Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:13][CH2:14][C:15]([OH:28])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:14][C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:28][CH2:10][C:9]1=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)N(CCC(O)(c1ccccc1)c1ccccc1)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1COC(c2ccccc2)(c2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C

Procedure:
The solution of 19.3 g of N-benzyl-N-chloroacetyl-3-hydroxy-3,3-diphenylpropylamine in 150 ml of dimethylformamide is added dropwise to the suspension of 1.2 g of sodium hydride in 50 ml of dimethylformamide while stirring and cooling with an ice-bath. The mixture is allowed to warm up to room temperature, stirred for 15 hours and evaporated. The residue is partitioned between 150 ml methylene chloride and 50 ml of N hydrochloric acid, the organic layer separated, washed with water, dried, filtered and evaporated. The residue is triturated with diethyl ether and recrystallized from ethanol, to yield the 4-benzyl-3-oxo-7,7-diphenyl-hexahydro-1,4-oxazepine of the formula ##STR7## melting at 185° to 186°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]2[C:7]([C:15]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[O:16])=[C:8]([C:10]3[CH:11]=[N:12][NH:13][CH:14]=3)[O:9][C:5]=2[CH:4]=1.ClCCl.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.O=O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]2[C:7]([C:15]([C:17]3[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=3)=[O:16])=[C:8]([C:10]3[CH:14]=[N:13][N:12]([C:39]4[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[CH:37][CH:38]=4)[CH:11]=3)[O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c(-c3cn[nH]c3)oc2c1
Agent: O=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-n2cc(-c3oc4cc(OC)ccc4c3C(=O)c3cc(OC)c(OC)c(OC)c3)cn2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 14.4 %

Procedure:
To an 8 mL screw cap glass vial was added [6-methoxy-2-(1H-pyrazol-4-yl)-benzofuran-3-yl]-(3,4,5-trimethoxyphenyl)-methanone (11 mg, 0.027 mmol), 3 Å molecular sieves, dichloromethane (0.5 mL), cupric acetate (10 mg, 0.054 mmol), 4-methoxy-phenyl boronic acid (9 mg, 0.059 mmol) and pyridine (15 μl, excess) and the capped vial was shaken at room temperature for two days with occasional removal of the cap to expose the mixture to atmospheric oxygen. After this time the reaction mixture was filtered through celite and the filtrate was concentrated and purified by silica-gel flash chromatography (eluent=hexane:ethyl acetate, 3:1) to afford the product as a yellow solid (2 mg, 15% yield). 1H-NMR (CDCl3) δ 8.56 (s, 1H), 8.17 (s, 1H), 7.60 (d, J=8.9 Hz, 2H), 7.15 (s, 2 H), 7.14 (d, J=8.7 Hz, 1H), 7.07 (d, J=2.0 Hz, 1H), 6.96 (d, J=8.9 Hz, 2H), 6.81 (dd, J=8.7, 2.0 Hz, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 3.84 (s, 3H), 3.78 (s, 6H).
Reaction SMILES: O[C:2]1([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH3:10])[CH2:4][CH2:3]1.O>C1(C)C=CC=CC=1>[CH2:8]([C@H:5]1[CH2:4][CH2:3][C@H:2]([C:11]2[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([F:17])[CH:16]=2)[CH2:7][CH2:6]1)[CH2:9][CH3:10]
Reactant: CCCC1CCC(O)(c2cc(F)cc(F)c2)CC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC[C@H]1CC[C@H](c2cc(F)cc(F)c2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a nitrogen atmosphere, 132 g of crude 1-(1-hydroxy-4-propylcyclohexyl)-3,5-difluorobenzene and 2.99 g of p-toluenesulfonic monohydrate were dissolved in 250 mL of toluene, and the resultant solution was stirred for 2 hours under reflux while the produced water was removed. After the solution was allowed to cool to room temperature, an organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine, and dried by adding sodium sulfate, and then the solvent was distilled off under reduced pressure. Then, the whole amount of the resultant residue was dissolved in 280 mL of ethyl acetate, and 7.1 g of palladium 5%/carbon was added to the solution, followed by stirring in a hydrogen atmosphere at 5 Mpa for 6 hours. After the palladium catalyst was filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. Then, the whole amount of the resultant product and 3.39 g of tertiary butoxypotassium were dissolved in 350 mL of DMF, followed by stirring at room temperature for 4 hours. Then, water and hexane were added to separate an organic layer. Further, an aqueous layer was subjected to extraction with hexane, and the hexane extract was combined with the organic layer and washed with saturated brine. The resultant mixture was dried by adding sodium sulfate, the solvent was distilled off, and distillation under reduced pressure (206 Pa, b. p.=110° C. to 112° C.) yielded 58.05 g of 1-(trans-4-propylcyclohexyl)-3,5-difluorobenzene.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9](Cl)[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15]CC)=O)[N:6]2[CH3:12].[CH3:18][NH2:19].CO>>[CH3:18][NH:19][C:13]([C:5]1[N:6]([CH3:12])[C:7]2[C:3]([CH:4]=1)=[CH:2][CH:10]=[CH:9][CH:8]=2)=[O:15]
Reactant: CCOC(=O)c1cc2c(Cl)cc(Cl)cc2n1C
Reactant: CN
Solvent: CO
Product: CNC(=O)c1cc2ccccc2n1C
Temperature: 50 °C
Reaction time: 17.5 h
Yield: 99 %

Procedure:
A suspension of ethyl 4,6-dichloro-1-methyl-1H-indole-2-carboxylate (1.06 g, 3.90 mmole) in 2.0 M CH3NH2/CH3OH (40 mL) in a sealed pressure bottle was heated in an oil bath preset at 50° C. A homogeneous solution formed within 2.5 hr. The reaction was kept at 50° C. for 17.5 hr, during which time a solid precipitated. The mixture was cooled to RT and poured into H2O (40 mL). The resulting mixture was concentrated on the rotavap to remove the methanol, and the solid was collected by suction filtration. This was washed with plenty of H2O and dried in high vacuum at 45–50° C. to afford the title compound (0.99 g, 99%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1 H), 7.16 (d, J=1.5 Hz, 1 H), 6.86 (s, 1 H), 6.21 (br s, 1 H), 4.02 (s, 3 H), 3.02 (d, J=4.9 Hz, 3 H); MS (ES) m/e257 and 259 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([OH:30])([C:28]#[CH:29])[CH3:27])[N:21]=1>>[F:19][C:3]1[C:2]([C:29]#[C:28][C:26]([OH:30])([C:22]2[N:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[CH3:27])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(C)(O)c1cccnn1
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1cccnn1
Yield: 9 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(pyridazin-3-yl)but-3-yn-2-ol to give the titled compound as a brown solid (26 mg, 9%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[C:17]([F:25])[CH:16]=2)=[N:4][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][CH3:14])[CH:12]=2)=[CH:6][N:7]=1.[Li+].[OH-].Cl>CO.C1COCC1>[NH2:1][C:2]1[C:3]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[C:17]([F:25])[CH:16]=2)=[N:4][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][CH3:14])[CH:12]=2)=[CH:6][N:7]=1
Reactant: CCn1cc(-c2cnc(N)c(-c3ccc(C(=O)OC)c(F)c3)n2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCn1cc(-c2cnc(N)c(-c3ccc(C(=O)O)c(F)c3)n2)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To methyl 4-(3-amino-6-(1-ethyl-1H-pyrazol-4-yl)pyrazin-2-yl)-2-fluorobenzoate (25 mg, 0.073 mmol) in MeOH (1 mL) and THF (2 mL) was added 1 M LiOH (0.220 mL, 0.2 20 mmol). The reaction mixture was stirred at room temperature for 4 h. The pH of reaction mixture was adjusted to ˜4 by 2 N HCl. The product was extracted with ethyl acetate twice. The combined organics extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated. The residue was proceeded to next step without further purification. LCMS (m/z): 328.1 (MH+), 0.607 min.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)COB([C:22]2[CH:23]=[CH:24][C:25]([F:37])=[C:26]([C:28]3[C:29]([C:35]#[N:36])=[CH:30][CH:31]=[C:32]([F:34])[CH:33]=3)[CH:27]=2)OC1>>[F:34][C:32]1[CH:33]=[C:28]([C:26]2[CH:27]=[C:22]([C:2]3[N:6]4[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]4=[N:4][CH:3]=3)[CH:23]=[CH:24][C:25]=2[F:37])[C:29]([C:35]#[N:36])=[CH:30][CH:31]=1
Reactant: CC1(C)COB(c2ccc(F)c(-c3cc(F)ccc3C#N)c2)OC1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Product: N#Cc1ccc(F)cc1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-5,2′-difluorobiphenyl-2-carbonitrile as described in Example 1 to give 5,2′-difluoro-5′-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile as an off-white solid: δH (360 MHz, CDCl3) 7.25-7.31 (2H, m), 7.44-7.50 (1H, m), 7.67 (1H, ddd, J 9, 5 and 2), 7.67 (1H, s), 7.69 (1H, s), 7.88 (1H, dd, J 9 and 6), 8.11 (1H, s), 9.05 (1H, d, J 7); m/z (ES+) 401 (M++H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.CCOC(C)=O>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:11]=1)[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: Brc1cccnc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(O)c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Oc2cccnc2)c1
Temperature: 115 °C
Yield: 48.4 %

Procedure:
A mixture of (S)-[1-(3-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (10 g, 42.1 mmol), 3-bromopyridine (8 g, 50.6 mmol), potassium carbonate (powder, 14 g, 101 mmol) and copper iodide (325 mesh powder, 6 g, 31.6 mmol) was heated at 115° C. for 48 h. The reaction mixture was cooled to room temperature and concentrated in vacuo then CH2Cl2 (100 mL) was added, the reaction mixture was filtered, and the filtrate was washed with H2O (3×50 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 2:1/Hexane:EtOAc to give the title product (6.4 g, 48% yield).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([NH:7][CH:8]([C:10](=O)[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH3:9])[CH3:6])C.C(OCC)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([NH:11][CH2:10][CH:8]([NH:7][CH:5]([CH3:6])[CH2:4][OH:3])[CH3:9])=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(C)NC(C)C(=O)Nc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(CO)NC(C)CNc1ccc(Cl)cc1
Yield: 98.5 %

Procedure:
95 Grams of 2-[1-(p-chlorophenylcarbamyl)ethylamino]-propionic acid ethyl ester dissolved in 1200 ml. of anhydrous diethyl ether is gradually added under stirring to a suspension of 38 g. of LiAlH4 in 2000 ml. of diethyl ether cooled to 0° C. The reaction mixture is refluxed for two hours with stirring, then the reaction complex is decomposed at 0° C. with water, stirred for 30 minutes at room temperature and the inorganic solids separated by filtration. The ether solution is dried and evaporated, and the residue, distilled in a bulb, yields 76 g. of the title compound. B.p. 170° C./0.4 mm Hg. yield 98.5%. The corresponding acetate, obtained by treatment of the title compound with acetyl chloride in acetic acid, boils at 160° C./0.5 mm Hg. In the same way, the corresponding m-chlorophenyl-substituted derivative is synthesized. B.p 170° C./0.5 mm Hg. The corresponding acetate boils at 160° C./0.5 mm Hg.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][NH:21]1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][N:21]1[C:11]1[CH:12]=[C:13]2[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]2[CH:1]2[CH2:3][CH2:2]2)=[CH:9][C:10]=1[F:15]
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: c1ccc2c(c1)CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2cc(N3Cc4ccccc4C3)c(F)cc2c1=O
Yield: 35.6 %

Procedure:
133 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 83 mg of isoindoline, 152 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 1 to produce 65 mg of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.CN(C)C=O.[NH2:22][C:23]([C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1)([CH3:27])[C:24]([OH:26])=[O:25]>CCOCC>[NH2:22][C:23]([C:28]1[CH:29]=[CH:30][C:31]([NH:34][CH:14]=[C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[C:8](=[O:12])[NH:7][C:6]2=[O:13])=[CH:32][CH:33]=1)([CH3:27])[C:24]([OH:26])=[O:25]
Reactant: CC(N)(C(=O)O)c1ccc(N)cc1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(N)(C(=O)O)c1ccc(NC=C2C(=O)NC(=O)c3ccc(Br)cc32)cc1
Temperature: 110 °C
Yield: 33 %

Procedure:
A mixture of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (191 mg, 0.50 mmole), N,N-dimethylformamide (2 mL) and 2-Amino-2-(4-amino-phenyl)-propionic acid (90 mg, 0.50 mmole) is stirred and heated at 110° C. for one hour, cooled in the refrigerator. The reaction mixture is diluted with ether, filtered, washed with acetonitrile and dried to give a dull yellow solid 71 mg (33%), mp 250-253° C.; MS (ESI): m/z 428.2, 430.2 (M−H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][CH2:18][C:17]3[C:16]([OH:20])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:25]1[C:34]2[C:29](=[C:30]([O:35][CH3:36])[CH:31]=[CH:32][CH:33]=2)[N:28]=[CH:27][CH:26]=1>>[CH3:36][O:35][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:29]=1[N:28]=[CH:27][CH:26]=[C:25]2[N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][CH2:18][C:17]3[C:16]([OH:20])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11]2)[CH2:2][CH2:3]1
Reactant: COc1cccc2c(Cl)ccnc12
Reactant: CCCN(CCN1CCNCC1)C1CCc2c(O)cccc2C1
Product: CCCN(CCN1CCN(c2ccnc3c(OC)cccc23)CC1)C1CCc2c(O)cccc2C1

Procedure:
This compound was prepared from 9b (0.668 g, 2.1 mmol) and 17 (0.4 g, 2.1 mmol) following the procedure I to get 18b as white wax (yield 0.76 g, 75%). 1H NMR (400 MHz, CDCl3) δ ppm 0.92-0.95 (t, 3H, J=6 Hz), 1.58-1.65 (m, 3H), 2.04-2.14 (m, 2H), 2.73-2.96 (m, 13H), 3.25 (bs, 4H), 3.48 (s, 1H), 4.04 (s, 3H), 6.57-6.59 (d, 1H, J=8 Hz), 6.66-6.68 (d, 1H, J=8 Hz), 6.86-6.87 (d, 1H, J=4 Hz), 6.92-6.96 (t, 1H, J=8 Hz), 6.99-7.01 (d, 1H, J=8 Hz), 7.37-7.41 (t, 1H, J=8 Hz), 7.54-7.56 (d, 1H, J=8 Hz), 8.72-8.73 (d, 1H, J=4 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[C:10](=S)(OCC)[S-:11].[K+]>C(O)C>[SH:11][C:10]1[O:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=2[N:1]=1
Reactant: Cc1cccc(O)c1N
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CCO
Product: Cc1cccc2oc(S)nc12

Procedure:
5 g (41 mmol) of 2-amino-3-methylphenol and 6.51 g (41 mmol) of potassium O-ethyl dithiocarbonate, in suspension in 70 ml of ethanol, are successively introduced into a 500 ml round-bottomed flask and the mixture is heated at reflux for 24 h. The solvent is removed by evaporation under reduced pressure, the residue is taken up-in 50 ml of water and 4 ml of acetic acid are added. The precipitate obtained is filtered off, rinsed with water and dried under vacuum.
Reaction SMILES: Br[C:2]([CH3:14])([CH:4]([Br:13])[C:5](=[O:12])[CH:6]([Br:11])[C:7](Br)([CH3:9])[CH3:8])[CH3:3].C(Cl)Cl.S(=O)(=O)(O)O>N1C=CC=CC=1>[Br:11][C:6]([C:5](=[O:12])[C:4]([Br:13])=[C:2]([CH3:14])[CH3:3])=[C:7]([CH3:9])[CH3:8]
Reactant: CC(C)(Br)C(Br)C(=O)C(Br)C(C)(C)Br
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)=C(Br)C(=O)C(Br)=C(C)C
Temperature: 0 °C

Procedure:
The above crude, 2,3,5,6-tetrabromo-2,6-dimethyl-4-heptanone was dissolved in 200 ml. of methylene chloride and the solution was cooled to about -10° C. with an ice-methanol bath. To this solution, 250 ml of pyridine was added under a nitrogen atmosphere. The mixture was stirred about fifteen hours while the temperature was maintained at less than 25° C. The reaction mixture was poured into 800 ml of 15% solution of sulfuric acid in ice water (prepared by the addition of ice to 400 ml of 30% of sulfuric acid solution until the total volume reached 800 ml). The aqueous layer was extracted with three 150 ml portions of methylene chloride. The combined methylene chloride extracts were washed with two 250 ml portions of 30% aqueous sulfuric acid and then with three 300 ml portions of water, dried over anhydrous sodium sulfate and evaporated under reduced pressure (pot temperature less than 50° C.). 3,5-Dibromo-2,6-dimethyl-2,5-heptadiene-4-one (wt. 157.75 g) was obtained as a light brown oil containing about 8% solvent.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:38][C:39]([CH2:46][CH2:47][CH3:48])([CH2:43][CH2:44][CH3:45])[C:40](Cl)=[O:41]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:40](=[O:41])[C:39]([CH3:38])([CH2:46][CH2:47][CH3:48])[CH2:43][CH2:44][CH3:45])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCCC(C)(CCC)C(=O)Cl
Product: CCCC(C)(CCC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 42.2 %

Procedure:
A procedure similar to that described in Example 4, above, was followed, but using 2.0 g (3.6 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] and 1.92 g (10.9 mmol) of 2-methyl-2-propylvaleryl chloride, to provide 1.05 g of the title compound.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:21]([OH:23])=[O:22])[CH2:16][CH2:17][C:18](=[O:20])[NH2:19])=[O:13])[CH3:11])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(O)(=O)C.Br>CCOCC>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:21]([OH:23])=[O:22])[CH2:16][CH2:17][C:18](=[O:20])[NH2:19])=[O:13])[CH3:11])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Reaction time: 1 h

Procedure:
To 2.10 g of Z-Leu-Ala-Gln-OH was added 20 ml of acetic acid solution containing 25% of hydrogen bromide, then the mixture was allowed to stand at a room temperature for 1 hour. After the completion of the reaction, dried ether was added to the reaction mixture to obtain H-Leu-Ala-Gln-OH.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[C:23]#[N:24])=[C:18]([F:29])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][C:31]1[CH:36]=[C:35]([CH3:37])[N:34]2[N:38]=[C:39]([CH:41]=O)[N:40]=[C:33]2[N:32]=1>CO>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[C:23]#[N:24])=[C:18]([F:29])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH:9]([CH2:41][C:39]3[N:40]=[C:33]4[N:32]=[C:31]([CH3:30])[CH:36]=[C:35]([CH3:37])[N:34]4[N:38]=3)[C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Reactant: CCC(C#N)(CC)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Solvent: CO
Product: CCC(C#N)(CC)c1ccc(CCC2(C3CCCC3)CC(=O)C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)cc1F
Reaction time: 12 h

Procedure:
A solution of 2-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-ethyl-butyronitrile (300 mg, 0.75 mmol) in anhydrous MeOH (3.0 mL) was treated with 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (198 mg, 1.1 mmol), followed by borane-dimethylamine complex (62 mg, 1.05 mmol) at room temperature. The reaction was stirred for 12 hours before it was quenched by the addition of CH2Cl2 (30 mL) and Amberlite IR 120(plus) (3 g). The reaction was stirred for 30 minutes, and then filtered. The filtrate was concentrated to an oil, dissolved in CH2Cl2 (25 mL, and then washed with 10 mL 1 N HCl. The aqueous layer was extracted with 2×25 mL CH2Cl2. The organic layers were combined and dried over Na2SO4. After removing the solids by filtration, the liquid was concentrated to an oil. The desired product was isolated by preparatory HPLC (76 mg, 18%). 1H NMR (400 MHz, CDCl3) δ: 0.74 (t, J=7.45 Hz, 6H), 1.37-1.59 (m, 8H), 1.79-1.88 (m, 4H), 1.94-2.03 (m, 2H), 2.21 (t, J=8.84 Hz, 3H), 2.36 (d, J=17.94 Hz, 1H), 2.47-2.55 (m, 5H), 2.59-2.63 (m, 4H), 3.95 (d, J=3.54 Hz, 2H), 6.66 (dd, J1=13.26 Hz, J2=1.64 Hz, 1H), 6.72-6.75 (m, 2H), 7.23 (t, J=8.21 Hz, 1H).
Reaction SMILES: [CH2:1]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][NH:16][CH2:15][CH2:14][C@@H:11]42)=[CH:8][C:7]([C:18]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:19]=2[CH:20]=[O:21])=[CH:6][C:5]=3[CH2:4][S:3][CH2:2]1.[CH3:28][Mg]Br>O1CCCC1>[CH2:1]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][NH:16][CH2:15][CH2:14][C@@H:11]42)=[CH:8][C:7]([C:18]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:19]=2[CH:20]([OH:21])[CH3:28])=[CH:6][C:5]=3[CH2:4][S:3][CH2:2]1
Reactant: C[Mg]Br
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c(C=O)c1
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c(C(C)O)c1

Procedure:
To a solution of 2-[(7bR,11aS)-1,2,7b,8,9,10,11,11a-octahydro-4H-pyrido[4,3-b)[1,4]thiazepino[6,5,4-hi]indol-6-yl]-5-methoxybenzaldehyde, the free base of EXAMPLE 16 (0.03 g, 0.08 mmol), in 5 mL of tetrahydrofuran at 0° C. was added methyl magnesium bromide (0.52 mL of a 3M solution in THF, 1.58 mmol). Stirred with warning to ambient temperature for several hours and then quenched with sat'd ammonium chloride. Extracted with ethyl acetate, washed organics with brine, dried (MgSO4) and concentrated. The residue was purified by prep HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA). Fractions containing desired compound were then immediately free based with 1 N sodium hydroxide, extracted with ethyl acetate, dried (MgSO4) and concentrated to afford the title compound of EXAMPLE 21. LRMS (ES+): 397.1 (M+H)+.