Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[N:9]2)[N:3]=1.[CH3:13][O-:14].[Na+]>CS(C)=O>[CH3:13][O:14][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[N:9]2)[N:3]=1
Reactant: C[O-]
Reactant: Clc1cccc(-n2ccnn2)n1
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccc(-n2ccnn2)n1
Temperature: 80 °C

Procedure:
A mixture of 4.00 g (20 mmol) of 2-chloro-6-(1H-1,2,3-triazol-1-yl)pyridine and 8.5 ml of sodium methoxide (25 percent in methanol, 40 mmol) in dimethyl sulfoxide was heated at 80° C. for six hours. The mixture was cooled, poured over ice and extracted with methylene chloride. The extract was dried over magnesium sulfate and stripped of solvent. The solid residue was triturated in a minimal amount of methanol and filtered to yield 0.4 g (10 percent of theory) of tan solid product; m.p., 75°-78° C. NMR (CDCl3): δ8.60 (s, 1H); δ7.94 (m, 3H); δ6.90 (m, 1H); δ4.06 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:16][CH2:15][CH2:14][CH2:13][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: ClCCCBr
Reactant: CCC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(=O)c1ccc(OCCCCl)cc1
Reaction time: 1.5 h
Yield: 99 %

Procedure:
A mixture of 37.6 g (0.25 mole) of 4'-hydroxypropiophenone (97%)*, 78.7 g (0.5 mole) of 1-bromo-3-chloropropane and 103.5 g (0.75 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 18 hr. The mixture was cooled, filtered, and the filtrate concentrated under reduced pressure. The oily residue was dissolved in 500 ml of benzene and the solution stirred with potassium hydroxide pellets for 1.5 hr to remove unreacted phenol. The mixture was filtered and the filtrate was concentrated to give 56.1 g (99% yield) of title compound as an oil. The oil gradually crystallized and a portion of the solid was recrystallized from petroleum ether (60°-110° C.) to yield title compound as a fluffy, white solid, mp 41°-43° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([O:22][C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:41][O:42][C:43](=[O:47])[CH2:44][CH2:45][NH2:46].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([O:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([NH:46][CH2:45][CH2:44][C:43]([O:42][CH3:41])=[O:47])=[O:28])=[CH:30][CH:31]=3)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)CCN
Reactant: CCCCCCC(Oc1ccc(C(=O)O)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC(Oc1ccc(C(=O)NCCC(=O)OC)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a mixture of 4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-heptyloxy}-benzoic acid (230 mg, 0.5 mmol) in methylene chloride (5 mL) are added triethyl amine (0.21 mL, 1.51 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl ester (210.5 mg, 1.51 mmol) and EDCI (290 mg, 1.51 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving methyl 3-(4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-heptyloxy}-benzoylamino)-propionoate (260 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH2:21][CH3:22])[CH:5]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:12]=2[CH2:21][CH3:22])[CH:5]=1
Reactant: BrCc1ccccc1
Reactant: CCc1[nH]c2cc(Cl)ccc2c1Sc1cccc(C(=O)OC)c1
Product: CCc1c(Sc2cccc(C(=O)OC)c2)c2ccc(Cl)cc2n1Cc1ccccc1

Procedure:
Prepared according to the procedure described in Example 10, Step 3, using the following starting materials: 3-(6-chloro-2-ethyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and benzyl bromide.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.C([O:16][N:17]=O)CCC>CCOCC>[C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[N:17][OH:16]
Reactant: CCCCON=O
Reactant: O=C1CCc2ccccc21
Agent: Cl
Solvent: CCOCC
Product: O=C1C(=NO)Cc2ccccc21
Reaction time: 2 h
Yield: 63.7 %

Procedure:
To a solution of 1-indanone (19.5 g, 0.15 mol) in 200 ml of ether was added 15 ml of concentrated HCl, then a solution of n-butylnitrite (18.75 ml, 0.16 mol) in 50 ml of ether at room temperature. The resulting mixture was stirred for 2 h, the precipitate was collected and dried to yield a white solid (15.4 g, 65% yield). LC-MS: 162 (MH+)
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[N:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1>CC[O-].[Na+]>[CH2:1]([S:8][C:10]1[N:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncc(Br)cn1
Reactant: SCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Product: Brc1cnc(SCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 81 %

Procedure:
Benzyl thiol (22 mmol) was added to 0.146 M ethanolic NaOEt (150 ml) at room temperature followed by 2-chloro-5-bromopyrimidine (20 mmol). The mixture was stirred at room temperature for 70 min, heated under reflux for 40 min, the solvent evaporated off at reduced pressure, the residue extracted with chloroform (100 ml), the chloroform solution washed with 2 M NaOH, and the dried (MgSO4) solution evaporated; yield 81%, m.p. 68°-69° C. (dil. MeOH). 1H NMR (CDCl3): δ4.36 (CH2), 7.26 (Ph), 8.50. (H-4, H-6).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:19]2[NH:23][C:22]([C:24]3[CH:29]=[C:28]([CH2:30][OH:31])[CH:27]=[CH:26][N:25]=3)=[CH:21][CH:20]=2)[CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(#N)C.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:19]2[NH:23][C:22]([C:24]3[CH:29]=[C:28]([CH:30]=[O:31])[CH:27]=[CH:26][N:25]=3)=[CH:21][CH:20]=2)[CH2:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3cc(CO)ccn3)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3cc(C=O)ccn3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
To a solution of [2-(5-{1-[4-(methylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-4-yl]methanol (457 mg) in acetonitrile (10 mL) was added Dess-Martin reagent (530 mg), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (380 mg, yield 83%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[CH:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1c[nH]c(Sc2cc(Cl)cc(Cl)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c(Sc2cc(Cl)cc(Cl)c2)c1

Procedure:
Methyl 5-(3,5-dichlorophenylthio)pyrrole-3-carboxylate (2.5 g.) was combined with 25 ml. of methanol and 25 ml. of 1N sodium hydroxide and refluxed for 3 hours. The methanol was allowed to evaporate, the aqueous residue diluted with approximately one volume of water and washed twice with ether. The aqueous phase was acidified with conc. hydrochloric acid and the product extracted into ethyl acetate. The two ethyl acetate extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to crude product (1.84 g., m.p. 169°-172° C.). Recrystallization from chloroform afforded purified 5-(3,5-dichlorophenylthio)pyrrole-3-carboxylic acid (1.3 g., m.p. 175°-177° C.).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[Na].Br[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]>CO.O>[CH:2]([C:1]([O:8][CH3:9])=[O:7])([C:3]([O:5][CH3:6])=[O:4])[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CCC/C=C\CBr
Reactant: COC(=O)CC(=O)OC
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC(=O)CCC/C=C\CC(C(=O)OC)C(=O)OC
Reaction time: 0.25 h

Procedure:
Dimethyl malonate (39.6 g) is added slowly with cooling and stirring to a solution of 6.9 g of sodium dissolved in 100 ml of absolute methanol and the mixture stirred for 15 min. The bromoester of formula 9, methyl cis-7-bromo-5-heptenoate (65.7 g) is added dropwise. The mixture is heated at reflux for 1 hr., cooled and diluted with water. The mixture is extracted with ether. The ether extracts are dried (Na2SO4) and concentrated. The residue is distilled under reduced pressure to give the title compound, b.p. 140°-150° C/0.7 mm.
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH2:19][CH2:20][CH2:21][N:22]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]>>[CH2:23]([N:22]([CH2:21][CH2:20][CH2:19][C@H:16]([N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:17]([OH:18])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH3:38])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCCCCCCCCCCCCCCBr
Reactant: O=C[C@H](CCCN(Cc1ccccc1)Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Product: CCCCCCCCCCCCCCC[C@@H](O)[C@H](CCCN(Cc1ccccc1)Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 23 (503 mg, 1.05 mmol) and 1-bromopentadecane (768; mg, 2.64 mmol), alcohol 77 was obtained as a colorless oil (350 mg, 48% yield).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH2:58])[S:55][C:45]=2[C:46]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[N:47][CH:48]=1>C1COCC1>[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH:58][C:1](=[O:9])[C:2]3[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=3)[S:55][C:45]=2[C:46]([N:49]2[CH2:50][CH2:51][O:52][CH2:53][CH2:54]2)=[N:47][CH:48]=1
Reactant: O=C(O)c1ccncc1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccncc3)nc12

Procedure:
From isonicotinic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 372 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(C(C3CCCCO3)=O)[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[N:21]=[CH:20][N:19](C5C=CC(C)=C(C)C=5C)[N:18]=4)[CH:15]=3)[NH:10][NH:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>Cl.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[N:21]=[CH:20][NH:19][N:18]=4)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C2(C(=O)C3CCCCO3)NNc3ccc(-c4ncn(-c5ccc(C)c(C)c5C)n4)cc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)cc1
Reaction time: 2 h
Yield: 40 %

Procedure:
2-{3-(4-Methylphenyl)-5-[1-(trimethylphenyl)(1,2,4-triazol-3-yl)]-1H-indazoyl}perhydro-2H-pyran (0.130 g, 0.216 mmol) was dissolved in 4 mL of 4.0 N HCl in dioxane and 2 mL of 6.0 N aqueous HCl were added. After 2 hours at room temperature, the reaction mixture was neutralized using aqueous sodium hydroxide (6.0 N) and the product was extracted with ethyl acetate. The extracts were dried under vacuum and dissolved in 5 mL of 6.0 N aqueous sodium hydroxide, side products extracted twice with diethyl ether. The aqueous phase was neutralized with 6.0 N HCl and the product was extracted with ethyl acetate. The crude was purified by preparative HPLC (15-80% acetonitrile in water) (0.024 g, 40% yield): 1H NMR (DMSO-d6) δ 13.4 (br s, 1H), 8.7 (s, 1H), 8.4 (br s, 1H), 8.1 (dd, 1H), 7.9 (d, 2H), 7.7 (d, 1H), 7.4 (d, 2H), 7.0 (d, 1H), 2.4 (s, 3H); ES-MS (m/z) 276 [M+]+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:4][CH2:3]1.[NH:19]1[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[O:25])[CH2:20]1>>[O:18]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[O:17])[N:8]1[CH:5]1[CH2:6][CH2:7][CH:2]([N:19]2[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=3)=[O:25])[CH2:20]2)[CH2:3][CH2:4]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(N3C(=O)c4ccccc4C3=O)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 2-(4-oxo-cyclohexyl)-isoindole-1,3-dione (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [C:1]([C:3]1[N:4](C(OC(C)(C)C)=O)[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([F:17])[CH:16]=2)[NH:13][C:12](=[O:18])[C:11]3([CH3:20])[CH3:19])=[CH:6][CH:7]=1)#[N:2]>CC(N(C)C)=O.C(OCC)(=O)C>[F:17][C:15]1[CH:16]=[C:8]([C:5]2[NH:4][C:3]([C:1]#[N:2])=[CH:7][CH:6]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12](=[O:18])[C:11]2([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1cc(F)c2c(c1)C(C)(C)C(=O)N2
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC1(C)C(=O)Nc2c(F)cc(-c3ccc(C#N)[nH]3)cc21
Temperature: 180 °C
Yield: 89.9 %

Procedure:
tert-butyl 2-cyano-5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1H-pyrrole-1-carboxylate (0.18 g, 0.50 mmol) was dissolved in 10 mL of dimethylacetamide and the solution was heated to 180° C. for 1 h. The mixture was cooled, diluted with ethyl acetate and washed with water, saturated aqueous NaCl, dried over MgSO4, and concentrated. Flash chromatography (25% acetone/hexane) afforded 0.121 g (91%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([C:6]1[CH:7]=[C:8]([CH:15]=[CH:16][CH:17]=1)[CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])[CH2:4][CH3:5].Cl.[CH3:19][C:20](=[CH2:22])[CH3:21].OS(O)(=O)=O>O1CCOCC1>[CH3:5][CH2:4][CH:3]([C:6]1[CH:7]=[C:8]([CH:15]=[CH:16][CH:17]=1)[CH2:9][C@@H:10]([C:12]([O:14][C:20]([CH3:22])([CH3:21])[CH3:19])=[O:13])[NH2:11])[CH2:2][CH3:1]
Reactant: CCC(CC)c1cccc(C[C@H](N)C(=O)O)c1
Reactant: C=C(C)C
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CCC(CC)c1cccc(C[C@H](N)C(=O)OC(C)(C)C)c1
Yield: 74 %

Procedure:
According to example 54, 0.60 g of 3-(3-pentyl)-L-phenylalanine.HCl was treated with 30 mL of isobutylene in 35 mL of 1,4-dioxane in the presence of 0.5 mL of conc. H2SO4. Work-up in the usual manner followed by acidification with 2 mL of 1N ethereal HCl afforded 0.53 g (74%) of tert-butyl 3-(3-pentyl)-L-phenylalaninate.HCl as a light yellow glass.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:25]4[C:26]([NH2:30])=[N:27][CH:28]=[CH:29][C:24]=4[S:23][CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11].C1C(=O)N([I:38])C(=O)C1.O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:25]4[C:26]([NH2:30])=[N:27][CH:28]=[C:29]([I:38])[C:24]=4[S:23][CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11]
Reactant: Nc1nccc2scc(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc(I)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 272.9 %

Procedure:
To a solution of 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}thieno[3,2-c]pyridin-4-amine (150 mg, 0.389 mmol) in DMF (6.0 mL) cooled in an ice-bath was added NIS (264 mg, 1.174 mmol). The reaction mixture was stirred at room temperature overnight. Water was poured into the mixture, the formed brown solid was filtered, dried to give the product 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-iodothieno[3,2-c]pyridin-4-amine as a brown solid (581 mg). LCMS (ES) m/z=548.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[OH-].[K+].[CH3:16]S(C)=O.IC>C(OCC)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:10])([CH3:12])[CH3:11])[C:3]=1[O:13][CH3:16]
Reactant: CS(C)=O
Reactant: Cc1cc(Br)c(O)c(C(C)(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: CCOCC
Product: COc1c(Br)cc(C)cc1C(C)(C)C
Temperature: 0 °C
Yield: 82.8 %

Procedure:
A 500 mL three-necked round-bottomed flask was charged with 2-bromo-6-tert-butyl-4-methylphenol (20.0 g, 82.3 mmol), potassium hydroxide (9.7 g, 164.5 mmol) and DMSO (dimethylsulfoxide) (100 mL), and the mixture was chilled to 0° C. After slowly injecting iodomethane (23.4 g, 164.5 mmol) thereto, the resultant mixture was stirred at ambient temperature for 12 hours. The reaction mixture was then poured into ice (200 g), and the resultant mixture stirred for 30 minutes. After adding diethyl ether, the organic layer was isolated and the residue was extracted with diethyl ether. The combined organic layer was dried over magnesium sulfate, and evaporated to remove volatiles. Recrystallization from mixture of hexane and dichloromethane gave 1-bromo-3-tert-butyl-2-methoxy-5-methylbenzene (17.5 g, yield: 82.8%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2([CH2:18][C:17](=O)[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]#[N:24])[CH:15]=3)[O:10]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C[Si]([N:32]=[C:33]=[N:34][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2([CH2:18][C:17](=[N:34][C:33]#[N:32])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:20]4[CH:27]=[CH:26][CH:25]=[C:22]([C:23]#[N:24])[CH:21]=4)[CH:15]=3)[O:10]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: CC(=O)N1CCC2(CC1)CC(=O)c1cc(-c3cccc(C#N)c3)ccc1O2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)N1CCC2(CC1)CC(=NC#N)c1cc(-c3cccc(C#N)c3)ccc1O2
Reaction time: 1 h

Procedure:
To a solution of 3-(1′-acetyl-4-oxospiro[chroman-2,4′-piperidine]-6-yl)benzonitrile (60 mg, 0.167 mmol) in anhydrous DCM (5 mL) under N2 atmosphere was added 1 M TiCl4 (in DCM, 0.35 mL, 0.35 mmol) dropwise within 15 min at room temperature. It was stirred another 1 h after the addition. To this mixture was added Bis-trimethylsilylcarbodiimide (0.086 mL, 0.367 mmol) dropwise. The resulting mixture was stirred overnight. The reaction mixture was quenched with ice-water (5 g), and stirred for 20 min, then it was transferred to a separating funnel, the separated aqueous phase was extracted 2 times with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered, and concentrated to give N-(1′-acetyl-6-(3-cyanophenyl)spiro[chroman-2,4′-piperidine]-4-ylidene)cyanamide as light brown solid which was used for next step without further purification. MS ESI+ve m/z 385 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]([CH:9]([OH:11])[CH3:10])[C:5]([F:8])=[CH:6][CH:7]=1>C(#N)C.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[C:3]([F:12])=[C:4]([C:9](=[O:11])[CH3:10])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: CC(O)c1c(F)ccc(Br)c1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC#N
Product: CC(=O)c1c(F)ccc(Br)c1F
Yield: 89.8 %

Procedure:
To a solution of 1-(3-bromo-2,6-difluorophenyl)ethanol (3.91 g) in acetonitrile (50 ml) was added manganese dioxide (2.87 g) at room temperature, and the mixture was heated under reflux for 20 hr. The reaction mixture was cooled, the insoluble material was filtered off, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.48 g).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH:4]([NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])=[O:24])=[CH:18][CH:17]=2)[CH:12]=1)=[O:10])[CH:5]([CH3:7])[CH3:6].[Li+].[OH-].Cl>C1COCC1>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:25][C:23](=[O:24])[NH:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:12]=[C:11]([C:9]([NH:8][CH:4]([CH:5]([CH3:6])[CH3:7])[C:3]([OH:33])=[O:2])=[O:10])[O:15][N:14]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1)C(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 63.2 %

Procedure:
2-[(3-{4-[3-(2-Fluoro-phenyl)ureido]-phenyl}-isoxazole-5-carbonyl)-amino]-3-methyl-butyric acid methyl ester (800 mg) was dissolved in THF (20 ml). 1M aqueous LiOH solution (3.52 ml) was added and stirred at RT for 14 h. The reaction mixture was acidified with dilute HCl and extracted with EtOAc. Organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to get off white solid which was crystallized from EtOAc to yield 490 mg (63%) white solid. MS (ES+): m/z 441 (M+1); 1HNMR (DMSO-d6, 300 MHz): δ 12.83 (bs, 1H), 9.34 (s, 1H), 8.95 (d, 1H), 8.63 (s, 1H), 8.13 (m, 1H), 7.85 (d, 2H), 7.68 (s, 1H), 7.62 (d, 2H), 7.24 (m, 1H), 7.14 (m, 1H), 7.02 (m, 1H), 4.26 (m, 1H), 2.21 (m, 1H), 0.95 (dd, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].Cl[CH:25](Cl)[C:26]([O:28]C)=[O:27].Cl>O.CN(C)C=O>[C:9]1([C:6]2[C:5]3[CH:15]=[CH:16][C:2]4[O:1][CH:25]([C:26]([OH:28])=[O:27])[O:17][C:3]=4[C:4]=3[O:8][N:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1ccc2c(-c3ccccc3)noc2c1O
Reactant: COC(=O)C(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)C1Oc2ccc3c(-c4ccccc4)noc3c2O1
Reaction time: 5 h
Yield: 57.3 %

Procedure:
A mixture of 6,7-dihydroxy-3-phenyl-1,2-benzisoxazole (2.1 g), potassium carbonate (7.7 g), methyl dichloroacetate (2.7 g) and N,N-dimethylformamide (50 ml) was stirred at 90°-100° C. for 5 hours. After addition of water (100 ml), the mixture was stirred at 90°-100° C. for 30 minutes, and after acidifying it with hydrochloric acid, extracted with ether. The ether layer was washed with water, dried and evaporated to remove the solvent. The residue was recrystallized from acetonitrile to give 1.5 g of 3-phenyl-1,3-dioxolo[4,5-g]-1,2-benzisoxazole-7-carboxylic acid. m.p.: 187°-190° C.