Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][OH:6])=[N+:2]=[N-:3].CN(C)C=O.CC([N:16]([C@H:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]#[CH:31])[CH:28]=2)[N:23]([C:32](=[O:34])[CH3:33])[C@@H:22]([CH3:35])[CH2:21]1)[C:17](=[O:19])[O-:18])(C)C>[Cu]I.CO>[C:32]([N:23]1[C:24]2[C:29](=[CH:28][C:27]([C:30]3[N:3]=[N:2][N:1]([CH2:4][CH2:5][OH:6])[CH:31]=3)=[CH:26][CH:25]=2)[C@H:20]([NH:16][C:17](=[O:19])[O:18][C:27]([CH3:30])([CH3:28])[CH3:26])[CH2:21][C@@H:22]1[CH3:35])(=[O:34])[CH3:33]
Reactant: C#Cc1ccc2c(c1)[C@H](N(C(=O)[O-])C(C)(C)C)C[C@H](C)N2C(C)=O
Reactant: [N-]=[N+]=NCCO
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)N1c2ccc(-c3cn(CCO)nn3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
Temperature: 25 °C
Yield: 83 %

Procedure:
A flask was charged with 2-azidoethanol (318 mg, 3.65 mmol) and copper(I) iodide (17.40 mg, 0.091 mmol) then filled with N,N-dimethylformamide (DMF) (13 mL) and methanol (1.5 mL). This mixture was treated with 1,1-dimethylethyl[(2S,4R)-1-acetyl-6-ethynyl-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 113) (600 mg, 1.827 mmol) and the resulting mixture was at 100° C. for 2 h under microwave irradiation then cooled to room temperature and partitioned between EtOAc and water. The layers were separated and the aqueous phase was extracted three times with EtOAc. The combined organic layers were washed twice with brine, and then dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 5% MeOH in DCM) gave 1,1-dimethylethyl {(2S,4R)-1-acetyl-6-[1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (659 mg, 1.523 mmol, 83% yield).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2)=[O:4].[NH:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>C1COCC1.CCOC(C)=O.C(=O)(O)[O-].[Na+]>[C:26]([O:25][C:23]([C@@H:19]1[CH2:20][CH2:21][CH2:22][N:18]1[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2)=[O:4])=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: O=C(CCl)N1CCSc2cc([N+](=O)[O-])ccc21
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1CC(=O)N1CCSc2cc([N+](=O)[O-])ccc21
Temperature: 55 °C
Reaction time: 17 h

Procedure:
A solution of 2-chloro-1-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethanone (1.0 g, 3.67 mmol) in THF (20 mL) was treated with (S)-tert-butyl pyrrolidine-2-carboxylate (0.942 g, 5.50 mmol), followed by saturated sodium bicarbonate (4 mL). The mixture was heated at 55° C. for 3 hours then stirred at room temperature overnight (17 hours). The mixture was diluted with EtOAc (50 mL) and saturated sodium bicarbonate (10 mL) then stirred for 20 minutes. The contents were poured into a separatory funnel, and the organic layer was separated, dried (Na2SO4), filtered, and concentrated to give a dark yellow residue. This residue was subjected to silica gel chromatography using the Biotage purification system (column: Silicycle 40 g; 20:80 EtOAc:hexanes gradient to 60:40 EtOAc:hexanes over 8 column volumes; flow rate: 35 mL/min; collection wavelength: 254 nm). A yellow residue was obtained (1.47 g, 98%). 1H-NMR (CDCl3) δ 8.09 (d, J=2.4 Hz, 1H), 7.91 (dd, J=2.4, 8.7 Hz, 1H), 7.75 (d, J=9.0 Hz, 1H), 4.10 (brs, 2H), 3.74 (brd, J=13.2 Hz, 1H), 3.40 (brd, J=13.5 Hz, 1H), 3.37-3.21 (m, 3H), 3.12-3.04 (m, 1H), 2.61 (brdd, J=8.1, 16.2 Hz, 1H), 2.21-2.07 (m, 1H), 1.95-1.77 (m, 3H), 1.43 (s, 9H); ESI-MS (m/z, %): 408 (MH+, 50), 352 (100).
Reaction SMILES: [NH2:1][N:2]1[C:11]([OH:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:19])[CH:9]=2)[N:4]=[CH:3]1.N1C=CC=CC=1.[C:26]1(=[O:41])[N:30]([CH2:31][CH2:32][C:33](Cl)=O)[C:29](=[O:36])[C:28]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:27]12.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:19][C:8]1[CH:7]=[CH:6][C:5]([N:4]2[CH:3]=[N:2][N:1]=[C:33]2[CH2:32][CH2:31][N:30]2[C:29](=[O:36])[C:28]3=[CH:37][CH:38]=[CH:39][CH:40]=[C:27]3[C:26]2=[O:41])=[C:10]([CH:9]=1)[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:18]
Reactant: O=C(Cl)CCN1C(=O)c2ccccc2C1=O
Reactant: NN1C=Nc2ccc(Cl)cc2C1(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)c1cc(Cl)ccc1-n1cnnc1CCN1C(=O)c2ccccc2C1=O
Temperature: 0 °C

Procedure:
A stirred mixture of 3-amino-6-chloro-3,4-dihydro-4-hydroxy-4-phenylquinazoline (2.74 g. 0.01 mole) in dry tetrahydrofuran (150 ml.) is cooled in an ice bath, under nitrogen, and treated with dry pyridine (1.77 ml., 0.022 mole). This mixture is then treated dropwise, during 1 hour with a solution of β-phthalimidopropionyl chloride (5.23 g., 0.022 mole) in tetrahydrofuran (25 ml.). The mixture is kept in the ice bath for 1 hour and at ambient temperature for 4 hours. It is then poured into cold, dilute aqueous sodium bicarbonate and extracted with chloroform. The extract is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is mixed with toluene (165 ml.), treated with trifluoroacetic acid (0.732 ml.) and warmed, under nitrogen at 100°-110° C. for 1.5 hours. The mixture is concentrated in vacuo and the residue mixed with cold water and extracted with chloroform. The extract is washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on silica gel (300 g) with 1.5% methanol-98.5% chloroform. The product thus obtained is crystallized to give 5-chloro-2-[3-(2-phthalimidoethyl)-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].Cl[CH2:24][CH:25]=O>>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[C:14]([Br:15])=[CH:13][N:12]2[CH:24]=[CH:25][N:16]=[C:11]2[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CCCl
Reactant: CC(C)(C)OC(=O)NCc1cc(N)ncc1Br
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(C)OC(=O)NCc1cc2nccn2cc1Br
Temperature: 25 °C
Yield: 78.8 %

Procedure:
A mixture of (2-amino-5-bromo-pyridin-4-ylmethyl)-carbamic acid tert-butyl ester (1.0 g, 3.3 mmol), NaHCO3 (474 mg, 5.6 mmol) and chloracetaldehyde (2.2 mL, 15.0 mmol) was vigorously stirred and refluxed for 14 h. The reaction mixture was cooled to RT, concentrated under vacuum and the remaining residue was suspended in DCM and brine. The aqueous layer was separated and extracted with DCM (5×), and the combined organic fractions were dried over Na2SO4, filtered, and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, hexane/DCM/TBME 10:10:1→1:1:18) to yield the title compound (860 mg, 2.6 mmol, 79%) as a pale yellow solid. MS: 327 [M+1]+; HPLC: AtRet=1.07; TLC: RF 0.16 (hexane/DCM/TBME 1:1:2).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[O:18][C:19]3[C:25]([C:26]([O:28]C)=O)=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH3:31]>CO>[C:26]([C:25]1[C:19]2[O:18][C:17]([CH:14]3[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])[CH2:16][CH2:15]3)=[N:21][C:20]=2[CH:22]=[CH:23][CH:24]=1)(=[O:28])[NH2:31]
Reactant: COC(=O)c1cccc2nc(C3CCN(C(=O)OCc4ccccc4)CC3)oc12
Reactant: N
Solvent: CO
Solvent: O
Product: NC(=O)c1cccc2nc(C3CCN(C(=O)OCc4ccccc4)CC3)oc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-(1-(benzyloxycarbonyl)piperidin-4-yl)benzo[d]oxazole-7-carboxylate (102 mg, 0.26 mmol) was added to a mixture of methanol (5 mL) and ammonia water (10 mL) and the mixture was stirred at room temperature for overnight. Then the solid was filtered. 98 mg of solid of benzyl 4-(7-carbamoylbenzo[d]oxazol-2-yl)piperidine-1-carboxylate was obtained. LC-MS (ESI) m/z: 380 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)=[CH:14][CH:13]=1.[ClH:33]>O1CCOCC1.CCOCC>[ClH:33].[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3F)cc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
1,1-Dimethylethyl 4-({[2′-fluoro-4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)-1-piperidinecarboxylate (Example 65, 0.484 g, 1.04 mmol) was dissolved in 1,4-dioxane (20 mL). To this solution was added ether (15 mL), followed by addition of 4.0M HCl in 1,4-dioxane (15 mL) and 2M HCl in ether (15 mL). The reaction mixture was stirred at ambient temperature overnight. The white solid was collected via filtration and washed with ether to yield 0.386 mg (92%) of 4-({[2′-fluoro-4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)piperidine hydrochloride as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.85-7.50 (m, 3H), 7.56 (d, 2H, J=7.3 Hz), 7.06 (d, 2H, J=8.7 Hz), 3.98 (d, 2H, J=5.9 Hz), 3.50-3.40 (m, 2H), 3.17 (s, 3H), 3.10-3.00 (m, 2H), 2.25-2.05 (m, 3H), 1.70-1.55 (m, 2H); LRMS (ESI), m/z 364 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.O.O.O.[F:23][C:24]([F:32])([F:31])[C:25]([C:27]([F:30])([F:29])[F:28])=[O:26]>C1(C)C=CC=CC=1.O.O.O.FC(F)(F)C(C(F)(F)F)=O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[CH:11]=[C:10]([C:25]([C:27]([F:30])([F:29])[F:28])([C:24]([F:32])([F:31])[F:23])[OH:26])[NH:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(-c2cc[nH]c2-c2ccc(F)cc2)cc1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O
Product: OC(c1cc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
A mixture of 20.4 g (0.08 mole) of 2,3-bis(4-fluorophenyl)-1H-pyrrole and 19.8 g (0.09 mole) of hexafluoroacetone trihydrate in 300 ml toluene was heated at reflux for 6 hours. Analysis by tlc indicated a small amount of starting material remained so another 1.0 g of hexafluoroacetone trihydrate was added and the mixture was refluxed another 0.5 hour. After stirring at room temperature overnight, the mixture was concentrated by rotary evaporation. The residue was purified by chromatography on 2 pounds of silica gel, eluting with toluene. The chromatographed product was decolorized with charcoal, then recrystallized from hexane to give 21.5 g (63%) of product, m.p. 112°-113°.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[C:7]([N:9]([CH3:11])[NH2:10])[CH:6]=[CH:5][CH:4]=1.[CH3:14][CH:15]([CH3:19])[C:16](=O)[CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:13][C:2]([F:1])([F:12])[C:3]1[N:8]=[C:7]([N:9]([CH3:11])[N:10]=[C:16]([CH:15]([CH3:19])[CH3:14])[CH3:17])[CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)C(C)C
Reactant: CN(N)c1cccc(C(F)(F)F)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=NN(C)c1cccc(C(F)(F)F)n1)C(C)C

Procedure:
A solution of 1-[6-trifluoromethylpyrid-2-yl]-1-methyl hydrazine (12.12 g; 0.069 mol), 3-methyl-2-butanone (5.96 g; 0.069 mol) and p-toluenesulphonic acid (0.13 g) in toluene (70 ml) was heated under reflux, with water removal (azeotrope), for 24 h. The solution was concentrated to yield an oil which was purified by flash-chromatography over silica (eluent: 20% diethyl ether in hexane) to yield 3-methyl-2-butanone 1-[6-trifluoromethylpyrid-2-yl]-1-methyl hydrazone as an orange oil (11.6 g; 71%). ##STR22##
Reaction SMILES: C([Mg]Br)C.C1COCC1.I[C:11]1[N:12]=[CH:13][N:14]2[CH:18]=[CH:17][S:16][C:15]=12.[C:19](=[O:21])=[O:20].[OH-].[Na+]>C1COCC1.CCOCC>[S:16]1[CH:17]=[CH:18][N:14]2[CH:13]=[N:12][C:11]([C:19]([OH:21])=[O:20])=[C:15]12
Reactant: Ic1ncn2ccsc12
Reactant: O=C=O
Agent: CC[Mg]Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)c1ncn2ccsc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
A 0.95 M ethylmagnesium bromide/THF solution (12.6 ml) was added dropwise to a solution (50 ml) of 2.501 g of 7-iodoimidazo[5,1-b]thiazole in THF at −70° C. The mixture was stirred for 30 min. Carbon dioxide (which had been evolved from about 5 g of dry ice and passed through a calcium chloride tube) was introduced into the reaction solution at the same temperature over a period of 40 min. The reaction solution was allowed to stand at −20° C. overnight, and then added to an ice cold mixed solution composed of an aqueous sodium hydroxide (0.41 g) solution (100 ml) and ether (200 ml) with stirring. The mixture was stirred for one hr. The organic layer was separated and concentrated under the reduced pressure by a minor amount, and the remaining organic solvent was removed by distillation. The residue was adjusted to pH 3.5 by the addition of 2 N hydrochloric acid under ice cooling. The resultant precipitate was washed with a minor amount of cold water, and then dried under the reduced pressure to give 1.407 g of imidazo[5,1-b]thiazole-7-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[N:32]1([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[N:32]1([CH:38]2[CH2:43][CH2:42][N:41]([CH:18]=[C:17]3[C:16]4[C:15]([CH3:30])([C:14]5[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]6([CH3:31])[CH:8]([C:13]=5[C:21](=[O:22])[C:20]=4[OH:19])[CH2:9][CH2:10][CH:11]6[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]3=[O:24])[CH2:40][CH2:39]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN2CCC(N3CCCCC3)CC2)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
17-Hydroxywortmannin (30 mg, 0.069 mmol) is dissolved in 2 ml methylene chloride and stirred at room temperature under nitrogen atmosphere as 4-piperidinopiperidine (0.069 mmol, 11.6 mg) is added. The reaction solution turns orange immediately. After 30 min, the solvent is evaporated and the solid is recrystallized from ethyl acetate/hexane (2:1). After filtration, the solid is washed with hexane and dried under vacuum to yield about 30 mg the title compound as an orange powder. UV λmax (CH3CN/H2O): 250 nm, 320 nm, 397 nm; Positive ESI-MS: m/z 599 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>CCCCCCC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: C1=COCCC1
Reactant: OCCCCCCCCBr
Solvent: CCCCCCC
Product: BrCCCCCCCCOC1CCCCO1
Reaction time: 22 h

Procedure:
To a stirred, room temperature suspension of Amberlyst 15 resin (2.37 g) in a solution of 8-bromo-1-octanol (9.50 g, 0.0454 mol) in heptane (95 mL) was added dropwise neat 3,4-dihydro-2H-pyran (5.0 mL, 0.055 mol) under a nitrogen atmosphere, and the mixture was stirred for 22 hours. The resin was filtered off, and the filtrate was rotoevaporated to an oil. The oil was chromatographed on silica gel (400 g, 230-400 mesh) using PET ether-diethyl ether (10:1, 10×500 mL) as eluent. Fractions containing title compound were rotoevaporated and dried in vacuo to give a clear, colorless oil, yield 10.92 g (82%). 1H NMR (CDCl3): δ 4.6 (dd, 1H), 3.9 (m, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 3.4 (m, 3H), 1.8 (m, 3H), 1.7 (m, 1H), 1.6 (m, 6H), 1.4 (m, 1H), 1.3 (m, 7H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].[K+].Cl[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=1>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(Cl)ccn1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)ccn1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
A mixture containing 1.4 mmol 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester, 4.8 mmol potassium fluoride, 1.4 mmol 4-chloro-2-picoline (commercial) and 0.03 mmol bis(tri-tert.-butylphosphine)palladium in 5 ml degazed dioxane was stirred at 100° C. for 1.5 hours. The solvent was removed in vacuo. The residue was taken in ethyl acetate. The mixture was washed twice with water. The aqueous layer was extracted once with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude oil was purified on a 20 g Flashpack cartridge (Eluent: Heptane/AcOEt) to afford the title compound as a yellow oil (69% yield). MS (m/e): 311.2 ([M+H]+, 100%)
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][S:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][S:10](=[O:23])[CH2:11][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(CN2CCSCC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S1CCN(Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A mixture of 4-(4-bromobenzyl)-thiomorpholine (0.20 g, 0.735 mmol) was dissolved in DCM (10 mL) under a nitrogen atmosphere and m-chloroperbenzoic acid (0.13 g, 0.74 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 1 h then purified by flash chromatography (silica, Biotage 50 g column, 0-75% (10% methanol in DCM)) to afford the title compound (0.125 g, 59%). 1H NMR (DMSO-D6, 400 MHz): 7.55-7.49 (m, 2H), 7.31-7.25 (m, 2H), 3.53 (s, 2H), 2.92-2.80 (m, 4H), 2.78-2.65 (m, 2H), 2.64-2.54 (m, 2H). LCMS (Method G): RT=2.66 min, M+H+=289.
Reaction SMILES: C(OP([CH:9]1[C:13](=[O:14])[NH:12][C:11](=[O:15])[N:10]1[CH3:16])(=O)OCC)C.O.[OH-].[Li+].[CH:20]([CH:22]([N:26]([CH3:49])[C:27]([CH:29]([NH:34][C:35](=[O:48])[CH:36]([NH:46][CH3:47])[C:37]([CH3:45])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:38])[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:23]([CH3:25])[CH3:24])=O>C(O)C.O>[CH3:47][NH:46][C@H:36]([C:35]([NH:34][C@H:29]([C:27]([N:26]([CH3:49])[C@H:22](/[CH:20]=[C:9]1\[N:10]([CH3:16])[C:11](=[O:15])[NH:12][C:13]\1=[O:14])[CH:23]([CH3:24])[CH3:25])=[O:28])[C:30]([CH3:31])([CH3:32])[CH3:33])=[O:48])[C:37]([CH3:38])([CH3:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCOP(=O)(OCC)C1C(=O)NC(=O)N1C
Reactant: CNC(C(=O)NC(C(=O)N(C)C(C=O)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C1/C(=O)NC(=O)N1C)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
The yield, (3-methyl-2,5-dioxo-imidazolidin-4-yl)-phosphonic acid diethyl ester (0.915 g, 3.0 mmol) in ethanol (9 mL) is added to lithium hydroxide monohydrate (139 mg, 2.1 mmol) in 0.9 ml water to give a yellow solution. It is then added to N-{1-[(1-formyl-2-methyl-propyl)-methyl-carbamoyl]-2,2-dimethyl-propyl}-3-methyl-2-methylamino-3-phenyl-butyramide (˜1 mmol, from Reference Example 12) in 3 mL ethanol. The reaction mixture is stirred at room temperature for 60 hours. Solvent is evaporated. The residue is diluted with dichloromethane/water. The aqueous layer is extracted twice with dichloromethane. The combined organic extracts are washed with brine, dried oversodium sulfate, filtered and concentrated in vacuo. The residue is chromatographed by reverse phase HPLC (0.01% trifluoroacetic acid in water/acetonitrile) to give the product as a white solid, N,beta,beta-trimethyl-L-phenylalanyl-N1,3-dimethyl-N1-{(1S)-2-methyl-1-[(Z)-(3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl]propyl}-L-valinamide: 25 mg (4%) MS (ES+): (M+H)=514.3
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[H-].[Na+].[CH3:14][O:15][C:16](=O)[O:17]C>>[CH3:14][O:15][C:16]([CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[C:7]1=[O:11])=[O:17]
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1Cc2cc(Br)ccc2C1=O

Procedure:
Use of 5-bromo-indan-1-one (Intermediate NINETEEN-1) in a reaction with NaH and dimethylcarbonate (refer to procedures in Method EIGHTEEN) produced 5-bromo-1-oxo-indan-2-carboxylic acid methyl ester (Intermediate NINETEEN-2). A solution of 5-bromo-1-oxo-indan-2-carboxylic acid methyl ester (4.75 g, 17.7 mmol) in TFA (80 mL) at 0° C. was treated with triethylsilane (TES) (17.0 mL, 6.0 eq) and stirred for 18 h. After evaporation of the solvent, the residue was diluted with Et2O and washed with H2O (5×100 mL), sat. NaHCO3 (3×50 mL), brine (1×75 mL) and dried over MgSO4 to give crude 5-bromo-indan-2-carboxylic acid methyl ester (Intermediate NINETEEN-3). A solution of 5-bromo-indan-2-carboxylic acid methyl ester (Intermediate NINETEEN-3) in AcOH containing 20% HCl was stirred overnight. After evaporation of the solvent, the residue was dissolved in 1N NaOH. The resulting mixture was washed with Et2O (3×75 mL) after which it was acidified with HCl (aq). The solution was extracted with CH2Cl2 (3×150 mL) and the combined organic extracts was washed with H2O (3×100 mL), brine (1×75 mL), dried over MgSO4 and concentrated to give crude 5-bromo-indan-2-carboxylic acid. Use of 5-bromo-indan-2-carboxylic acid in Method EIGHTEEN produced 4-(5-bromo-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound 148).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Br[C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1>>[N:14]1[CH:13]=[C:12]([N:4]([C:1](=[O:3])[CH3:2])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:17]=[N:16][CH:15]=1
Reactant: Brc1cncnc1
Reactant: CC(=O)Nc1ccccc1
Product: CC(=O)N(c1ccccc1)c1cncnc1
Yield: 61 %

Procedure:
Using acetanilide (8.25 g) and 5-bromopyrimidine, a reaction was made in the same manner as in 1) of Production Example 2. The subsequent purification by silica gel column chromatography (developing solvent, ethyl acetate:hexane=1:1 to 3:1) produced N-(5-pyrimidinyl)acetanilide (7.98 g; yield, 61%) as a pale yellow oil.