Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1COCC1.Br[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Fc1ccc(Br)nc1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(-c2ccc(F)cn2)c(Cl)cc1Cl
Yield: 67 %

Procedure:
To the solution of methyl 2,4-dichloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate in anhydrous THF (Preparation 45, 10 mL, 1.61 g, 4.88 mmol) was added 2-bromo-5-fluoropyridine (856 mg, 4.88 mmol), sodium carbonate (1.55 g, 14.59 mmol) and water (2 mL). The reaction was degassed with nitrogen for 15 minutes followed by the addition of Pd(PPh3)4 (280 mg, 0.244 mmol) with further degassing for 5 minutes. The reaction was heated to reflux under a nitrogen atmosphere for 2 hours. The reaction was concentrated in vacuo and the residue partitioned between EtOAc (35 mL) and water (35 mL). The organic layer was dried over magnesium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 5-20% EtOAc in heptanes to afford the title compound as a white solid (1 g, 67%).
Reaction SMILES: CO[C:3]1[CH:4]=C2C(=C[CH:12]=1)C=NC(C(O)=O)=C2.C[O:17][C:18]([CH:20]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([OH:30])[CH:27]=2)[CH2:22][N:21]1C(OC(C)(C)C)=O)=[O:19]>>[CH:3]([O:30][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[CH2:22][NH:21][CH:20]([C:18]([OH:17])=[O:19])[CH2:29]2)([CH3:4])[CH3:12]
Reactant: COc1ccc2cnc(C(=O)O)cc2c1
Reactant: COC(=O)C1Cc2cc(O)ccc2CN1C(=O)OC(C)(C)C
Product: CC(C)Oc1ccc2c(c1)CC(C(=O)O)NC2
Yield: 9.1 %

Procedure:
0.2 g (9.1%, 4 steps) of the 6-isopropoxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid was prepared according to procedure described for the synthesis of 6-methoxy-isoquinoline-3-carboxylic acid (in Example 294) starting from 0.67 g (2.18 mmol) of 6-hydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester. LCMS: 232 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:4](=[C:5]([N+:18]([O-:20])=[O:19])[CH:6]=[CH:7][C:8]=2[C:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH:12]=2)[C:3]1=[O:21].[P:22]([O:29]CC)([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25].Cl.CCOCC>C(Cl)Cl>[CH2:24]([O:23][P:22]([C:14]1([OH:17])[CH2:15][CH2:16][C:11]([C:8]2[CH:7]=[CH:6][C:5]([N+:18]([O-:20])=[O:19])=[C:4]3[C:9]=2[CH2:10][N:2]([CH3:1])[C:3]3=[O:21])=[CH:12][CH2:13]1)(=[O:29])[O:26][CH2:27][CH3:28])[CH3:25]
Reactant: CCOP(OCC)OCC
Reactant: CN1Cc2c(C3=CCC(=O)CC3)ccc([N+](=O)[O-])c2C1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCOP(=O)(OCC)C1(O)CC=C(c2ccc([N+](=O)[O-])c3c2CN(C)C3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
2-methyl-7-nitro-4-(4-oxocyclohex-1-en-1-yl)-2,3-dihydro-1H-isoindol-1-one (Compound 193D) was dissolved in DCM (10 mL), then triethyl phosphite (520 mg, 3.1 mmol) and 1N HCl/Et2O (3.1 mmol, 3.1 mL) were added at 0° C. under nitrogen. The resulting mixture was slowly warmed to rt and stirred at rt overnight. The solvent was evaporated, and the residue was purified by silica gel chromatography (ISCO Combi-flash system, eluting with 0-10% MeOH/DCM) to give the title compound as a yellow solid, 470 mg, 71% yield (over two steps). 1H NMR (CDCl3): 1.39 (t, J=7.1 Hz, 6H), 2.02 (m, 1H), 2.20 (m, 1H), 2.30-2.47 (m, 2H), 2.65-2.83 (m, 2H), 3.20 (s, 3H), 4.21-4.29 (m, 4H), 4.42, 4.48 (AB, JAB=18.0 Hz, 2H), 5.86 (m, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.71 (d, J=7.3 Hz, 1H). MS (ES+): m/z=425.12 [MH+]. HPLC: tR=3.19 min (ZQ3, polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:26]=[CH:25][C:16]([O:17][CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=1.[CH:27](OCC)(OCC)OCC>>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[CH:4][C:3]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:25][CH:26]=3)[CH:27]=[N:1][C:2]=2[CH:7]=1
Reactant: CCOC(=O)C(C)Oc1ccc(Nc2ccc(C(F)(F)F)cc2N)cc1
Reactant: CCOC(OCC)OCC
Product: CCOC(=O)C(C)Oc1ccc(-n2cnc3cc(C(F)(F)F)ccc32)cc1

Procedure:
5.3 g of 1C was dissolved in 50 ml of triethyl orthoformate, the solution was refluxed for 1 hour, then concentrated under reduced pressure. The residue, an oil, was chromatographed over silica gel, using as eluent a 2:15:33 v/v/v mixture of tetrahydrofuran, ethyl acetate and hexane (hereinafter, Solvent A), to give 1, as a viscous liquid.
Reaction SMILES: [C:1]1([OH:8])(O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:12]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[C:24]([CH3:31])[CH:23]=2)[CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2>CC(N(C)C)=O.ClCCl>[OH:8][C@H:1]1[CH2:2][CH2:3][C@H:4]([C:12]2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[C:24]([CH3:31])[CH:23]=3)[CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[N:17]3)[CH2:5][CH2:6]1
Reactant: OC1(O)CCCCC1
Reactant: Cc1cc(-c2cc3ncccc3c(Cl)n2)ccc1N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: Cc1cc(-c2cc3ncccc3c([C@H]3CC[C@H](O)CC3)n2)ccc1N(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
200 mg (1.7 mmol) cyclohexanediol was placed in 1.5 ml dimethylacetamide and 47 mg (1.17 mmol) sodium hydride (60%) were added and the mixture was stirred for 15 min at ambient temperature. Then 100 mg (0.31 mmol) 6.1 was added and the mixture was stirred for 2 h at 70° C. The reaction mixture was diluted with dichloromethane and extracted 1× with water. The organic phase was dried with MgSO4 and evaporated down. The residue was purified by chromatography (RP-HPLC-MS). The corresponding fractions were freeze-dried.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH2:22][CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)=[C:19]([O:36][CH3:37])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH2:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[C:19]([O:36][CH3:37])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1CCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ncccc13)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2c(c1CCC1CCNCC1)O/C(=C\c1n[nH]c3ncccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A solution of tert-butyl (Z)-4-(2-{2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}ethyl)piperidine-1-carboxylate (0.0652 g, 0.129 mmol) in methylene chloride (5 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and then added with saturated aqueous sodium hydrogencarbonate, and the precipitated solid was collected by filtration. The solid was washed with water, and then dried under reduced pressure to obtain (Z)-2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-6-methoxy-7-[2-(piperidin-4-yl)ethyl]benzofuran-3(2H)-one (0.0402 g, 77%).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[CH3:16][C:17]([CH3:24])=[CH:18][CH2:19][CH2:20][CH:21]1[CH2:23][O:22]1.Cl>CC(OC)(C)C>[CH3:16][C:17]1([CH3:24])[CH:18]2[CH:19]1[CH2:20][CH2:21][CH:23]2[OH:22]
Reactant: CC(C)=CCCC1CO1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Product: CC1(C)C2CCC(O)C21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2,2,6,6-Tetramethylpiperidine (9.70 g, 69 mmol) was taken up in MTBE (100 mL) and chilled to −78° C. n-Butyllithium (43 mL, 1.6 M in n-hexane, 69 mmol) was added cautiously and the resulting solution allowed to stir at −78° C. for 30 minutes. The pale yellow solution was added via cannular transfer to a chilled (0° C.) solution of 2-(4-methyl-pent-3-enyl)-oxirane (4.33 g, 34.3 mmol) in MTBE (30 mL) over 30 minutes, allowed to warm slowly to room temperature and stirred under argon for 18 hours. The solution was then added to 1M aqueous hydrochloric acid (50 mL) and extracted into further MTBE (200 mL). Solvent was removed under reduced pressure and the resulting oil purified by column chromatography (0–40% EtOAc/n-hexane, silica). (±)-6,6-Dimethyl-bicyclo[3.1.0]hexan-2-ol was obtained as a yellow oil. 1H NMR (CDCl3): δ 4.15–4.10 (m, 1H), 2.10–2.00 (m, 1H), 1.90–1.80 (m, 1H), 1.80–1.70 (m, 1H), 1.62 (br s, OH), 1.56 (ddd, 1H, J1=12.9, J2=9.5, J3=2.9), 1.48 (br s, 1H), 1.14 (dd, 1H, J1=6.3, J2=1.2), 0.99 (s, 3H), 0.93 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][NH2:12])[CH2:6][CH2:5]1.[CH2:13]1[NH:15][CH2:14]1.[Cl-].[NH4+]>>[NH2:15][CH2:14][CH2:13][NH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][NH2:12])[CH2:6][CH2:5]1
Reactant: C1CN1
Reactant: NCCC1CCC(CCN)CC1
Agent: [Cl-]
Agent: [NH4+]
Product: NCCNCCC1CCC(CCN)CC1

Procedure:
1,4-Bis(2-aminoethyl) cyclohexane (68 g,m., 0.4 mole) and ethyleneimine (4.3 gm., 0.1 mole) with 0.4 g. ammonium chloride are mixed in a glasslined pressure reactor and filled with nitrogen to 100 psi. The mixture is shaken and heated at 85° C.-95° C. for 48 hours. After cooling, it is distilled rapidly free of the salt and then fractionated under high vacuum. The starting diamine is readily distinguished from the triamine product by thin layer chromatography and silica gel using a mixture of 1 volume concentrated aqueous ammonium hydroxide with 4 volume methyl alcohol, the diamine having a much higher Rf.
Reaction SMILES: FC1C(F)=C(F)C(F)=C(F)C=1[C:12]1[N:13]([CH3:31])[C:14](=[O:30])[CH:15]=[C:16]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])[C:17]=1[C:18]([O-:20])=O.CCN(C(C)C)C(C)C.[NH2:41][CH2:42][CH2:43][OH:44]>C1COCC1>[F:29][C:23]1[CH:24]=[C:25]([I:28])[CH:26]=[CH:27][C:22]=1[NH:21][C:16]1[C:17]([C:18]([NH:41][CH2:42][CH2:43][OH:44])=[O:20])=[CH:12][N:13]([CH3:31])[C:14](=[O:30])[CH:15]=1
Reactant: NCCO
Reactant: Cn1c(-c2c(F)c(F)c(F)c(F)c2F)c(C(=O)[O-])c(Nc2ccc(I)cc2F)cc1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1cc(C(=O)NCCO)c(Nc2ccc(I)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
2,3,4,5,6-Pentafluorophenyl-4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate (600 mg, 1.08 mmol) was dissolved in THF (15 mL) to which was added DIEA (697 mg, 5.40 mmol), followed by 2-aminoethanol (132 mg, 2.17 mmol). This mixture was stirred at R.T. for 2 h., then the reaction solvent removed under reduced pressure and the resulting white solid suspended in Et2O. The solid was collected by filtration, then recrystallised from EtOAc/MeOH to give 4-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (394 mg, 85%) as a white solid, m.p. (EtOAc/MeOH) 205-208° C. 1H NMR [(CD3)2SO, 400 MHz] δ 10.10 (s, 1H), 8.43 (br s, 1H), 8.28 (s, 1H), 7.72 (dd, J=10.2, 1.8 Hz, 1H), 7.56 (br d, J=8.5 Hz, 1H), 7.28 (t, J=8.5 Hz, 1H), 5.58 (s, 1H), 4.76 (br t, J=5.2 Hz, 1H), 3.50 (q, J=5.8 Hz, 2H), 3.36 (s, 3H), 3.32-3.26 (m, 2H). Anal. Calcd for C15H15FIN3O3: C, 41.8; H, 3.5; N, 9.8. Found: C, 4.19; H, 3.2; N, 9.7.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][C:5]([O:10][CH2:11][CH2:12][O:13][CH:14]([CH3:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8].[B:18]1([OH:28])[C:22]2[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][C:21]=2[CH2:20][O:19]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[Cl:1][C:2]1[C:3]([O:27][C:25]2[CH:24]=[CH:23][C:22]3[B:18]([OH:28])[O:19][CH2:20][C:21]=3[CH:26]=2)=[N:4][C:5]([O:10][CH2:11][CH2:12][O:13][CH:14]([CH3:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: OB1OCc2cc(O)ccc21
Reactant: CC(C)OCCOc1nc(Cl)c(Cl)cc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)OCCOc1nc(Oc2ccc3c(c2)COB3O)c(Cl)cc1C#N
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen were placed a solution of 5,6-dichloro-2-(2-isopropoxyethoxy)nicotinonitrile (1.13 g, 4.12 mmol, 1.00 equiv) in DMSO (80 mL), benzo[c][1,2]oxaborole-1,5(3H)-diol (650 mg, 4.33 mmol, 1.00 equiv) and Cs2CO3 (1.6 g, 4.91 mmol, 1.20 equiv). The resulting mixture was stirred for 2 h at 40° C., then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate. The organic layers were combined, washed with 2×50 mL of water, then dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 5-chloro-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-2-(2-isopropoxyethoxy)nicotinonitrile (1.3 g, 80%) as a white solid. LC-MS (ES, m/z): 389 [M+H]+. 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 9.260 (1H, s), 8.596 (1H, s), 7.817-7.791 (1H, d, J=7.8 Hz), 7.337 (1H, s), 7.268-7.235 (1H, m), 5.007 (2H, s), 4.105-4.072 (2H, t), 3.495-3.435 (2H, m), 3.415-3.395 (1H, t), 1.016-0.995 (6H, d, J=6.3 Hz).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][N:30]=2)=[CH:26][CH:27]=1)([OH:20])=[O:19]
Reactant: N[C@@H](Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[C:11]([C:17]([OH:19])=O)[NH:12]2.Cl.Cl.Cl.[N:23]1([CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:30][CH2:31][N:32]2[CH2:33][CH2:34][CH:35]([NH:38][C:17]([C:11]3[NH:12][C:13]4[C:9]([CH:10]=3)=[C:8]([O:7][CH2:6][C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[CH:16]=[CH:15][CH:14]=4)=[O:19])[CH2:36][CH2:37]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Reactant: O=C(O)c1cc2c(OCc3ccco3)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(OCc3ccco3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-(furan-2-ylmethoxy)-1H-indole-2-carboxylic acid 93 (preparation see below) and amine 5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:21]2[CH:22]=[N:23][C:24]([C:27](=[O:29])[CH3:28])=[N:25][CH:26]=2)=[N:6][CH:7]=1.[CH3:30][Mg]Br>C1COCC1.[NH4+].[Cl-]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:21]2[CH:22]=[N:23][C:24]([C:27]([OH:29])([CH3:30])[CH3:28])=[N:25][CH:26]=2)=[N:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1ncc(-c2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ncc(-c2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cn1
Yield: 47.4 %

Procedure:
A solution of 1-(5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyrimidin-2-yl)ethanone (Example 73) (12 mg, 0.03 mmol) in THF (5 mL) was treated with methylmagnesium bromide (0.09 mL, 0.3 mmol, 3.0 M in THF) at rt. Upon completion of the reaction as judged by TLC analysis, the solution was diluted with saturated aq NH4Cl solution and extracted with EtOAc. The organic layer was removed, dried over MgSO4, filtered and concentrated giving rise to an oil. The oil was purified on silica gel to afford the title compound (6.3 mg). LC/MS: m/e 443.0 (M+H)+. 1H NMR (500 MHz, Acetone-d6): δ 1.54 (s, 6H), 4.56 (s, 1H), 7.39 (m, 2H), 7.47 (d, J=8.5 Hz, 1H), 7.82 (m, 1H), 8.25 (m, 2H), 8.45 (d, J=2.5 Hz, 1H), 9.39 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH2:14][C:15]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(C(OCC)=O)[C:16]([O:18]CC)=[O:17])=[CH:12][N:11]=[C:10]1[S:33][CH2:34][CH2:35][CH3:36].[OH-].[K+].O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH2:14][CH:15]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:16]([OH:18])=[O:17])=[CH:12][N:11]=[C:10]1[S:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCSc1ncc(CC(Cc2ccccc2)(C(=O)OCC)C(=O)OCC)n1Cc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCSc1ncc(CC(Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl
Yield: 87.4 %

Procedure:
A mixture of diethyl [1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]methyl-2-benzyl-malonate (0.72 g, 1.36 mmol), potassium hydroxide (0.83 g, 14.7 mmol), water (15 mL) and ethanol (25 mL) was refluxed for 4 hours. The ethanol was evaporated, the residual aqueous layer was extracted with diethyl ether, and the basic solution was adjusted to pH 3.75 with concentrated hydrochloric acid. The precipitated product was extracted into methylene chloride, dried, and concentrated. This crude product was flash chromatographed on silica gel with 10% methanol in methylene chloride to give 0.51 g (86%) of 3-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]-2-benzylpropanoic acid; mp 123°-127° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:13]1([C:11]2[S:12][C:8]([CH2:7][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:9]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[N:10]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)c1nc(-c2ccccc2)sc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1nc(-c2ccccc2)sc1CN1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Pyrrolidine (0.5 ml) was added to a solution of tert-butyl 5-(bromomethyl)-2-phenylthiazole-4-carboxylate (1.029 g, 2.90 mmol) and diisopropylethylamine (DIPEA) (1.5 ml) in CH2Cl2 (10 ml). The mixture was stirred at rt for 30 min, concentrated in vacuo and purified by flash chromatography to give tert-butyl 2-phenyl-5-(pyrrolidin-1-ylmethyl)thiazole-4-carboxylate as a yellow solid (920 mg, 98% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]([NH:14]C(=O)C)[CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7])[CH3:2].Cl>[OH-].[Na+]>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOc1cc(NC(C)=O)ccc1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(N)ccc1C(=O)O
Temperature: 25 °C
Yield: 100.2 %

Procedure:
A suspension of methyl 2-ethoxy-4-acetamidobenzoate (50 g, 211 mmol) in aqueous solution of NaOH (15% W/W, 200 ml) was gently refluxed for 16 hours. The resulting pale brown solution was allowed to cool to room temperature and then further cooled in an ice water bath. Concentrated HCl (37% w/w) was added until the solution reached a pH of 6. The solid precipitated from the solution was filtered under vacuum, dried at 50° C. to give 38.3 g of the title compound (yield 100%).
Reaction SMILES: [CH3:1][C@@H:2]1[O:6][C:5](=[O:7])[CH:4]=[CH:3]1.[CH:8]1[O:9][CH:10]=[C:11]2[C:16]=1[CH2:15][CH2:14][CH2:13][CH2:12]2.C(Cl)Cl>CCOCC.Cl([O-])(=O)(=O)=O.[Li+]>[O:9]1[C@@H:10]2[C@H:4]3[C@H:3]([C@H:8]1[C:16]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=12)[C@H:2]([CH3:1])[O:6][C:5]3=[O:7]
Reactant: C[C@H]1C=CC(=O)O1
Reactant: c1occ2c1CCCC2
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@H]1OC(=O)[C@@H]2[C@@H]1[C@@H]1O[C@H]2C2=C1CCCC2
Temperature: 25 °C
Reaction time: 168 h
Yield: 58.2 %

Procedure:
To 224.0 mg(2.28 mmol) of (S)-5-methyl-2(5H)-furanone were added 557.9 mg(1.5 equivalents) of 4,5,6,7-tetrahydroisobenzofuran in 2 ml of dehydrated ether solution and 1.06 g of lithium perchlorate, and, after flushing with argon, the mixture was stirred for 168 hours at room temperature. The reaction mixture was poured into 20 ml of water, which was extracted with methylene chloride(10 ml×3). The organic layer was dried over anhydrous magnesium sulfate, filtered and solvent was distilled off under reduced pressure. The residue was purified by means of silica gel column chromatography(methylene chloride, then methylene chloride:ethyl acetete=10:1) to obtain 292.2 mg of (3S, 3aS, 4S, 9R, 9aR)-4,9-epoxy-3-methyl-3a,4,5,6,7,8,9,9a-octahydronaphtho[2,3-c]furan-1(3H)-one (yield 58%).
Reaction SMILES: O/[C:2](=[C:8]1/[CH2:9][O:10][CH2:11][CH2:12][C:13]/1=O)/[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.[NH2:16][NH2:17]>CO>[N:16]1[NH:17][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]2[CH2:9][O:10][CH2:11][CH2:12][C:13]=12
Reactant: CCOC(=O)/C(O)=C1\COCCC1=O
Reactant: NN
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1[nH]nc2c1COCC2
Temperature: 25 °C

Procedure:
(Z)-ethyl 2-hydroxy-2-(4-oxo-2H-pyran-3(4H, 5H, 6H)-ylidene)acetate (2.5 g, 12.49 mmol) was dissolved in methanol (10 ml). Hydrazine hydrochloride (2.57 g, 37.5 mmol) was added and the resulting mixture was refluxed for one hour. The mixture was allowed to warm to RT and the solvent was evaporated. The residue was dissolved in DCM and extracted twice with water. The organic layer was dried with Na2SO4, filtered and evaporated. The product was purified with flash chromatography. 1H-NMR (400 MHz; d6-DMSO): δ 1.27 (d, 3H), 2.70 (t, 2H), 3.81 (t, 2H), 4.24 (q, 2H), 4.69 (s, 2H), 13.40 (bs, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[C:9]1([S:15]([NH2:18])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:18][S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])[CH:2]=1
Reactant: O=Cc1cccnc1
Reactant: NS(=O)(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=S(=O)(N=Cc1cccnc1)c1ccccc1
Temperature: 40 °C

Procedure:
A stirred mixture consisting of 4.00 g (37 mmol) of 3-pyridinecarboxaldehyde, 5.88 g (37 mmol) of benzenesulfonamide and 20 mg of p-toluenesulfonic acid monohydrate in 120 mL of toluene was heated to reflux under a blanket of nitrogen. The reaction vessel was equipped with a Soxhlet extractor containing 4A molecular sieves. After heating 18 hours, the mixture was allowed to cool to approximately 40° C. and was filtered to remove colored impurities. Addition of hexane to the filtrate led to precipitation of a white solid. Filtration provided 9.10 g (73%) of sulfonimine: mp 123° C.; IR (Nujol) 1640, 1605, 1585, 1560, 1300, 1280, 1220, 860 cm-1 ; 1H NMR (CDCl3, TMS, 60 MHz) δ9.15 (s, 1), 8.9-8.7 (m, 2), 8.4-7.4 (m, 7).