Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]([S:16][CH3:17])[C:13]3[N:18]([CH3:21])[CH:19]=[N:20][C:12]=3[CH:11]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:30])C=1.[OH2:33].CCOC(C)=O>C(Cl)Cl>[C:1]([N:5]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]([S:16]([CH3:17])(=[O:30])=[O:33])[C:13]3[N:18]([CH3:21])[CH:19]=[N:20][C:12]=3[CH:11]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1nc(-c2cnn(C(C)(C)C)c2)cc2ncn(C)c12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1cnc2cc(-c3cnn(C(C)(C)C)c3)nc(S(C)(=O)=O)c21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 6-(1-tert-butyl-1H-pyrazol-4-yl)-3-methyl-4-(methylthio)-3H-imidazo[4,5-c]pyridine 2.39 and 6-(1-tert-butyl-1H-pyrazol-4-yl)-3-methyl-4-(methylthio)-3H-imidazo[4,5-c]pyridine 2.40 (1.44 g, 4.78 mmol) in DCM at 0° C. was added mCPBA (2.47 g, 14.3 mmol) and the reaction was stirred for 5 min at 0° C. and warmed to rt for 2 hours. Water (20 mL) and EtOAc (40 mL) were added and the layers were separated and the aqueous was extracted with EtOAc (3×40 mL). The combined organics were washed with saturated NaHCO3 (2×50 mL), dried (MgSO4), filtered and concentrated. The residue was purified by flash chomatrography to afford 6-(1-tert-butyl-1H-pyrazol-4-yl)-3-methyl-4-(methylsulfonyl)-3H-imidazo[4,5-c]pyridine 2.41.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:3]=[N:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(=O)c1ncc(F)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ncc(Oc2ccc(F)cc2)cn1
Temperature: 50 °C
Yield: 25.4 %

Procedure:
A solution of 1-(5-fluoropyrimidin-2-yl)ethanone (700 mg, 5.0 mmol) and 4-fluorophenol (616 mg, 5.50 mmol) in 6 mL DMF was treated with potassium carbonate (829 mg 6.0 mmol) and heated to 50° C. for 3.5 h. The reaction mixture was poured into 20 mL water, and extracted with EtOAc (2×20 mL). Organics were washed with 20 mL each water, brine, and dried over Na2SO4. Mixture was filtered and concentrated on silica gel. Column chromatography (10-100% EtOAc/hept) gave 295 mg (25%) 1-(5-(4-fluorophenoxyl)pyrimidin-2-yl)ethanone as a white solid used directly in the following step. MS m/z 233.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 2H), 7.23-7.07 (m, 4H), 2.78 (s, 3H).
Reaction SMILES: [N:1]1([CH2:5][C:6]2[N:10]([CH3:11])[N:9]=[C:8]([N+:12]([O-])=O)[CH:7]=2)[CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[N:1]1([CH2:5][C:6]2[N:10]([CH3:11])[N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cn1nc([N+](=O)[O-])cc1CN1CCC1
Agent: [Pd]
Solvent: CCO
Product: Cn1nc(N)cc1CN1CCC1
Reaction time: 48 h
Yield: 98.7 %

Procedure:
To a solution of 5-(azetidin-1-ylmethyl)-1-methyl-3-nitro-1H-pyrazole (349 mg, 1.78 mmol) in ethanol (20 mL) was treated with palladium on carbon (10%, 50 mg). The resulting mixture was stirred under a hydrogen (1 atm) for 48 h. The reaction mixture was filtered through a celite pad, and the pad washed with ethanol. The filtrate was concentrated in vacuo to give 5-(azetidin-1-ylmethyl)-1-methyl-1H-pyrazol-3-amine (292 mg, 99%) as a light yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].[CH3:5][C:6]([CH:8]([CH3:10])[CH3:9])=O.C1C=CC=CC=1>O>[CH:8]([C:6]1([CH3:5])[NH:1][CH2:2][CH2:3][S:4]1)([CH3:10])[CH3:9]
Reactant: NCCS
Reactant: CC(=O)C(C)C
Solvent: O
Solvent: c1ccccc1
Product: CC(C)C1(C)NCCS1
Yield: 77.5 %

Procedure:
15.43 g (0.2 mol) of cysteamine and 29.0 g (0.2 mol) of isopropyl methyl ketone were treated with 200 ml of benzene and boiled under an inert gas atmosphere for 14 hours on a water-separator. The solution was concentrated on a rotary evaporator and filtered over 25 g of neutral aluminium oxide (activity I). The aluminium oxide was then flushed with ether. The filtrate was again concentrated and subsequently distilled under a high vacuum through a Widmer column. 22.51 g (yield 77% of theory) of 2-isopropyl-2-methylthiazolidine (nD20 = 1.5085) passed over in a boiling range of 40°-42°C and at a pressure of 0.009 mm Hg. IR: νmax = 1440, 1370, 790 cm-1. Odour: camphorous, woody; flavour: greenish.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[H][H].Cl>CO.O.[Pt](=O)=O>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: NC(=O)c1cccc2nc(-c3ccc(-c4ccncc4)cc3)oc12
Agent: O=[Pt]=O
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=O)c1cccc2nc(-c3ccc(C4CCNCC4)cc3)oc12
Yield: 3.3 %

Procedure:
2-(4-(Pyridin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide (135 mg, 0.43 mmol) and platinum (IV) oxide monohydrate (70 mg) in methanol (20 mL) was purged with 20 atm of hydrogen at 50° C. for 24 h. Then the mixture was filtered and adjusted to pH=9. The solvent was removed in vacuum. The crude was purified by chromatography (dichloromethane:methanol=8:1) to give the solid. The solid was acidified by hydrochloride acid. 4.6 mg of 2-(4-(piperidin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained. Yield: 3%. 1H-NMR (400 MHz, CD3OD-d4) δ 1.89 (m, 2H), 2.03 (m, 2H), 2.95 (m, 1H), 3.09-3.12 (m, 2H), 3.43-3.46 (m, 2H), 7.40-7.46 (m, 3H), 7.81 (t, J=8.4 Hz, 2H), 8.21 (d, J=8.0 Hz, 2H). LC-MS (ESI) m/z: 316 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].Br[C:9]1[CH:10]=[C:11]([CH2:23][C@H:24]([NH:36][S:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=[O:39])=[O:38])[C:25]2[NH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:28][N:29]=2)[CH:12]=[CH:13][C:14]=1[CH:15]1[S:19](=[O:21])(=[O:20])[NH:18][C:17](=[O:22])[CH2:16]1.[CH3:46][N:47](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:46]([C:9]1[CH:10]=[C:11]([CH2:23][C@H:24]([NH:36][S:37]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)(=[O:39])=[O:38])[C:25]2[NH:26][C:27]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:28][N:29]=2)[CH:12]=[CH:13][C:14]=1[CH:15]1[S:19](=[O:20])(=[O:21])[NH:18][C:17](=[O:22])[CH2:16]1)#[N:47]
Reactant: O=C1CC(c2ccc(C[C@H](NS(=O)(=O)c3ccccc3)c3ncc(-c4ccccc4)[nH]3)cc2Br)S(=O)(=O)N1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(C[C@H](NS(=O)(=O)c2ccccc2)c2ncc(-c3ccccc3)[nH]2)ccc1C1CC(=O)NS1(=O)=O
Yield: 60 %

Procedure:
A solution of N-[(1S)-2-[3-bromo-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]-1-(5-phenyl-1H-imidazol-2-yl)ethyl]benzenesulfonamide trifluoroacetate (3.5 mg, 4.8 μmol), zinc cyanide (1.7 mg, 14 μmol), tetrakis(triphenylphosphine)palladium(0) (1.11 mg, 960 nmol) and N,N-dimethylformamide (1.5 mL) was heated at 175° C. for 4 min in the microwave. The reaction filtered, concentrated in vacuo and purified by preparative LCMS to yield the desired product (2.0 mg, 60%). 1H NMR (400 MHz, CD3OD): δ 7.8–7.3 (m, 13H), 5.3–5.0 (m, 2H), 3.5–3.4 (m, 2H), 3.3–3.2 (m, 2H); MF=C29H24F3N5O7S2; LCMS found for C27H24N5O5S2(M+H)+: m/z=562.
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH3:19]>CN(C=O)C>[Br:1][C:2]1[C:9]([O:10][CH2:18][CH3:19])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cccc(O)c1Br
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccc(C=O)c1Br
Temperature: 70 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
The suspension of 2-bromo-3-hydroxybenzaldehyde (120 g, 0.60 mol), K2CO3 (247 g, 1.79 mol) and bromoethane (135 mL, 1.79 mol) in DMF (700 mL) was stirred at 70° C. for 3 h. After the reaction was quenched with water (50 mL), the resulting mixture was extracted with EtOAc (3×60 mL). The combined organic layers were washed with water (50 mL) and aqueous LiCl solution (50 mL), dried over anhydrous Na2SO4 and concentrated to dryness in vacuo. The residue was purified by column chromatography on silica gel to give the target compound (128 g, yield 94%). 1H NMR (400 MHz, DMSO-d6 δ 10.45 (s, 1H), 7.52-7.50 (d, 1H), 7.38-7.34 (t, 1H), 7.13-7.10 (d, 1H), 4.18-4.13 (m, 2H), 1.53-1.50 (m, 3H).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.C(Cl)Cl.C(N(CC)CC)C.[CH2:32]([O:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([N:43]=[C:44]=[O:45])=[CH:39][CH:38]=1)=[O:36])[CH3:33]>O1CCCC1>[ClH:21].[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][NH:4][C:44]([NH:43][C:40]3[CH:39]=[CH:38][C:37]([C:35]([O:34][CH2:32][CH3:33])=[O:36])=[CH:42][CH:41]=3)=[O:45])[CH2:9][CH2:10]2)=[CH:20][CH:19]=1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NC(=O)NCCCN2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Yield: 62.8 %

Procedure:
The procedure described in Example 3 was followed, using 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (7.54 g; 20 mmole), methylene chloride (50 ml), tetrahydrofuran (50 ml), triethylamine (8.4 ml; 60 mmole) and 4-ethoxycarbonylphenyl isocyanate (3.8 g; 20 mmole). Recrystallization from methanol provided the title compound (3.11 g; 34% yield) as colorless crystals, m.p. 233°-234° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([CH3:17])[S:8][C:6]=2[N:7]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>ClCCl.C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][N:21]([C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)=[O:34])[CH2:22][CH2:23]2)[C:5]2[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:9]([CH3:17])[S:8][C:6]=2[N:7]=1
Reactant: Cc1sc2nc(N)nc(N3CCNCC3)c2c1-c1ccccc1
Reactant: COc1ccc(N=C=O)cc1
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc(NC(=O)N2CCN(c3nc(N)nc4sc(C)c(-c5ccccc5)c34)CC2)cc1
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To a solution of Example 11 (50 mg, 0.16 mmol) in dichloromethane (2 mL) and acetonitrile (1 mL) was added 4-methoxyphenyl isocyanate (22 μL, 0.17 mmol). The reaction mixture was stirred overnight. The reaction mixture was evaporated in vacuo and the crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 1% to 2% methanol in dichloromethane), yielding the title compound (49 mg) as a white powder. 13C NMR δ (75 MHz, acetone-d6) 169.83, 161.99, 159.36, 155.05, 154.65, 135.58, 133.58, 130.55, 130.10 (2C), 127.84 (2C), 127.00, 126.13, 121.29 (2C), 113.26 (2C), 110.65, 64.94, 54.72 (2C), 49.33 (2C), 13.54. MS (m/z) 475 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:11]=1)[C:5]([O:7]C)=[O:6].[Br-].[CH:17]1([Zn+])[CH2:19][CH2:18]1.CN1CCN(C)C1=O.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH:17]1([C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:11]=2)[C:5]([OH:7])=[O:6])[CH2:19][CH2:18]1
Reactant: COC(=O)c1cc(Cl)cc(S(C)(=O)=O)c1
Reactant: [Zn+]C1CC1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN1CCN(C)C1=O
Product: CS(=O)(=O)c1cc(C(=O)O)cc(C2CC2)c1
Reaction time: 22 h

Procedure:
To a solution of methyl 3-chloro-5-(methylsulfonyl)benzoate (1.32 g, 5.31 mmol) in THF (15 mL) were added PEPPSI-IPr (72.1 mg, 106 μmol, CAS RN 905459-27-0), cyclopropylzinc(II) bromide (0.5 M solution in THF, 25.5 mL, 12.7 mmol) and 1,3-dimethyl-2-imidazolidinone (3 mL) and the reaction mixture was heated to reflux for 22 hours before another batch of cyclopropylzinc(II) bromide (0.5 M solution in THF, 12.7 mL, 6.37 mmol) was added. Stirring at reflux was continued for 22 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed once with saturated aqueous NaHCO3 solution. The pH of the aqueous phase was adjusted to 1, saturated with solid sodium chloride and extracted three times with EtOAc. The organic layers were dried over MgSO4, filtered and evaporated. The product was purified by preparative SFC (Waters Viridis SFC 2-Ethylpyridine column) using an isocratic mixture of MeOH:carbondioxide (40:60). Light brown solid (0.119 g; 9%). MS (ESI): m/z=239.0 [M+H]+.
Reaction SMILES: [ClH:1].[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[S:7]([O-:9])=[O:8].[Li+].ClCl>O>[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[S:7]([Cl:1])(=[O:9])=[O:8]
Reactant: Cl
Reactant: O=S([O-])c1ccco1
Agent: ClCl
Agent: [Li+]
Solvent: O
Product: O=S(=O)(Cl)c1ccco1
Reaction time: 0.5 h

Procedure:
Ninety ml of water, 410 ml of conc. HCl, and 68.0 g of lithium 2-furansulfinate were stirred and cooled to 10°-15°. Liquid chlorine (12.3 ml, 39.4 g) was added dropwise over a 30-minute period. The mixture was stirred an additional 30 minutes at 5°, poured onto ice and extracted with methylene chloride. Evaporation of the methylene chloride yielded 44 g 2-furansulfonyl chloride, b.p. 95° at 7 mm Hg;
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.[NH:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[NH2:20]>ClC(Cl)(Cl)C(O)=O.C1(C)C=CC=CC=1>[CH:16]1[CH:17]=[CH:18][C:10]([OH:9])=[C:11]([C:12]2[N:13]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[N:20]=2)[CH:15]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Temperature: 110 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A suspension of 0.7 g (2.92 mmol) of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 5 g of trichloroacetic acid and 5 ml of toluene is heated to 110° C. The mixture is maintained and stirred at this temperature for 3 hours. After completion of the reaction, the mixture is cooled and poured onto crushed ice. The resulting crystals are aspirated and washed with water and ethyl acetate. After drying, 0.6 g of raw deferasirox is obtained, i.e. 55% of the theory, with an HPLC content of 99.56% and a melting temperature of 258 to 262° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17](NC(=O)C)=[CH:16][CH:15]=1.[NH2:24][C@H:25]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].[B-](F)(F)(F)F.C[CH2:47][O:48]C(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.FC(F)(F)C([O-])=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[C:18]([CH:17]=[CH:16][CH:15]=1)[C:47]([NH:24][C@@H:25]([CH2:26][C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:48]
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(=O)Nc1ccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)cc1
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])C(F)(F)F
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2)C1

Procedure:
300 mg (0.9 mmol) of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzoic acid (Example 14, intermediate 5) were reacted in a similar manner to the method described in Example 14 with 304 mg (1.0 mmol) of di-tert-butyl aspartate in a TOTU-mediated coupling reaction to obtain 170 mg of the title compound as the trifluoroacetate after purification on a preparative HPLC.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[CH:9][C:8](C#CC3C=CC(C(OCC)=O)=CC=3)=[CH:7][C:6]=2[C:5]([C:25]#[C:26][CH2:27][CH2:28][CH3:29])=[CH:4][CH2:3]1.FC(F)(F)S(OC1C2C=CC([C:49]#[C:50][C:51]3[CH:61]=[CH:60][C:54]([C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:53][CH:52]=3)=CC=2C(C)(C)CC=1)(=O)=O>>[CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[C:9]([C:49]#[C:50][C:51]3[CH:61]=[CH:60][C:54]([C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:53][CH:52]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:25]#[C:26][CH2:27][CH2:28][CH3:29])=[CH:4][CH2:3]1
Reactant: CCCC#CC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc21
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3OS(=O)(=O)C(F)(F)F)cc1
Product: CCCC#CC1=CCC(C)(C)c2cc(C#Cc3ccc(C(=O)OCC)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl]benzoate (Compound 75), 200 mg (0.42 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 87) was converted into the title compound (pale yellow oil) using 286 mg (4.2 mmol) of pentyne, 60 mg (0.08 mmol) of bis(triphenylphosphine)palladium (II) chloride and 20 mg (0.11 mmol) of cuprous iodide.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([O-:13])(=[O:12])[CH3:11].[NH4+:14].C(O)(=O)CC(O)=O>C(O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([CH2:11][C:10]([OH:13])=[O:12])[NH2:14])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: [NH4+]
Reactant: CC(=O)[O-]
Agent: O=C(O)CC(=O)O
Solvent: CCO
Product: NC(CC(=O)O)c1ccc(Br)cc1
Temperature: 70 °C
Yield: 34.2 %

Procedure:
4-Bromobenzaldehyde (10 g, 54 mmol), ammonium acetate (8.663 g, 112.4 mmol) and malonic acid (5.6762 g, 54.5 mmol) were refluxed (slow) in absolute ethanol (45 mL) for 150 hours. White solid was filtered and dissolved into a warm (70° C.) solution of 50 mL of Na2CO3 and 50 mL of H2O. This solution was then extracted with 100 mL of diethyl ether three times. The aqueous layer was further acidified to pH 7 to produce white solid β-4-bromophenyl-β-alanine (4.5140 g, 18.49 mmol, 34.2%); MP: 234° C.; IR (KBr): 3061, 1594 cm−1; TLC: RF=0.35 (solvent 24), 0.32 (solvent 25); 1H NMR (D2O/K2CO3): δ 7.42-7.38 (m, 2H), 7.17-7.14 (m, 2H), 4.11-4.07 (t, J=7.25 Hz, 1H), 2.48-2.36 (m, 2H). Anal. Calcd for C9H10BrNO2: C, 44.29; H, 4.13; N, 5.74. Found: C, 44.35; H, 3.93; N, 5.70.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:18]=[C:17]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[C:23](Cl)=[C:22]3[C:30]#[N:31])[C:16]([CH2:32][CH3:33])=[C:15]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:18]=[C:17]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[C:23]([N:48]2[CH2:52][CH2:51][CH2:50][CH2:49]2)=[C:22]3[C:30]#[N:31])[C:16]([CH2:32][CH3:33])=[C:15]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: CCc1c(-c2ccc3c(c2)c(C#N)c(Cl)n3C)nc(OCc2ccccc2)c(C(=O)OC)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1c(-c2ccc3c(c2)c(C#N)c(N2CCCC2)n3C)nc(OCc2ccccc2)c(C(=O)OC)c1OCc1ccccc1
Temperature: 60 °C
Yield: 89.2 %

Procedure:
To a solution of methyl 2,4-bis(benzyloxy)-6-(2-chloro-3-cyano-1-methyl-1H-indol-5-yl)-5-ethylnicotinate (143 mg, 0.25 mmol) in DMF (2 mL) was added potassium carbonate (70 mg, 0.50 mmol, 2.0 eq) followed by pyrrolidine (0.05 mL, 0.61 mmol, 2.4 eq) at room temperature. The reaction was heated to 60° C. and the progress was monitored by LC-MS. Upon completion, the reaction was quenched with water then extracted with EtOAc (3×25 mL). The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (0-10% EtOAc in 1/1 CH2Cl2/hexanes) to afford the title compound (134 mg, 89%).
Reaction SMILES: [CH3:1][O:2][C@@H:3]([CH3:6])[CH2:4][OH:5].[CH3:7]CN(CC)CC.[C:14]1(C)[C:15]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=1>C(Cl)Cl>[CH3:7][C:18]1[CH:19]=[CH:14][C:15]([S:20]([O:5][CH2:4][C@@H:3]([O:2][CH3:1])[CH3:6])(=[O:21])=[O:22])=[CH:16][CH:17]=1
Reactant: CCN(CC)CC
Reactant: CO[C@@H](C)CO
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Product: CO[C@@H](C)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a stirred solution of (S)-2-methoxypropan-1-ol (1.00 g, 11.1 mmol) in DCM (50 mL) was added Et3N (2.33 mL, 16.6 mmol). A solution of toluene sulfonyl chloride (2.54 g, 13.3 mmol) in DCM (20 mL) was added dropwise at 0° C. under nitrogen. The reaction mixture was allowed to warm to ambient temperature and was stirred overnight. The reaction was diluted with DCM, washed with saturated aqueous NaHCO3 and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (hexanes:EtOAc, 10:1 to 4:1) to give (S)-2-methoxypropyl 4-methylbenzenesulfonate (2.03 g, 75%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:16][CH:17]1[CH2:19][CH2:18]1>CN(C=O)C.C(OCC)(=O)C>[CH:17]1([CH2:16][O:8][C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][N:6]=2)[CH2:19][CH2:18]1
Reactant: BrCC1CC1
Reactant: Oc1ccc(I)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Ic1ccc(OCC2CC2)nc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 32.9 %

Procedure:
To a solution of 5-iodopyridin-2-ol (5.32 g, 24.0 mmol) in DMF (50 mL) were added cesium carbonate (23.4 g, 72.0 mmol) and (bromomethyl)cyclopropane (4.67 mL, 48.2 mmol), and the mixture was stirred at 60° C. for 15 min. The reaction mixture was diluted with ethyl acetate, and the mixture was washed three times with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 1:4) to give the title compound (2.17 g, yield 32%) as an oil.
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1.[I:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19]>CCOCC>[I-:12].[C:18]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][N+:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1)(=[O:20])[CH3:19]
Reactant: Cc1ccnc2ccccc12
Reactant: CC(=O)OCCCCI
Solvent: CCOCC
Product: CC(=O)OCCCC[n+]1ccc(C)c2ccccc21
Product: [I-]

Procedure:
10 mmol (1.43 g) lepidine and 10 mmol (2.42 g) 4-iodobutylacetate are heated 4 h at 120° C. and after cooling repeatedly stirred with ether, decanted a finally dried in vacuum.