Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[C:8]1([NH:14][NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O=[C:17]([C:24]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=1[F:32])[CH2:18][C:19](OCC)=[O:20]>CCO>[C:8]1([N:14]2[C:19](=[O:20])[CH2:18][C:17]([C:24]3[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=3[F:32])=[N:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1CC(c2cc(F)c(F)cc2F)=NN1c1ccccc1
Temperature: 70 °C

Procedure:
Potassium carbonate (153 mg, 1.10 mmol) was added to a stirred mixture of phenyl hydrazine HCl salt (160 mg, 1.10 mmol) and ethyl 3-oxo-3-(2,4,5-trifluorophenyl)propanoate (272 mg, 1.10 mmol) in EtOH (6 mL) and the mixture was heated at 70° C. for 1 hour. The solution was cooled to room temperature and was concentrated to give the title compound, which was taken on to the next step.
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].C([Li])CCC.[C:14](Cl)(=[O:18])/[CH:15]=[CH:16]/[CH3:17].C([O-])(O)=O.[Na+]>O1CCCC1>[C:14]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])(=[O:18])/[CH:15]=[CH:16]/[CH3:17]
Reactant: CC(C)(C)OC(N)=O
Reactant: C/C=C/C(=O)Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: C/C=C/C(=O)NC(=O)OC(C)(C)C
Temperature: -78 °C
Yield: 27.9 %

Procedure:
1,1-Dimethylethyl carbamate (5 g, 42.7 mmol) was dissolved in tetrahydrofuran (THF) (100 mL) in a 500 mL 3 necks round bottom flask and cooled at −78° C. under nitrogen. n-Butyl lithium (1.6 M in THF, 26.7 mL, 42.7 mmol) and (2E)-2-butenoyl chloride (4.55 mL, 42.7 mmol) were added in slow successive additions as follow: 1) n-Butyl lithium: 13.4 mL and (2E)-2-butenoyl chloride 2.28 mL; 2) n-Butyl lithium:6.8 mL and (2E)-2-butenoyl chloride 1.14 mL; 3) n-Butyl lithium:3.34 mL and (2E)-2-butenoyl chloride 0.57 mL; 4) n-Butyl lithium: 1.67 mL and (2E)-2-butenoyl chloride 0.28 mL (2×). A five to ten minutes waiting time was observed between each double addition, and the final mixture was stirred for an extra 30 minutes period at −78° C. The temperature was kept below −60° C. during the additions. The reaction mixture was then slowly poured into a stirred saturated NaHCO3 aqueous solution (250 mL). The aqueous layer was extracted with AcOEt (2×250 mL). The combined organic phases were washed with brine (150 mL), dried over MgSO4 and concentrated in vacuovacuo. Purification of the residue by flash chromatography on silica gel (gradient:50 to 100% AcOEt in Hexanes) gave 1,1-dimethylethyl (2E)-2-butenoylcarbamate (2.21 g, 11.93 mmol, 28%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:9]1[N:14]=[C:13]2[N:15]([Si](C(C)C)(C(C)C)C(C)C)[CH:16]=[CH:17][C:12]2=[CH:11][CH:10]=1.[Br-].C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:2]1([NH:1][C:9]2[N:14]=[C:13]3[NH:15][CH:16]=[CH:17][C:12]3=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(Br)nc21
Reactant: Nc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccc3cc[nH]c3n2)cc1

Procedure:
A 1 dram vial was charged with aniline (2-3 equiv), and 0.200 mL of the 588 stock solution of bromide in toluene was added. A catalyst stock solution containing 3 mmol Pd(OAc)2, 3 mmol biphenyl-2-yl-di-tert-butyl-phosphane and 15 mL of toluene was prepared and 0.050 mL of the catalyst solution was added to the reaction. An excess of NaOtBu was added as a solid to the reaction. The vial was placed in an 80° C. oven for 60 minutes (shaken several times over the hour). After cooling, the reaction was neutralized with 0.100 mL of TPA. After 30 minutes the sample was evaporated and resolvated in 0.300 mL of DMSO. The desired compound was isolated by preparative HPLC/MS. MS(ESI) [M+H+]+=210.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[C:15]([F:18])[CH:14]=[CH:13][CH:12]=3)[C:5]([OH:8])=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30].CC(=O)OCC>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[F:33][C:32]([F:35])([F:34])[S:29]([O:8][C:5]1[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[C:15]([F:18])[CH:14]=[CH:13][CH:12]=3)=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)(=[O:30])=[O:28]
Reactant: Oc1ncc(Br)cc1-c1cc2c(F)cccc2[nH]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(Oc1ncc(Br)cc1-c1cc2c(F)cccc2[nH]1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.8 %

Procedure:
To a mixture of 5-bromo-3-(4-fluoro-1H-indol-2-yl)pyridin-2-ol (1.0 g, 3.26 mmol), DIPEA (1.26 g, 9.77 mmol) and DMAP (80 mg, 0.65 mmol) in 15 mL of DCM was added Tf2O (1.84 g, 6.51 mmol) at 0 dropwise. After stirring at room temperature for 3 hours, the mixture was suspended in water and extracted with DCM. Then the combined organic phase was washed with brine, dried over sodium sulfate and concentrated. After column chromatography (PE:EA=20:1), 5-bromo-3-(4-fluoro-1H-indol-2-yl)pyridin-2-yl trifluoromethanesulfonate (1.0 g, yield: 52%) was obtained. 1H-NMR (DMSO-d6, 400 MHz) δ 12.28 (s, 1H), 8.81 (s, 1H), 8.60 (s, 1H), 7.32 (d, J=8.40 Hz, 1H), 7.18˜7.22 (m, 1H), 7.05 (s, 1H), 6.84˜6.87 (m, 1H). MS (M+H)+: 439/441.
Reaction SMILES: [H-].[Na+].[I-].C[S+](C)(C)=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2([O:21][CH3:22])[CH2:20][CH2:19]2)=[O:17])=[CH:12][CH:11]=1.[C:23](OCC)(=O)C>CS(C)=O>[CH3:22][O:21][C:18]1([C:16]2([C:13]3[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=3)[CH2:23][O:17]2)[CH2:20][CH2:19]1
Reactant: COC1(C(=O)c2ccc(Cl)cc2)CC1
Reactant: CCOC(C)=O
Agent: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Product: COC1(C2(c3ccc(Cl)cc3)CO2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A suspension of 0.82 g (0.0342 mol) of sodium hydride, 7.5 g (0.0342 mol) of trimethylsulphoxonium iodide and 50 ml of dimethyl sulphoxide is initially stirred at room temperature for 30 minutes and then a solution of 6.0 g (0.0285 mol) of 1-methoxy-cyclopropyl 4-chlorophenyl ketone in 10 ml of dimethyl sulphoxide is added at 10° C. After addition is complete, the mixture is warmed to room temperature and stirred for a further 3 hours. 10 ml of ethyl acetate are then added to the reaction mixture and it is stirred for a further 5 minutes. The reaction mixture is poured into ice-water, the resulting mixture is extracted three times with cyclohexane, and the combined organic phases are dried over sodium sulphate and concentrated by stripping off the solvent under reduced pressure. 5.4 g (84% of theory) of 2-(1-methoxy-cyclopropyl)-2-(4-chlorophenyl)-oxirane are obtained in this manner and reacted further without additional purification. ##STR38##
Reaction SMILES: ClC1C=CC(B(O)O)=CC=1.BrC1N=CNC=1.Br[C:18]1[N:19]=[CH:20][N:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:22]=1.[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1B(O)O>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([N:21]2[CH:22]=[C:18]([C:31]3[O:30][CH:34]=[CH:33][CH:32]=3)[N:19]=[CH:20]2)=[CH:24][CH:25]=1
Reactant: Clc1ccc(-n2cnc(Br)c2)cc1
Reactant: OB(O)c1ccco1
Agent: Brc1c[nH]cn1
Agent: OB(O)c1ccc(Cl)cc1
Product: Clc1ccc(-n2cnc(-c3ccco3)c2)cc1
Yield: 12 %

Procedure:
The procedure described above for Formula Ic-iii in Example 16 was followed, starting from 4-chloro-phenylboronic acid and 4-bromo-1H-imidazole, to prepare 4-bromo-1-(4-chlorophenyl)-1H-imidazole, which was then reacted with furan-2-ylboronic acid to prepare the desired 1-(4-chlorophenyl)-4-(furan-2-yl)-1H-imidazole (15 mg, 0.061 mmol, yield 12%) as an off-white solid. The HPLC purity of the final product was 95.45%. LC-MS [M+H] 245 (C13H9ClN2O+H expected 245.04). The 1H-NMR spectra was in accordance with the chemical structure.
Reaction SMILES: Cl.O1CCOCC1.[C:8]([NH:11][CH2:12][CH2:13][CH:14]([NH:22][C:23]([C:25]1([NH:40]C(=O)OC(C)(C)C)[CH2:30][CH2:29][N:28]([C:31]2[C:32]3[CH:39]=[CH:38][NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH2:27][CH2:26]1)=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)(=[O:10])[CH3:9]>C(Cl)Cl>[C:8]([NH:11][CH2:12][CH2:13][CH:14]([NH:22][C:23]([C:25]1([NH2:40])[CH2:30][CH2:29][N:28]([C:31]2[C:32]3[CH:39]=[CH:38][NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH2:27][CH2:26]1)=[O:24])[C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)NCCC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)NCCC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 70 h
Yield: 18.8 %

Procedure:
Hydrogen chloride (4M) in 1,4-Dioxane (0.430 mL, 1.72 mmol) was added to tert-butyl 4-(3-acetamido-1-(4-chlorophenyl)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 28) (98 mg, 0.17 mmol) in DCM (4 mL) at 20° C. The resulting suspension was stirred at 20° C. for 70 hours. The reaction mixture was evaporated to dryness. The crude product was purified by preparative HPLC (Waters XTerra C18 column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N-(3-acetamido-1-(4-chlorophenyl)propyl)-4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (15.00 mg, 18.5%) as a white dry film. 1H NMR (399.9 MHz, DMSO-d6) δ 1.42-1.47 (2H, m), 1.79 (3H, s), 1.85 (1H, t), 1.89-1.93 (1H, m), 2.10 (2H, s), 3.00 (2H, t), 3.55 (2H, d), 4.36-4.40 (2H, m), 4.80 (1H, d), 6.58-6.60 (1H, m), 7.16 (1H, t), 7.34-7.39 (4H, m), 7.80 (1H, t), 8.13 (1H, s), 8.39 (1H, s), 11.64 (1H, s) No visible NH2. m/z (ESI+) (M+H)+=470; HPLC tR=1.56 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([OH:12])=O.[CH:13]([NH:16][NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:15])[CH3:14].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([N:16]([CH:13]([CH3:15])[CH3:14])[NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:12]
Reactant: O=C(O)CSc1ccccc1Br
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CSc1ccccc1Br

Procedure:
A solution of (2-bromo-phenylsulfanyl)-acetic acid (694 mg, 2.81 mmol) and benzoic acid N′-isopropyl-hydrazide (500 mg, 2.81 mmol) in DMF (10 mL) was treated with triethylamine (1.17 ml, 8.43 mmol), HOBT (455 mg, 3.37 mmol) and EDCI (645 mg, 3.37 mmol) at room temperature overnight. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was successively washed with 1N HCl, aqueous saturated sodium bicarbonate, and brine, then dried over sodium sulfate, filtered and concentrated. Pure product was obtained by crystallization from ethyl acetate (611 mg, 54%).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:10][CH3:11].[C:12]1(OB(O)O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>O1CCOCC1.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>[C:20]1([C:2]2[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=2[O:10][CH3:11])[C:21]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: COc1cccc(OC)c1Br
Reactant: OB(O)Oc1cccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cccc(OC)c1-c1cccc2ccccc12
Yield: 78.2 %

Procedure:
To a solution of 1-bromo-2,6-dimethoxybenzene, (2.63 g, 12.1 mmol), tetrakis(triphenylphosphine)palladium (0) (0.91 g, 0.76 mol) and 1-naphthylboric acid (4.16 g, 23.9 mmol) in 1,4-dioxane (160 ml), a 2N aqueous solution of sodium hydroxide (13 ml) was added, and the mixture was heated to reflux. After cooling, the solvent was evaporated off, and the residue was dissolved in diethyl ether. The diethyl ether solution was washed with water and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated off, and the residue was purified by silica gel column chromatography (developing phase: n-hexane/ethyl acetate=5/1) to obtain 1-naphthyl-2,6-dimethoxybenzene (2.50 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.[H][H]>[C].[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH2:22])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2N)CC1
Yield: 96.4 %

Procedure:
In this reference example, 40 g of 1-tert.-butoxycarbonyl-4-(2-nitrophenylmethylamino)-piperidine obtained in the same manner as that of Reference Example 6, 100 ml of ethanol, 60 ml of methanol and 4 g of palladium carbon are mixed. The mixture is shaken in an atmosphere of hydrogen at room temperature under 40-45 psi. The catalyst is filtered off and the filtrate is concentrated to obtain 35.1 g of oily material as the residue. The residue is crystallized with the addition of n-hexane to obtain 28.3 g of the crude crystals. Though the crude crystals are usable to the following reaction, a part of the crystals is recrystallized from n-hexane to obtain the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=2)[N:13]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: C#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(C#Cc2ccc(C(F)(F)F)cn2)cc1
Yield: 20.5 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-2, 0.100 g, 0.319 mmol), 2-bromo-5-(trifluoromethyl)pyridine (0.108 g, 0.479 mmol), TBAF (0.201 g, 0.638 mmol), bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.028 mmol) and DMSO (3.0 mL). The obtained product was purified with column chromatography on silica gel eluting with 1.0% MeOH:DCM to afford 0.030 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.51 (t, J=8.7 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.70 (t, J=6.3 Hz, 1H), 7.79 (d, J=8.7 Hz, 2H), 7.89 (d, J=8.1 Hz, 1H), 8.06 (d, J=8.4 Hz, 2H), 8.29 (d, J=7.8 Hz, 11-0, 9.00 (s, 1H), 12.75 (br s, 1H). MS (m/z): 459.37 (M+).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.O>C1(C)C=CC=CC=1>[CH3:5][C:4]1[CH2:11][C:1]2[C:6]([CH:3]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[C:3]1[CH:4]=[CH:5][C:6]2[C:1](=[CH:11][CH:2]=[CH:1][CH:6]=2)[CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=Cc2cccc(-c3ccc4ccccc4c3)c2C1
Yield: 2472.1 %

Procedure:
The crude product was taken up in 500 cm3 of toluene, admixed with 1.5 g of p-toluenesulfonic acid and heated under reflux for 2 hours with a water separator. The reaction mixture was washed 3 times with 50 cm3 of saturated aqueous NaHCO3 solution and the solvent was removed under reduced pressure. Filtration through 200 g of silica gel (hexane/methylene chloride) gave 18.4 g (72%) of 17 as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7](=O)[C:6]=2[CH:15]=1>[Pd].C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8][CH2:7][C:6]=2[CH:15]=1
Reactant: O=C(O)c1cc(=O)c2cc(F)ccc2o1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(O)C1CCc2cc(F)ccc2O1

Procedure:
6-Fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid (III) was reacted with 10% palladium on carbon in acetic acid as solvent under hydrogen atmosphere to give 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (IV) as shown in Reaction-2 given below by a known process (U.S. Pat. No. 4,654,362).
Reaction SMILES: [I:1]NC(=O)CCC(N)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:23]([O:27][C:28]1[N:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([OH:32])=[O:31])[CH:24]([CH3:26])[CH3:25]>FC(F)(F)C(O)=O>[CH2:23]([O:27][C:28]1[N:36]=[CH:35][C:34]([I:1])=[CH:33][C:29]=1[C:30]([OH:32])=[O:31])[CH:24]([CH3:26])[CH3:25]
Reactant: NC(=O)CCC(=O)NI
Reactant: CC(C)COc1ncccc1C(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC(C)COc1ncc(I)cc1C(=O)O

Procedure:
N-Iodosuccinamide (18.22 g, 0.08 mol), trifluoroacetic acid (100 mL) and trifluoroacetic anhydride (25 mL) were added to 2-isobutoxynicotinic acid (10.55 g, 0.054 mol). The mixture was refluxed for 2.5 h, cooled and the solvents evaporated. The residue was extracted from water with ethyl acetate and the organics washed with water (twice) and brine (twice), dried (MgSO4) and concentrated. The red residue was redissolved in ethyl acetate washed with sodium thiosulfate solution (twice), water (twice), brine (twice), redried (MgSO4) and concentrated to give the desired product as a yellow solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:47])=[C:8]([N:10]2[CH2:46][CH2:45][C:13]3[N:14]=[C:15]([C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[C:27]([CH3:44])=[CH:28][N:29]5[S:34]([C:37]4[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=4)(=[O:36])=[O:35])[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][NH:21][C@H:20]([CH3:24])[CH2:19]4)[C:12]=3[CH2:11]2)[CH:9]=1)([CH3:3])[CH3:2].[O:48]1[CH2:51][C:50](=O)[CH2:49]1>C(Cl)Cl.CCOC(C)=O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:47])=[C:8]([N:10]2[CH2:46][CH2:45][C:13]3[N:14]=[C:15]([C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[C:27]([CH3:44])=[CH:28][N:29]5[S:34]([C:37]4[CH:38]=[CH:39][C:40]([CH3:41])=[CH:42][CH:43]=4)(=[O:35])=[O:36])[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][N:21]([CH:50]5[CH2:51][O:48][CH2:49]5)[C@H:20]([CH3:24])[CH2:19]4)[C:12]=3[CH2:11]2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: O=C1COC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc5c(c(N6CCN[C@H](C)C6)n4)CN(c4cc(C(C)C)ccc4C)CC5)cccc32)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc5c(c(N6CCN(C7COC7)[C@H](C)C6)n4)CN(c4cc(C(C)C)ccc4C)CC5)cccc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (R)-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-4-(3-methylpiperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (53 mg, 0.082 mmol), oxetan-3-one (17.6 mg, 0.245 mmol) and Na(AcO)3BH (51.9 mg, 0.245 mmol) in DCM (3 mL) was stirred at rt for 3 h. At that point starting material remained so additional oxetan-3-one (17.7 mg, 0.245 mmol) and Na(AcO)3BH (51.9 mg, 0.245 mmol) were added and the reaction stirred for 16 h. The mixture was then diluted with EtOAc, washed with sat NaHCO3 and brine. The organic layer was then dried over Na2SO4, filtered and concentrated. The residue was purified by FCC (5-65% EtOAc/heptane) to provide (R)-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-4-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 705.5 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:23][O:24][C:25]1[C:34]([O:35][CH3:36])=[N:33][C:32]2[C:31]([CH:37]=[O:38])=[CH:30][CH:29]=[CH:28][C:27]=2[N:26]=1.[OH-].[Na+]>FC(F)(F)C(O)=O>[CH3:23][O:24][C:25]1[C:34]([O:35][CH3:36])=[N:33][C:32]2[C:31]([CH:37]=[O:38])=[CH:30][C:29]([N+:1]([O-:4])=[O:2])=[CH:28][C:27]=2[N:26]=1
Reactant: O=[N+]([O-])O
Reactant: COc1nc2cccc(C=O)c2nc1OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1nc2cc([N+](=O)[O-])cc(C=O)c2nc1OC
Temperature: 0 °C

Procedure:
44 ml of 100% nitric acid, 44 ml of 97% sulfuric acid and 44 ml of trifluoroacetic anhydride are added in succession to a solution, cooled to 0° C., of 22 g (100.8 mmol) of 2,3-dimethoxy-quinoxaline-5-carbaldehyde in 88 ml of trifluoroacetic acid. The mixture is maintained at 0° C. for 2 hours and is then carefully poured onto a mixture of 4N NaOH and ice. The temperature should not exceed 20° C. The mixture is extracted with ethyl acetate. The organic phase is washed with an aqueous 1 N NaOH solution, water and brine and dried over sodium sulfate. Crystallization of the crude product yields the title compound in the form of light-yellow crystals. M.p.: 147-149° C.; TLC (EtOAc/hexane 1:3): Rf =0.25.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[C:12]([O:17][CH2:18][CH3:19])(=[O:16])[C:13]#[C:14][CH3:15].C(N(CC)CC)C>C(OCC)C>[CH2:18]([O:17][C:12]([C:13]1[C:3]([C:4]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=2)=[N:2][O:1][C:14]=1[CH3:15])=[O:16])[CH3:19]
Reactant: O/N=C(\Cl)c1ccc(F)cc1
Reactant: CC#CC(=O)OCC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(-c2ccc(F)cc2)noc1C
Temperature: 25 °C
Yield: 61.4 %

Procedure:
To a solution of (E)- and/or (Z)—N-hydroxy-4-fluoro-benzenecarboximidoyl chloride (15.4 g, 89 mmol) (11.1 g, 64 mmol) in diethylether (151 mL) was added ethyl 2-butynoate (7.2 g, 7.5 mL, 64 mmol) at 0° C. followed by the dropwise addition of triethylamine (7.8 g, 10.7 mL, 77 mmol) and the resulting mixture allowed to warm up to room temperature overnight. The mixture was then poured onto ice-water, and extracted with diethylether. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (9.8 g, 44%) which was obtained as an off white solid. MS: m/e=250.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20]([N:22]2[C@@H:26]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)[C@H:25]([CH2:35][O:36]C3CCCCO3)[O:24][C:23]2=[O:43])=[O:21])[CH2:12][CH2:11]1)#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20]([N:22]2[C@@H:26]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)[C@H:25]([CH2:35][OH:36])[O:24][C:23]2=[O:43])=[O:21])[CH2:12][CH2:11]1)#[N:2]
Reactant: N#Cc1cc(F)ccc1C1CCN(CCCNC(=O)N2C(=O)O[C@@H](COC3CCCCO3)[C@@H]2c2ccc(F)c(F)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: N#Cc1cc(F)ccc1C1CCN(CCCNC(=O)N2C(=O)O[C@@H](CO)[C@@H]2c2ccc(F)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (4S,5R)-4-(3,4-difluorophenyl)-5-(tetrahydropyran-2-yloxymethyl)-2-oxo-oxazolidine-3-carboxylic acid {3-[4-(2-cyano-4-fluorophenyl)piperidin-1-yl]propyl}amide (122 mg, 0.20 mmol) in methanol (5 mL) was added p-toluenesulfonic acid (38 mg, 0.20 mmol). The reaction mixture was stirred at room temperature for 18 h. The volatiles were removed under reduced pressure, the residue taken up in ethyl acetate (100 mL), washed with 10% sodium carbonate solution (2×50 mL), dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure to afford (4S,5R)-4-(3,4-difluorophenyl)-5-hydroxymethyl-2-oxo-oxazolidine-3-carboxylic acid {3-[4-(2-cyano-4-fluorophenyl)piperidin-1-yl]propyl}amide. The hydrochloride salt was prepared according to standard procedures to provide a white solid.