Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]([CH2:21][CH3:22])([CH2:19][CH3:20])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:16]=2)[CH2:11][C@H:10]1[S:31]C(=O)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+]>CO>[C:27]([O:26][C:24](=[O:25])[O:23][C:15]1[CH:14]=[CH:13][C:12]2[CH2:11][C@@H:10]([SH:31])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:18]([CH2:21][CH3:22])([CH2:19][CH3:20])[C:17]=2[CH:16]=1)([CH3:29])([CH3:30])[CH3:28]
Reactant: CCC1(CC)c2cc(OC(=O)OC(C)(C)C)ccc2C[C@@H](SC(C)=O)[C@@H]1NC(=O)OC(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC1(CC)c2cc(OC(=O)OC(C)(C)C)ccc2C[C@@H](S)[C@@H]1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Thioacetic acid S-(trans-3-tert-butoxycarbonylamino-6-tert-butoxycarbonyloxy-4,4-diethyl-1,2,3,4-tetrahydro-naphthalen-2-yl) ester (234 mg, 0.47 mmol) in MeOH (5 mL) was added the sodium methoxide (54 μL, 0.95 mmol) and stirred at 0° C. for 30 min. The mixture was quenched with H2O, diluted with Et2O (50 mL), washed with H2O, HCl (10%), H2O, brine, dried over MgSO4. The residu was used without any other purification (151 mg, 71%). 1H NMR (CDCl3): 7.10-6.95 (3H, m, Har), 4.58 (1H, d, J=11.0 Hz, NH), 4.00 (1H, t, J=11 Hz, CHNH), 3.40-3.25 (2H, m), 2.98 (1H, m), 1.80-1.45 (22H, m), 0.80-0.70 (6H, m, CH3).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([OH:14])=O)[C:6]=2[CH2:5][CH2:4][N:3]1[CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18].Cl.[NH2:23][C@@H:24]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@H:25]([OH:39])[CH2:26][NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl.O>[CH2:40]([C@H:24]([NH:23][C:12]([C:7]1[C:6]2[CH2:5][CH2:4][N:3]([CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[C:2](=[O:1])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:14])[C@H:25]([OH:39])[CH2:26][NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[CH:30]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)CNCc1cccc(C(F)(F)F)c1
Reactant: CCCC(CCC)N1CCc2c(C(=O)O)cccc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCCC(CCC)N1CCc2c(C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CNCc3cccc(C(F)(F)F)c3)cccc2C1=O
Reaction time: 20 h
Yield: 110.4 %

Procedure:
43 mg of 1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid are dissolved in 2.5 cm3 of dichloromethane under an inert atmosphere at a temperature close to 20° C. 62 mg of (2R,3S)-3-amino-4-phenyl-1-{[3-(trifluoromethyl)benzyl]amino}butan-2-ol hydrochloride (2:1), 3 mg of hydroxybenzotriazole and 34 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added to the solution. 0.124 cm3 of N,N-diisopropylethylamine is poured into the reaction medium. This medium is kept stirring for 20 h at a temperature close to 20° C. 10 cm3 of dichloromethane are added to the reaction mixture, then 10 cm3 of water. After decantation, the organic phase is washed with 5 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The 100 mg of colorless oil obtained are purified by flash chromatography over silica (column: 7 g; particle size: 20-40 μm spherical; flow rate: 20 cm3/min; eluent: 100% ethyl acetate). After concentrating the fractions under reduced pressure, 40 mg of N-[(1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide are obtained in the form of a colorless oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH:10]([F:17])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Cl[C:19]1[N:20]=[C:21]2[CH:29]=[CH:28][N:27]=[CH:26][C:22]2=[N:23][C:24]=1[Cl:25].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:25][C:24]1[N:23]=[C:22]2[CH:26]=[N:27][CH:28]=[CH:29][C:21]2=[N:20][C:19]=1[N:14]1[CH2:15][CH2:16][CH:11]([CH:10]([C:4]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=2[F:2])[F:17])[CH2:12][CH2:13]1
Reactant: Clc1nc2ccncc2nc1Cl
Reactant: Fc1ccc(C(F)C2CCNCC2)c(F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Fc1ccc(C(F)C2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 102 %

Procedure:
A mixture of 4-((2,4-difluorophenyl)fluoromethyl)piperidine hydrochloride (247 mg, 0.929 mmol), 2,3-dichloropyrido[3,4-b]pyrazine (169 mg, 0.845 mmol) and DIPEA (441 μL, 2.53 mmol) in DCM (1.69 mL) was stirred at 0° C. for 5 min then at rt for 30 min. The mixture was then partitioned between EtOAc and saturated aqueous NH4Cl. The organic layer was washed with brine, dried over Na2SO4, filtered, and evaporated. The residue was dissolved in EtOAc and filtered through a pad of silica. The filtrate was concentrated to afford 3-chloro-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)pyrido[3,4-b]pyrazine (338.4 mg) as a yellow foam. ESI-MS m/z [M+H]+ 393.2.
Reaction SMILES: [O:1]1[CH2:4][C:3](=[C:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2]1>CCO.[Pd]>[O:1]1[CH2:2][CH:3]([CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4]1
Reactant: CCOC(=O)C(C)=C1COC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)C1COC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (i) (151 mg, 0.97 mmol) in EtOH (54 mL) was added 10% Pd/C (50 mg, 0.05 mmol). The reaction was degassed and purged with hydrogen at balloon pressure (×3) then stirred under hydrogen at RT for 16 h. The reaction mixture was filtered and the residue washed with acetonitrile (10 mL). The combined organics were concentrated in vacuo and the residue, (ii) (148 mg), was used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]([NH:19][CH:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21](O)=[O:22])=[O:18])=[CH:11]2>>[CH2:24]([CH:20]([NH:19][C:17]([C:12]1[NH:13][C:14]2[C:10]([CH:11]=1)=[CH:9][C:8]([Cl:7])=[CH:16][CH:15]=2)=[O:18])[C:21]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:22])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C1COCCN1
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Product: O=C(NC(Cc1ccccc1)C(=O)N1CCOCC1)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 18 h

Procedure:
Morpholine (0.33 mmol) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid (0.30 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 48 hour reaction time). The crude product was chromatographed on silica gel eluted with 1:1 ethyl acetate/hexanes, the desired fractions concentrated, the residue dissolved in chloroform and methanol and the resulting solution stirred 18 hours with approx. 128 mg dimethylaminopyridine-polystyrene resin (Fluka Chemical Co.). The solution was filtered, concentrated and the residue triturated with ether: Yield, 51%; HPLC (60/40) 5.92 min (98%);
Reaction SMILES: [OH:1]O.[C:3]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([OH:23])=[C:11]([CH:22]=1)[C:12](=[O:21])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:5])[CH3:4].[OH-].[Na+].Cl>C(O)C>[C:3]([NH:6][C:7]1[CH:22]=[C:11]2[C:10](=[CH:9][CH:8]=1)[O:23][C:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[C:13]([OH:1])[C:12]2=[O:21])(=[O:5])[CH3:4]
Reactant: OO
Reactant: CC(=O)Nc1ccc(O)c(C(=O)C=Cc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)Nc1ccc2oc(-c3ccccc3)c(O)c(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
Aqueous hydrogen peroxide (30% w/v, 4 mL) was added to an ice-cold suspension of 5′-acetamido-2′-hydroxychalcone (5) (2.00 g, 7.11 mmol) and 1 M NaOH (20 mL) in ethanol (60 mL). The mixture was allowed to warm to room temperature and was vigorously stirred overnight. The mixture was acidified with 1 M HCl and the precipitate formed was collected by filtration to afford the flavonol (6) as a bright yellow powder (1.04 g, 50%), m.p. 241-242° C. 1H NMR (399.7 MHz, d6-DMSO) δ 2.10 (s, 3H, CH3); 7.48-7.59 (m, 3H, H3′,4′,5′); 7.73 (d, 1H, J7,8 9.2 Hz, H8); 7.89 (dd, 1H, J5,7 2.8, J7,8 9.2 Hz, H7); 8.21 (app. d, 2H, J=7.6 Hz, H2′,6′); 8.44 (d, 1H, J5,7 2.8 Hz, H5), 9.60 (br s, 1H, OH); 10.28 (s, 1H, NH).
Reaction SMILES: [CH2:1]([O:8][C@:9]1([CH:37]=[CH2:38])[C@@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:23]2[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[C@@H:10]1[O:32]S(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Na+].Cl>C(O)C>[CH2:1]([O:8][C@:9]1([CH:37]=[CH2:38])[C@@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:23]2[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[C@H:10]1[OH:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1OS(C)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=C[C@]1(OCc2ccccc2)[C@H](O)[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1COCc1ccccc1
Yield: 74.4 %

Procedure:
A solution of nucleoside 25 (2.53 g, 4.66 mmol) in a mixture of ethanol (50 cm3), water (50 cm3) and 1 M aqueous sodium hydroxide (15 cm3) was stirred under reflux for 16 h. The mixture was neutralised using dilute aqueous hydrochloric acid, the solvent was evaporated under reduced pressure, and the residue was extracted with dichloromethane (3×120 cm3). The combined extract was washed with saturated aqueous sodium hydrogencarbonate (3×150 cm3) and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (99:1) as eluent to give 26 as a white foam (1.61 g, 74%). δH (CDCl3) 9.89 (1H, br s, NH), 7.50 (1H, d, J 1.1, 6-H), 7.41-7.26 (Bn), 6.28 (1H, d, J 2.8, 1′-H), 6.05 (1H, dd, J 11.1, 17.9, 1″-H), 5.58-5.50 (2H, m, 2″-Ha, 2″-Hb), 4.98 (1H, d, J 9.0, 2′-OH), 4.64-4.31 (6H, m, 2′-H, 4′-H, Bn), 3.73 (2H, m, 5′-Ha, 5′-Hb), 1.73 (1H, d, J 0.6, CH3). δC (CDCl3) 165.1 (C-4), 150.5 (C-2), 138.4, 138.0, 136.7 (C-6, Bn), 130.4 (C-1″), 128.8, 128.6, 128.5, 128.1, 128.0, 127.8 (Bn), 120.6 (C-2″), 108.1 (C-5), 88.6 (C-1′), 87.9 (C-3′), 87.2 (C-4′), 73.7 (C-2′), 71.8 (C-5′), 69.7, 66.3 (Bn), 12.3 (CH3). Found. C, 66.8; H, 6.2; N, 5.9; C26H28N2O6 requires C, 67.2; H, 6.1; N, 6.0.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[CH3:15][C:16]1[N:21]=[CH:20][C:19]([CH2:22][C:23]2[C:24](=[O:31])[NH:25][C:26](SC)=[N:27][CH:28]=2)=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:26]2[NH:25][C:24](=[O:31])[C:23]([CH2:22][C:19]3[CH:20]=[N:21][C:16]([CH3:15])=[CH:17][CH:18]=3)=[CH:28][N:27]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CSc1ncc(Cc2ccc(C)nc2)c(=O)[nH]1
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCSCc3ccc(CN(C)C)o3)[nH]c2=O)cn1

Procedure:
A mixture of 2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamine (1.30 g), 5-(6-methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidone (1.41 g) and pyridine (10 ml) was heated under reflux for 46 hours and evaporated to dryness. The residue was washed with hot water to give 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone as an oil and this oil was treated with excess of hydrogen chloride in ethanol and evaporated to dryness. The residue was recrystallised from aqueous ethanol containing HCl to give 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone trihydrochloride m.p. 210°-213°. A sample recrystallised a further time from aqueous ethanol containing HCl had m.p. 224°-227°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:9]([O:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15]Br)[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:15][CH2:14][CH2:13][C:12]([O:11][CH2:9][CH3:10])=[O:17]
Reactant: Oc1cccc(F)c1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(F)c1
Temperature: 100 °C

Procedure:
A mixture of 3-fluorophenol (10.0 g, 89.2 mmol), ethyl-4-bromobutanoate (21.5 g, 110 mmol), potassium carbonate (17.3 g, 125 mmol) and 100 mL of N,N-dimethylformamide was stirred and heated at 100° C. under nitrogen for 16 hours. The reaction mixture was cooled and partitioned between ethyl acetate and water. The aqueous portion was separated and extracted with 2×50 mL of ethyl acetate. The combined organic extracts were washed with 3×50 mL of water and 1×50 mL of brine and dried over sodium sulfate. The organic solution was concentrated and the residue was purified via flash chromatography on a silica gel column (95:5 hexane:ethyl acetate) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.18 (t, J=7.12 Hz, 3H) 1.91-2.00 (m, 2H) 2.44 (t, J=7.29 Hz, 2H) 4.00 (t, J=6.44 Hz, 2H) 4.07 (q, J=7.12 Hz, 2H) 6.71-6.82 (m, 3H) 7.25-7.34 (m, 1H); MS (DCI+) m/z 244.1 [M+NH4]+.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[S:26][N:25]=[C:24]([CH2:27][CH3:28])[CH:23]=3)[C:19]3[C:29](=[O:39])[N:30](C(OC(C)(C)C)=O)[CH2:31][C:18]=3[C:17]=2[F:40])[CH2:13][CH2:12][O:11][CH2:10]1)=O)(C)(C)C.Cl.O1CCOCC1.CCO>CO>[NH2:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[S:26][N:25]=[C:24]([CH2:27][CH3:28])[CH:23]=3)[C:19]3[C:29](=[O:39])[NH:30][CH2:31][C:18]=3[C:17]=2[F:40])[CH2:13][CH2:12][O:11][CH2:10]1
Reactant: CCc1cc(-c2nc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)N(C(=O)OC(C)(C)C)C3)sn1
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: C1COCCO1
Product: CCc1cc(-c2nc(N[C@@H]3CCOC[C@@H]3N)c(F)c3c2C(=O)NC3)sn1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
To a stirred solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-(3-ethylisothiazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (53 mg, 0.092 mmol) in MeOH (10 mL) was added 4N HCl/dioxane (10.0 mL, 40.0 mmol). The mixture was heated to 60° C. for 1 hour and then concentrated in vacuo. The residue was triturated with EtOAc and filtered. The filter cake was washed with EtOAc to give a yellow solid, which was suspended into EtOH. The mixture was stirred at 80° C. for 30 minutes and then cooled to room temperature. The resulting precipitate was collected by filtration and washed with EtOH to give a hydrochloride salt of the title compound as an off-white solid (26.8 mg, 70%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.26 (t, J=7.57 Hz, 3H), 1.74-1.83 (m, 1H), 2.07-2.20 (m, 1H), 2.81 (q, J=7.60 Hz, 2H), 3.57-3.67 (m, 1H), 3.73-3.84 (m, 2H), 3.96-4.09 (m, 2H), 4.28-4.36 (m, 1H), 4.43-4.53 (m, 2H), 7.46 (d, J=5.37 Hz, 1H), 8.05 (br s, 3H), 8.68 (s, 1H), 8.80 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C17H20FN5O2S, 378. found, 378.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1([CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH2:6][CH2:5]1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:9]1[CH:8]=[C:7]2[C:12]([C:4]([CH3:14])([CH3:3])[CH2:5][CH2:6]2)=[CH:11][C:10]=1[OH:13]
Reactant: CC1(C)CCc2ccc(O)cc21
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CCc2cc(Br)c(O)cc21
Reaction time: 8 h
Yield: 72 %

Procedure:
128 g of bromine in 100 ml of carbon tetrachloride were added dropwise over the course of 4.5 hours to a solution of 162 g of 3,3-dimethyl-5-hydroxy-indane in 400 ml of carbon tetrachloride at -9° to -2° C. The reaction solution was left to stand overnight at room temperature. It was then washed until neutral, and dried. Fractional distillation gave 139 g of 6-bromo-3,3-dimethyl-5-hydroxy-indane; boiling point: 141.5° C/10 mm Hg. ##STR32##
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O.[H][H]>CO.[Pd]>[CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11]
Reactant: CC(C)(C)C=Cc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)CCc1ccccc1N

Procedure:
1 g (4.87 mmol) of 1-[3,3-dimethylbut-1-en-1-yl]-2-nitrobenzene are stirred in 20 ml of methanol with 0.26 g of palladium/carbon (10%) at 40° C. under 60 bar of hydrogen pressure for 24 hours. Subsequently, the solution is filtered with suction through Celite and the filtrate is concentrated by rotary evaporation. This gives 0.8 g (58% of theory) of an oil. Purity (GC-MS): 63%.
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[N:15][C:6]2[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:21]([NH:23][CH2:24][CH3:25])=[O:22].[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C>C(#N)CC>[Cl:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:30][CH2:31][N:32]([CH2:2][C:3]2[CH:16]=[N:15][C:6]3[C:7]4[N:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=[O:11])[NH:10][C:5]=3[CH:4]=2)[CH2:33][CH2:34]1)[C:21]([NH:23][CH2:24][CH3:25])=[O:22]
Reactant: O=c1[nH]c2cc(CO)cnc2c2cccn12
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(Cl)c1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)[nH]c(=O)n3cccc43)CC2)c(Cl)c1
Temperature: 95 °C
Reaction time: 6 h
Yield: 66.4 %

Procedure:
To a suspension of 3-(hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (25.00 mg, 0.116 mmol), 3-chloro-N-ethyl-4-(piperazin-1-yl)benzamide (38.9 mg, 0.145 mmol) and (cyanomethyl)trimethylphosphonium iodide (45.2 mg, 0.186 mmol) in Propiononitrile (Volume: 1.0 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.101 mL, 0.581 mmol) at 23° C. The reaction was stirred at 95° C. for 6 hr. The suspension was cooled to 23° C., filtered, rinsed with ACN (3×1 mL) and dried in vacuo to provide 3-chloro-N-ethyl-4-(4-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide (0.0359 g, 0.077 mmol, 66.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.20 Hz, 3 H) 2.53-2.67 (m, 4 H) 2.98-3.14 (m, 4 H) 3.21-3.30 (m, 2 H) 3.65 (s, 2 H) 6.70-6.77 (m, 1 H) 7.08 (dd, J=3.54, 1.52 Hz, 1 H) 7.19 (d, J=8.59 Hz, 1 H) 7.58 (d, J=1.77 Hz, 1 H) 7.68 (dd, J=3.03, 1.52 Hz, 1 H) 7.77 (dd, J=8.34, 2.02 Hz, 1 H) 7.88 (d, J=2.02 Hz, 1 H) 8.37 (d, J=1.77 Hz, 1 H) 8.44 (t, J=5.43 Hz, 1 H) 11.63 (br. s., 1 H). ESI-MS: m/z 465.4 (M+H)+. mp=266.1-271.2° C.
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]1[CH2:15][CH:14]2[CH2:16][CH:11]1[CH2:12][NH:13]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1.C(=O)(O)[O-]>CS(C)=O>[CH2:3]([N:10]1[CH2:15][C@H:14]2[CH2:16][C@@H:11]1[CH2:12][N:13]2[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(CN2CC3CC2CN3)cc1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2C[C@H]3C[C@@H]2CN3Cc2ccccc2)cc1
Yield: 51.2 %

Procedure:
A stirring solution of title compound 206 (0.5 g, 1.914 mmol) and ethyl 4-fluorobenzoate (0.421 ml, 2.87 mmol) in DMSO (19.14 mL) was stirred at 140° C. overnight. The mixture was cooled down and poured over a diluted aqueous solution of bicarbonate and extracted with ethyl acetate (twice). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography: 0% to 60% ethyl acetate in hexanes over 20 min on 20 g SiO2 to afford title compound 207 (0.33 g, 51%) as beige oil. LRMS: (calc) 336.18 (found) 337.4 (MH)+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:15][C:16]1[O:17][C:18]([CH2:23][CH3:24])=[C:19]([CH2:21][CH3:22])[N:20]=1>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:6]=1[C:7]([NH:15][C:16]1[O:17][C:18]([CH2:23][CH3:24])=[C:19]([CH2:21][CH3:22])[N:20]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: CCc1nc(N)oc1CC
Reactant: CC(=O)Oc1ccc(Br)cc1C(=O)O
Product: CCc1nc(NC(=O)c2cc(Br)ccc2OC(C)=O)oc1CC
Yield: 22 %

Procedure:
Using 2-acetoxy-5-bromobenzoic acid and 2-amino-4,5-diethyloxazole as the raw materials, the same operation as the Example 24 gave the title compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH2:14]([NH:21][C:22]([C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26](Br)[N:25]=1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.C(OCC)(=O)C.[Cu](Cl)Cl>[CH2:14]([NH:21][C:22]([C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[N:25]=1)=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1cc(Br)nc(C(=O)NCc2ccccc2)c1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: Cl[Cu]Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NCc2ccccc2)c1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
1.04 g (0.0029×2.2 mol) of 3-(trifluoromethyl) phenol was dissolved in about 10 ml of DMF. The obtained solution was further mixed with 0.24 g (ca. 60% in mineral oil; 0.0029×2.0 mol) of NaH and then with 0.94 g (0.0029 mol) of N-benzyl-6-bromo-4-methoxy-2-pyridine carboxamide. After adding 0.15 g (0.0029×0.5 mol) of copper chloride (I), the solution was stirred at about 120° C. for about 5 hours, and then allowed to stand for cooling to room temperature. After the reaction solution was distributed in ethyl acetate-saturated sodium bicarbonate water, the organic phase of the solution was washed with saturated brine and dried with anhydrous sodium sulfate, followed by concentration thereof. Thereafter, the concentrated solution was purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:13]([CH:23]2[CH2:25][CH2:24]2)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[CH2:26]([N:28]([CH2:36][CH3:37])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)[CH3:27].CN1C(=O)CCC1>CO>[CH:23]1([N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:4]2[C:5]3[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=3)[N:7]=[C:2]([NH:35][C:32]3[CH:31]=[CH:30][C:29]([N:28]([CH2:36][CH3:37])[CH2:26][CH3:27])=[CH:34][CH:33]=3)[CH:3]=2)[CH2:25][CH2:24]1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: CCN(CC)c1ccc(N)cc1
Solvent: CO
Solvent: CN1CCCC1=O
Product: CCN(CC)c1ccc(Nc2cc(N(Cc3ccc(OC)cc3)C3CC3)c3ncc(C#N)n3n2)cc1
Yield: 12.2 %

Procedure:
A microwave tube was charged with 1G (30 mg, 0.085 mmol), N1,N1-diethylbenzene-1,4-diamine (139 mg, 0.85 mmol), and NMP (1 mL). The mixture was irradiated in a microwave for three cycles of 15 min. (300W), 120° C. The crude reaction mixture was dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min., 30 min. gradient, monitored at 220 nm) to afford 244A, (5 mg, 9.0% yield). HPLC: Rt=3.896 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=482.1 [M+H]+.
Reaction SMILES: [NH3:1].Br[C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].O>CS(C)=O>[Br:9][C:7]1[CH:6]=[CH:5][C:4]([N+:10]([O-:12])=[O:11])=[C:3]([NH2:1])[CH:8]=1
Reactant: N
Reactant: O=[N+]([O-])c1ccc(Br)cc1Br
Solvent: CS(C)=O
Solvent: O
Product: Nc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 18 h

Procedure:
In a sealed reaction tube, add cautiously 6 mL of an aqueous solution of ammonia (32%) to a solution of 2,4-dibromonitrobenzene (1,6 g) in 2 mL of DMSO. Stir for 18 hours at 100° C. and cool to room temperature. Pour the heterogeneous mixture into water and filter the title compound (1.1 g, 92%) as a yellow solid.