN(C)C=O>[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:12]2[CH:13]=[C:14]([C:15](=[O:17])[CH3:16])[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[N:11]2)=[CH:28][CH:27]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(=O)c1c[nH]nc1-c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(C(C)=O)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
320 mg (1.39 mmol) of 1-[3-(3-nitrophenyl)-1H-pyrazol-4-yl]ethanone were dissolved with 15 ml of dry dimethylformamide and 540 mg (1.66 mmol) of cesium carbonate and 189 μl (1.39 mmol) of p-methoxybenzyl chloride were added. The reaction mixture was maintained at 70° C. under stirring for 8 hours. The solvent was then removed under reduced pressure and the residue taken up with dichloromethane and washed with water. The organic layer was dried over sodium sulphate and evaporated. The crude was finally purified by flash-chromatography on a silica gel column (cyclohexane-ethylacetate; from 4/1 to 3/2), giving 470 mg (97%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([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]=1.[Li]CCCC.CN([CH:34]=[O:35])C>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]([CH:34]=[O:35])[N:5]([C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=1
Reactant: Brc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1nc(Br)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 57.8 %

Procedure:
To 4-bromo-1-trityl-1H-imidazole (2.00 g, 5.14 mmol) in 30 mL THF at 0° C., was added a solution of BuLi (1.6M in hexanes, 3.85 mL, 6.17 mmol). The mixture was stirred at 0° C. for 1.25 h, then DMF (0.80 mL, 10.3 mmol) was added. The mixture was stirred for 1 h at 0° C. and 1 h at rt, then was quenched with sat. NH4Cl. The mixture was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4), filtered through a 1″ pad of SiO2 and concentrated. The crude product was purified by flash chromatography (0 to 40% EtOAc/hexanes gradient) to afford 1.24 g of Intermediate 175.1 as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH3:26][O:27][CH2:28][CH2:29]Br>COCCBr.O>[CH3:26][O:27][CH2:28][CH2:29][O:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1O
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cc([N+](=O)[O-])ccc1NC(C)=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
The mixture of N-(2-hydroxy-4-nitrophenyl)acetamide (93 g, 0.47 mol, 1.00 equiv), potassium carbonate (184 g, 1.33 mol, 2.81 equiv) and dimethylformamide (465 ml) was stirred at 60° C. as 2-bromoethyl methyl ether (90 g, 0.647 mol, 1.36 equiv) was added over 15 minutes. After 1 hour, additional 2-bromoethyl methyl ether (4 g, 0.028 mol, 0.059 equiv) was added and the mixture was stirred at 60° C. for another hour. The mixture was cooled to room temperature and poured into 1 L of water. After 30 minutes, the product was formed and collected by filtration and washed with water and heptane. The product was dried in a vacuum oven at 60° C. to give the title compound 97 g. MS (ESI) m/z: 255 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([OH:29])[CH3:28].[CH3:30][O:31][C:32]([C:34]1[S:35][C:36]([N:40]2[CH:44]=[CH:43][N:42]=[CH:41]2)=[CH:37][C:38]=1O)=[O:33].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:30][O:31][C:32]([C:34]1[S:35][C:36]([N:40]2[CH:44]=[CH:43][N:42]=[CH:41]2)=[CH:37][C:38]=1[O:29][CH:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[Cl:20])[CH3:28])=[O:33]
Reactant: COC(=O)c1sc(-n2ccnc2)cc1O
Reactant: CC(O)c1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1sc(-n2ccnc2)cc1OC(C)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
Triphenyl phosphine (304 mg, 1.16 mmol, 1.3 Eq.), 1-(2-Chloro-phenyl)-ethanol (182 mg, 1.16 mmol, 1.3 Eq.) and 3-Hydroxy-5-imidazol-1-yl-thiophene-2-carboxylic acid methyl ester (200 mg, 0.89 mmol, 1.0 Eq.) in anhydrous THF (5 mL) were cooled to 0° C. under nitrogen. Diethyl azodicarboxylate (183 μL, 1.16 mmol, 1.3 Eq.) was added dropwise. The reaction was stirred at 0° C. for 30 minutes then warmed to ambient temperature for 3.5 hours. The solvent was removed in vacuo and the residue re-dissolved in DCM and absorbed onto SiO2. The crude product wad purifird by column chromatography (75% EtOAc/petroleum ether) to give the sub-title compound as a light yellow foam (290 mg, 0.80 mmol, 84%); 1H NMR (400 MHz, d-6 DMSO) δ 1.60 (3H, d), 3.80 (3H, s), 5.90 (1H, q), 7.14 (1H, d), 7.31-7.37 (1H, m), 7.43-7.49 (3H, m), 7.74-7.78 (2H, m), 8.29 (1H, d).
Reaction SMILES: Cl.[CH2:2]([N:5]1[C:13]2[N:12]=[C:11]([CH2:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=4)[CH:18]=[N:17][CH:16]=3)[NH:10][C:9]=2[C:8](=[O:29])[N:7]([CH3:30])[C:6]1=[O:31])[CH:3]=[CH2:4].[OH-:32].[Na+].OO>C1COCC1>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[CH:18]=[N:17][CH:16]=[C:15]2[CH2:14][C:11]1[NH:10][C:9]2[C:8](=[O:29])[N:7]([CH3:30])[C:6](=[O:31])[N:5]([CH2:2][CH2:3][CH2:4][OH:32])[C:13]=2[N:12]=1
Reactant: C=CCn1c(=O)n(C)c(=O)c2[nH]c(Cc3cncc4cc(OC)c(OC)cc34)nc21
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CCCO)c2cc1OC
Temperature: 50 °C

Procedure:
A suspension of the product of Example 13, 3-allyl-8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-1-methyl-3,7-dihydro-purine-2,6-dione hydrochloride salt (0.760 g, 1.87 mmol), 9-borabicyclo[2.2.0 ]nonane (0.5M THF solution, 18.7 ml, 9.35 mmol) and diisopropylethylarine (0.33 ml, 1.89 mmol) in THF (9 ml) is heated to reflux for 2.5 hours. Sodium hydroxide (4M aqueous solution, 6 ml) and hydrogen peroxide (27.5%, 3 ml) are added sequentially and the reaction heated at 50° C. for 1.5 hours. After evaporation, the crude product is purified by flash chromatography (19:1 CH2Cl2:-methanol elultion,) and triturated with water to afford 8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-3-(3-hydroxy-propyl)-1-methyl-3,7-dihydro-purine-2,6-dione, [MH]+ 426.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]23[CH2:17][CH2:16][CH:13]([CH2:14][CH2:15]2)[O:12][CH2:11]3)[OH:9])=[CH:4][CH:3]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]23[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17]2)[O:12][CH2:11]3)=[O:9])=[CH:6][CH:7]=1
Reactant: OC(c1ccc(Br)cc1)C12CCC(CC1)OC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=C(c1ccc(Br)cc1)C12CCC(CC1)OC2
Reaction time: 20 h
Yield: 90.7 %

Procedure:
To a solution of (4-Bromo-phenyl)-(2-oxa-bicyclo[2.2.2]oct-4-yl)methanol (224 mg, 0.821 mmol) in DCM (13 ml) was added a total of manganese dioxide (1.414 g, 16.264 mmol) at RT and the reaction mixture was stirred for 20 hrs. The suspension was filtered through a pad of hyflo and the residue was washed with DCM, dried in vacuo to yield the title intermediate (220 mg, 0.745 mmol, 91%) as a colourless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:30][C:31]1[CH:36]=[C:35]([Cl:37])[C:34]([Cl:38])=[CH:33][C:32]=1OC(ON=C(C#N)C(OCC)=O)=O>C(OCC)(=O)C>[Cl:30][C:31]1[CH:36]=[C:35]([Cl:37])[C:34]([Cl:38])=[CH:33][C:32]=1[O:21][C:20](=[O:22])[C@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CCOC(=O)C(C#N)=NOC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)Oc1cc(Cl)c(Cl)cc1Cl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.2 %

Procedure:
To a solution of N-benzyloxycarbonyl-L-phenylalanine (1.5 g) and triethylamine (0.7 ml) in ethyl acetate (20 ml), ethyl 2-(2,4,5-trichlorophenyl)oxycarbonyloxyimino-2-cyanoacetate (1.9 g) is added, and the resulting mixture is stirred at room temperature for 4 hours. The reaction mixture is treated as in Example 16 to give N-benzyloxycarbonyl-L-phenylalanine 2,4,5-trichlorophenyl ester (1.9 g). M.P. 139° - 140°C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[Cl:26])[N:18]=[CH:17][N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:27]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>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]>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:19]1[C:15]([C:13]2[N:14]=[C:7]3[C:6]4[CH:27]=[C:2]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:3]=[CH:4][C:5]=4[O:11][CH2:10][CH2:9][N:8]3[CH:12]=2)=[N:16][CH:17]=[N:18]1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccccc1-n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Clc1ccccc1-n1ncnc1-c1cn2c(n1)-c1cc(-c3ccccc3)ccc1OCC2
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
A mixture of 10-bromo-2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.5 mmol), phenylboronic acid (200 mg, 0.75 mmol), Cs2CO3 (490 mg, 1.5 mmol) was stirred in dioxane and water (5:1, 3.0 mL) followed by the addition of Pd(dppf)Cl2 (30 mg). The reaction mixture was bubbled with N2 gas for 10 min, the reaction tube was sealed, and the contents were stirred at 130° C. under microwave irradiation for 30 min. The mixture was filtered through celite and the filtrate was concentrated and purified with prep-HPLC to give 563 (82 mg, 38%). 1H-NMR (DMSO, 400 MHz): δ 8.18 (s, 1H), 8.01 (s, 1H), 7.89 (s, 1H), 7.38-7.70 (m, 10H), 7.14 (d, J=7.6 Hz, 1H), 4.45-4.51 (m, 4H)
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:13]([OH:27])[CH2:14][N:15]1[C@H:19]([C:20]([NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][S:17][CH2:16]1)=O)C1C=CC=CC=1.[BrH:35]>C(O)(=O)C.C(OCC)C>[BrH:35].[BrH:35].[NH2:11][C@@H:12]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C@H:13]([OH:27])[CH2:14][N:15]1[C@H:19]([C:20]([NH:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH2:18][S:17][CH2:16]1
Reactant: CC(C)(C)NC(=O)[C@@H]1CSCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)(C)NC(=O)[C@@H]1CSCN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2 g of 3-[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-4(R)-thiazolidinecarboxamide and 4.1 ml of 32% (w/w) hydrogen bromide in glacial acetic acid was stirred at room temperature for 1 hour. The resulting solution was diluted with anhydrous diethyl ether and the precipitated, product was rapidly filtered off and washed with fresh diethyl ether. There were obtained 2.01 g of 3-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-4(R)-thiazolidinecarboxamide dihydrobromide as a white solid; 1H NMR (300 MHz): δ(D2O) 1.37 (9H, s), 3.0 (2H, m), 3.09 (2H, dq), 3.29 (2H, d), 3.85 (2H, m), 4.16 (1H, m), 4.3 (2H, q) and 7.42 (5H, m) ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11](OS(C(F)(F)F)(=O)=O)[C:5]=2[C:4](=[O:20])[O:3]1.[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC.[Cl-].[Li+].C(N(CC)CC)C>O1CCOCC1.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>[CH:22]([C:11]1[C:5]2[C:4](=[O:20])[O:3][C:2]([CH3:21])([CH3:1])[O:7][C:6]=2[CH:8]=[CH:9][CH:10]=1)=[CH2:23]
Reactant: CC1(C)OC(=O)c2c(cccc2OS(=O)(=O)C(F)(F)F)O1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C=Cc1cccc2c1C(=O)OC(C)(C)O2
Temperature: 100 °C
Yield: 80.8 %

Procedure:
A mixture of 2,2-dimethyl-5-trifluoromethanesulfonyloxy-4H-1,3-benzodioxin-4-one (9.90 g, 30.3 mmol), tributyl(vinyl)tin (10.10 g, 31.9 mmol), lithium chloride (8.70 g, 205 mmol), and triethylamine (5.0 mL, 36.0 mmol) in 1,4-dioxane (300 mL) was deoxygenated by bubbling nitrogen through the mixture for 1 hour. To the mixture was added tetrakis(triphenylphosphine)palladium (3.40 g, 2.90 mmol) and the mixture was heated at 100° C. for 3 hours. The mixture was allowed to cool to room temperature and was filtered. The filtrate was concentrated and purified by flash chromatography (1:12, EtOAc/hexanes) to provide 5-ethenyl-2,2-dimethyl-4H-1,3-benzodioxin-4-one (5.00 g, 81%) as a yellow oil: H NMR: (CDCl3) δ1.72 (s, 6H), 5.43 (dd, J=11.0, 1.3 Hz, 1H), 5.72 (dd, J=17.5, 1.3 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 7.73 (dd, J=17.5, 11.0 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:4]1>CCO.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:5]2[CH2:6][CH2:7][C@@H:3]([N:2]([CH3:22])[CH3:1])[CH2:4]2)=[C:10]([C:18]([F:21])([F:19])[F:20])[CH:11]=1
Reactant: CN(C)[C@@H]1CCN(Cc2ccc([N+](=O)[O-])cc2C(F)(F)F)C1
Agent: [Pd]
Solvent: CCO
Product: CN(C)[C@@H]1CCN(Cc2ccc(N)cc2C(F)(F)F)C1

Procedure:
To a solution of (R)—N,N-dimethyl-1-(4-nitro-2-(trifluoromethyl)benzyl)pyrrolidin-3-amine (1.20 g, 3.79 mmol) in 20 mL of wet EtOH was added 0.26 g of Pd/C (10% Pd on C) and the mixture shaken in a Parr apparatus (pressure reaction vessel purged thoroughly with H2 and pressure regulated at 45 psi throughout) for 2-3 h. The reaction mixture was filtered through a small pad of celite, washed with EtOAc, and the combined organics concentrated to provide a quantitative yield of a light yellow oil. This material was used directly in the next step.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:13]=2)O1.Br[C:22]1[N:27]=[C:26]([S:28]([NH2:31])(=[O:30])=[O:29])[CH:25]=[CH:24][CH:23]=1>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:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:12]2[CH:13]=[C:9]([C:22]3[N:27]=[C:26]([S:28]([NH2:31])(=[O:30])=[O:29])[CH:25]=[CH:24][CH:23]=3)[CH:10]=[N:11]2)[CH:15]=1
Reactant: NS(=O)(=O)c1cccc(Br)n1
Reactant: CC1(C)OB(c2cnn(-c3cccnc3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: NS(=O)(=O)c1cccc(-c2cnn(-c3cccnc3)c2)n1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
Under argon, 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]pyridine (0.2 g, 0.74 mmol, prepared by the methods described in WO 2011/045224), 6-bromopyridin-2-sulphonamide (0.175 g, 0.74 mmol) and tetrakis(triphenylphosphine)palladium (0.025 g, 0.022 mmol) were added to a mixture, degassed by means of argon, of sodium carbonate solution in water (2.9 ml, 2 M/L) and acetonitrile (4 ml). The reaction mixture was stirred at 70° C. for 18 h. After cooling, the reaction mixture was poured onto water and the precipitated crystals were filtered off with suction. They were subsequently stirred with diethyl ether and filtered off with suction. This gave 0.23 g (97% of theory) of 6-[1-(pyridin-3-yl)-1H-pyrazol-4-yl]pyridine-2-sulphonamide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([N+:14]([O-])=O)[C:5]=1[O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[O:24][CH:23]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:22][CH2:21]2)([O-])=O.C1(C2CCC3C(=CC=C(OC4C=CC=CC=4N)C=3)O2)C=CC=CC=1>[Zn].C(O)(=O)C>[NH2:14][C:6]1[C:5]([O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[O:24][CH:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:22][CH2:21]3)=[C:4]([CH:9]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:7]=1)[NH2:1]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Oc1ccc2c(c1)CCC(c1ccccc1)O2
Agent: Nc1ccccc1Oc1ccc2c(c1)CCC(c1ccccc1)O2
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1cc(C(F)(F)F)cc(N)c1Oc1ccc2c(c1)CCC(c1ccccc1)O2

Procedure:
2,6-Dinitro-1-(2-phenylchroman-6-yloxy)-4-trifluoromethylbenzene (0.198 g; 0.43 mmol) was reduced to corresponding diamino compound as described for 2-(2-phenylchroman-6-yloxy)-aniline in Example 29 except that 25 ml of glacial acetic acid and 1.525 g of metallic zinc powder were used. Product was purified by column chromatography (100% CH2Cl2 as the eluant). 1H-NMR (400 MHz; d6-DMSO): δ 7.45-7.28 (m, 5H), 6.76 (d, 1H, J=8.8 Hz), 6.65 (dd, 1H, J=8.7 Hz, J=3.0 Hz), 6.62 (d, 1H, J=2.8 Hz), 5.04 (dd, 1H, J=10.0 Hz, J=2.1 Hz), 4.98 (s, 4H), 2.98-2.86 (m, 1H), 2.70-2.60 (m, 1H), 2.18-2.09 (m, 1H), 2.00-1.88 (m, 1H).