Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[N:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][NH2:15].C(N(CC)CC)C>CN1C(=O)CCC1>[F:8][C:7]1[C:2]([NH:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:11]([F:10])[CH:12]=2)=[N:3][C:4]([F:9])=[CH:5][CH:6]=1
Reactant: Fc1ccc(F)c(F)n1
Reactant: NCc1cccc(F)c1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Fc1cccc(CNc2nc(F)ccc2F)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
2,3,6-trifluoropyridine (1.07 mL, 1.5 g, 11.27 mmol), 3-fluorobenzylamine (3.18 mL, 3.53 g, 28.2 mmol), and triethylamine (4.71 mL, 3.42 g, 33.8 mmol) were dissolved in NMP (39 mL) to form a mixture This mixture reaction mixture was stirred at 100° C. for 1 hr. The reaction mixture was then extracted with EtOAc (3×75 mL). The combined extracts were washed with H2O (4×75 mL) followed by brine (1×75 mL). The organic layer was dried (Na2SO4), filtered, and the solvent removed in vacuo. The resulting residue was subjected to silica gel column chromatography. Elution using 100 hexanes to 30 EtOAc/70 hexanes yielded 2.63 g (98%) of 3,6-difluoro-N-(3-fluorobenzyl)pyridine-2-amine. LCMS (m/z): 239.1 (MH+), retention time=1.01 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH:9]=[CH2:10])[CH2:7][O:6][C:5](=[O:8])[CH2:4]1.N1C=CC=CC=1.CN(C1C=CC=CN=1)C.[C:26](Cl)(=[O:40])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C(Cl)Cl>[C:26]([O:1][CH2:2][C:3]1([CH:9]=[CH2:10])[CH2:7][O:6][C:5](=[O:8])[CH2:4]1)(=[O:40])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: C=CC1(CO)COC(=O)C1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CC1(COC(=O)CCCCCCCCCCCCC)COC(=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
A solution of 8b (0.2 g, 1.4 mmol) in CH2Cl2 (20 mL) was treated with pyridine (0.45 mL, 5.6 mmol), dimethylaminopyridine (0.034 g, 0.28 mmol), and tetradecanoyl chloride (0.76 mL, 2.8 mmol). After stirring for 2 h at room temperature, the reaction mixture was concentrated, and residue was purified by flash column chromatography over silica gel with hexane:EtOAc (3:1) as eluant to give 8c (0.49 g, 99%) as an oil: IR (neat) 1788 and 1741 cm-1 (C=O); 1H NMR (CDCl3) δ 0.86 (distorted t, 3 H, CH3), 1.25 (m, 20 H, CH3 (CH2)10CH2CH2CO), 1.60 (m, 2 H, CH3 (CH2)10CH2CH2CO), 2.31 (t, J=7.4 Hz, 2 H, CH3 (CH2)10CH2CH2CO), 2.60 (s, 2 H, H-3), 4.12 (AB q, J=11.3 Hz, 2 H, CH2OCOC13H27), 4.20 (AB q, J=9.3 Hz, 2 H, H-5), 5.19 (d, J=17.6 Hz, 1 H, CH=CHH), 5.28 (d, J=10.9 Hz, 1 H, CH=CHH), 5.84 (dd, J=10.9, 17.6 Hz, CH=CH2), 13C NMR (CDCl3) δ 14.02, 22.58, 24.69, 28.99, 29.11, 29.24, 29.34, 29.48, 29.53, 29.56, 31.81, 33.93, 36.57, 45.76, 66.63, 73.60, 116.63, 136.81, 173.27, 175.03. Anal. Calcd for C21H36O4 : C, 71.55; H: 10.30. Found. C, 71.46; H, 10.30.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=2)[N:4]=1.[SH:27][CH2:28][CH2:29][OH:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:24][O:23][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:25][CH3:26])[N:4]=[C:3]([CH2:2][S:27][CH2:28][CH2:29][OH:30])[N:12]=[C:11]2[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1
Reactant: COc1ccc(-c2nc(CCl)nc3cc(OC)c(OC)cc23)cc1OC
Reactant: OCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(CSCCO)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A mixture of 2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinazoline (4.5 g), 2-mercaptoethanol (1.13 g), potassium carbonate (2.8 g) and N,N-dimethylformamide (50 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate. Evaporation of the solvent gave 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(2-hydroxyethyl-thiomethyl)quinazoline (4.1 g, 82%) which was then recrystallized from ethanol. Colorless prisms. mp. 154°-155° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:14]([OH:16])=O)=[C:8]([CH3:13])[N:9]2[CH3:12])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[CH2:23]([NH2:27])[CH2:24][CH2:25][CH3:26]>>[CH2:23]([NH:27][C:14]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:9]([CH3:12])[C:8]=1[CH3:13])=[O:16])[CH2:24][CH2:25][CH3:26]
Reactant: COc1ccc2c(C(=O)O)c(C)n(C)c2c1
Reactant: CCCCN
Agent: O=C(Cl)C(=O)Cl
Product: CCCCNC(=O)c1c(C)n(C)c2cc(OC)ccc12
Yield: 70.6 %

Procedure:
This material was prepared from the reaction of 6-methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid (1.12 g, 5.11 mmole) 16c with oxalyl chloride (0.682 ml, 13.6 mmole) and butan-1-amine (1.51 ml, 15.33 mmole) in a manner as previously described for example 16d to give a yellow solid (0.990 g, 71%). 1H NMR (300 MHz, CDCl3) δ8.01 (1H, d, J=8.6 Hz), 7.31 (1H, dd, J=2.3, 8.6 Hz), 7.25 (1H, d, J=2.3 Hz), 6.32 (1H, s), 4.34 (3H, s), 4.09 (3H, s), 3.95 (2H, m), 3.16 (3H, s), 2.10 (2H, m), 1.92 (2H, m), 1.44 (3H, t, J=7.4 Hz); ESIMS (MH+): 275.15.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[C:10]([O:17][CH3:18])[CH:9]=2)=[CH:4][C:3]=1[C:19]1[N:20]=[N:21][N:22]([CH:24]([CH3:26])[CH3:25])[CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[O:13])=[C:10]([O:17][CH3:18])[CH:9]=2)=[CH:4][C:3]=1[C:19]1[N:20]=[N:21][N:22]([CH:24]([CH3:25])[CH3:26])[CH:23]=1
Reactant: COc1cc(-c2cnc(N)c(-c3cn(C(C)C)nn3)c2)ccc1C(=O)O
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(-c2cnc(N)c(-c3cn(C(C)C)nn3)c2)ccc1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
To a solution of 4-(6-amino-5-(1-isopropyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-2-methoxybenzoic acid (260 mg, 0.735 mmol) and HATU (418 mg, 1.10 mmol) in DMF (10.0 mL) were added morpholine (77 mg, 0.88 mmol) and DIPEA (0.4 mL, 2.205 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was poured into ice cold water, extracted with EtOAc (100 mL). The organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. Crude compound was purified by column using 100-200 mesh silica gel. The column was eluted with 100% EtOAc to afford 250 mg (yield: 80.64%) of the title compound as pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]([F:17])([F:16])[F:15])=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][C:4]=1[NH2:18].[C:19](OC(=O)C)(=[O:21])[CH3:20].C1(C)C=CC=CC=1.CC(C)=O.C1(C)C=CC=CC=1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]([F:15])([F:16])[F:17])=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][C:4]=1[NH:18][C:19](=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2[nH]c(=O)cc(C(F)(F)F)c2cc1N
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2[nH]c(=O)cc(C(F)(F)F)c2cc1NC(C)=O

Procedure:
27,85 mg of 7-methoxy-6-amino-4-trifluoromethyl-2-(1H)-quinolone are dissolved in 0,5 ml of glacial acetic acid, mixed with 0.15 ml acetic acid anhydride and made to react for 2 hours at 20° C. After subtracting the solvent, the remainder is cleaned with Flash chromatography (silica gel, toluene/acetone 1:1). Yield: 30.7 mg (99%). Melting point 280° C. (toluene, dec), UV λ max 368 nm, emission max 448 nm, IR 1680 (CO).
Reaction SMILES: [O:1]([CH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:15]=[C:16]([NH:31][CH2:32][C:33](=O)[NH:34][C@@H:35]1[CH2:39]CNC1)[CH2:17][NH:18][C:19](=[O:30])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.C(Cl)Cl.CCOC(C)=O>[O:15]=[C:16]([NH:31][C@@H:32]1[CH2:39][CH2:35][N:34]([CH:11]2[CH2:12][CH2:13][CH:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)[CH2:33]1)[CH2:17][NH:18][C:19](=[O:30])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1
Reactant: O=C1CCC(Oc2ccccc2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC(=O)N[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCC(Oc3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-phenoxycyclohexanone (0.091 g, 0.475 mmol) and N-[2-oxo-2-({2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}amino)ethyl]-3-(trifluoromethyl)benzamide in 2% AcOH/CH2Cl2 (10 mL) was added NaB(OAc)3H (0.134 g, 0.634 mmol). After being stirred overnight at room temperature under N2, the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3. The aqueous was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), concentrated and flash chromatographed (EtOAc to EtOAc:MeOH:Et3N=9:1:0.1) to give 0.12 g of the title compound. MS (EI) calcd: (M+H)+=490.2; found 490.0.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=O)(C)(C)C.[ClH:27]>C(OCC)C.O1CCOCC1>[ClH:27].[NH2:8][C@@H:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
Benzyl (2S)-2-(tert-butoxycarbonylamino)-3-phenyl-propanoate (12.8 g, 36 mmol) was stirred in HCl, 2 M in diethyl ether (90 mL) and HCl, 4 M in dioxane (18 mL) and the resulting mixture was stirred overnight at room temperature. The mixture was then diluted with hexanes (100 mL) and filtered to collect the title compound (7.98 g, 76%) as a fine white powder. 1H NMR (CD3OD, 400 MHz): δ (ppm) 7.40-7.15 (m, 10H), 5.23 (s, 2H), 4.36-4.31 (m, 1H), 3.26-3.12 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:9]2[C:5]([S:6][CH:7]=[CH:8]2)=[CH:4][N:3]=1.[I:10]N1C(=O)CCC1=O>ClCCl.IN1C(=O)CCC1=O>[I:10][C:4]1[N:3]=[C:2]([CH3:1])[N:9]2[CH:8]=[CH:7][S:6][C:5]=12
Reactant: Cc1ncc2sccn12
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: Cc1nc(I)c2sccn12
Temperature: 25 °C
Reaction time: 24 h
Yield: 105.1 %

Procedure:
5-Methylimidazo[5,1-b]thiazole (6.90 g) was dissolved in 500 ml of dichloromethane. N-Iodosuccinimide (10.6 g) was added to the solution. The mixture was stirred at room temperature for 24 hr. N-Iodosuccinimide (1.06 g) was added thereto, followed by stirring for additional one hr. The reaction solution was washed with an aqueous sodium thiosulfate solution and brine in that order, dried over anhydrous magnesium sulfate, and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was dissolved in 200 ml of dichloromethane and 100 ml of ethyl acetate. Silica gel (30 g) was added to the solution. The mixture was stirred. The silica gel was removed by filtration. The filtrate was washed with 200 ml of a mixed solution of dichloromethane:ethyl acetate=2:1. The filtrate was concentrated under the reduced pressure to give 13.08 g of 7-iodo-5-methylimidazo[5,1-b]thiazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[O:24][CH3:25])=[N:16][N:17]=3)[CH:14]=2)=[CH:5][C:4]=1[N+:26]([O-])=O.[NH4+].[Cl-:30]>C(O)C.O.Cl.C(OCC)(=O)C.[Fe]>[ClH:30].[NH2:26][C:4]1[CH:5]=[C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[O:24][CH3:25])=[N:16][N:17]=3)[CH:14]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: [Cl-]
Reactant: COc1ccccc1-c1nnc2ccc(-c3ccc(OC)c([N+](=O)[O-])c3)cn12
Agent: [Fe]
Agent: Cl
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2ccc3nnc(-c4ccccc4OC)n3c2)cc1N
Temperature: 70 °C
Reaction time: 3 h
Yield: 17.7 %

Procedure:
A mixture of 6-(4-methoxy-3-nitrophenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine (80 mg, 0.21 mmol), iron (59 mg, 1.06 mmol) and NH4Cl (6 mg, 0.11 mmol) in ethanol (10 mL) and water (10 ml) was stirred for 3 h at 70° C. The mixture was concentrated under reduced pressure at 50° C. to remove ethanol, and was extracted with ethyl acetate (40 mL×4). The combined organic phase were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a product. The product was dissolved in HCl/ethyl acetate (2M, 20 mL), stirred at room temperature for 30 min, and concentrated to dryness to give the title compound (7.45 mg, 10.2% yield) as yellow solids. 1H NMR (DMSO-d6): 8.14 (m, 1H), 8.05 (dd, J=9.6 and 0.9 Hz, 1H), 7.88 (dd, J=9.6 and 1.5 Hz, 1H), 7.71-7.58 (m, 4H), 7.35 (d, J=8.1 Hz, 1H), 7.26-7.19 (m, 2H), 3.92 (s, 3H), 3.89 (s, 3H). MS: m/z 347.2 [M+H+].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH3:18])[C:13]=1[O:14][CH2:15][CH:16]=[CH2:17])[O:10][C:9](=[O:19])[CH:8]=[C:7]2[CH3:20])([O-])=O.[Sn].[Sn](Cl)Cl.Cl>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH3:18])[C:13]=1[O:14][CH2:15][CH:16]=[CH2:17])[O:10][C:9](=[O:19])[CH:8]=[C:7]2[CH3:20]
Reactant: C=CCOc1c([N+](=O)[O-])cc2c(C)cc(=O)oc2c1C
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Sn]
Solvent: CCO
Product: C=CCOc1c(N)cc2c(C)cc(=O)oc2c1C
Yield: 82 %

Procedure:
To a round bottom flask was added finely ground 6-nitro-4,8-dimethyl-7-allyloxycoumarin of Example 2 (3.00 g, 10.9 mmoles), tin (3.24 g, 27.3 mmoles), tin (II) chloride (3.04 g, 16.0 mmoles) and 9 ml concentrated hydrochloric acid in 200 ml ethanol. The mixture was stirred overnight during which all tin dissolved. Most of the ethanol was removed in vacuo. As the solution was allowed to cool, a gel formed which was filtered to recover a small amount of pearlized crystals (the hydrochloride salt). Water was added and a drop of iso-amyl alcohol was added to prevent frothing as solid sodium bicarbonate was added with stirring until the solution was basic. Ether was added to the filtrate arid a precipitate formed which was filtered and rinsed with ether to remove tin (II) chloride. The solids were dried and extracted with hot ethanol on the funnel of a filtration flask. Evaporation of the ethanol gave a crude product that was recrystallized from ethanol to provide 2.20 grams (82% yield) bright mustard yellow crystals: mp 145.6-147.4° C.; 1H-nmr (dimethyl sulfoxide-d6):δ 2.28 (s, 3H), 2.49 (s, 3H), 4.54 (d, 2H), 5.28 (d, 1H), 5.48 (d, 1H), 5.98-6.32 (m, 1H), 6.39 (s, 1H), 7.58 (s, 1H); 13C-nmr (dimethyl sulfoxide-d6):δ 9.4, 18.1, 74.6, 113.6, 115.1, 116.0, 118.7, 120.1, 125.5, 133.5, 147.0, 151.5, 152.5, 159.6.
Reaction SMILES: CN(C)C=O.C(Cl)(=O)C(Cl)=O.[C:12]([CH2:15][C:16]1[C:25]2[C:20](=[C:21]([NH:26][C:27](=[O:36])[C:28]3[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:35])[CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][C:17]=1[CH:37]=[CH2:38])([OH:14])=O.NCC1C=CC=CN=1>ClCCl>[Cl:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([Cl:34])[C:28]=1[C:27]([NH:26][C:21]1[C:20]2[C:25](=[C:16]3[C:17](=[CH:18][N:19]=2)[CH:37]=[CH:38][C:12]([OH:14])=[CH:15]3)[CH:24]=[CH:23][CH:22]=1)=[O:36]
Reactant: C=Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CC(=O)O
Agent: NCc1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cccc2c1ncc1ccc(O)cc12)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.3 %

Procedure:
To a mixture of dimethylformamide (80.5 mg) and dichloromethane (2 ml) was added oxalyl chloride (140 mg), and the mixture was stirred for 30 minutes at ambient temperature. To the mixture was added 4-carboxymethyl-8-(2,6-dichlorobenzoylamino)-3-vinylquinoline (340 mg) at 0° C., and the mixture was stirred for 30 minutes at the same temperature. To the mixture was added a solution of 2-aminomethylpyridine (458 mg) in dichloromethane (2 ml) at 0° C., and the mixture was stirred for 30 minutes at the same temperature. The mixture was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was washed with saturated ammonium chloride solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane-methanol) to give 4-(2,6-dichlorobenzoylamino)-9-hydroxyphenanthridine (75.7 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([OH:21])=O)=[CH:11]2)[C:4]=1[CH3:22].CN1C(=O)CCC1.C(N(CC)CC)C.Cl.[F:38][C:39]([F:45])([F:44])[O:40][CH2:41][CH2:42][NH2:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CO>[CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([NH:43][CH2:42][CH2:41][O:40][C:39]([F:45])([F:44])[F:38])=[O:21])=[CH:11]2)[C:4]=1[CH3:22]
Reactant: NCCOC(F)(F)F
Reactant: COc1ncnc(Cn2cc(C(=O)O)c3ncccc32)c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: CO
Product: COc1ncnc(Cn2cc(C(=O)NCCOC(F)(F)F)c3ncccc32)c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 28.2 %

Procedure:
See FIG. 21(c). 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (40 mg, 0.13 mmol) was taken in a 50 ml single necked flask equipped with an air condenser connected to nitrogen source. NMP (3 ml, 31.17 mmol) was added to get a solution. Triethyl amine (0.056 ml, 0.40 mmol) was added followed by the addition of 2-(trifluoromethoxy)ethanamine hydrochloride (44.4 mg, 0.27 mmol). The reaction mass was stirred at RT for 5 minutes. HATU (61.2 mg, 0.16 mmol) was added and stirred at RT for 30 min. After the completion of the reaction, few drops of methanol was added and clear solution was subjected for reverse phase HPLC purification to get 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-N-(2-(trifluoromethoxy)ethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (15.00 mg, 27.3%). ES+MS m/z: 410 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.25 (s, 3 H ) 3.68-3.80 (m, 2 H ) 3.93 (s, 3 H ) 4.24 (t, J=5.27 Hz, 2 H ) 5.69 (s, 2 H ) 7.26 (dd, J=8.29, 4.71 Hz, 1 H ) 7.94 (d, J=7.35 Hz, 1 H ) 8.28 (s, 1 H ) 8.38-8.54 (m, 2 H ) 8.96 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([CH3:22])[NH:17][C:16]2=[O:23])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[N+:24]([O-])([OH:26])=[O:25]>C(Cl)Cl.S(=O)(=O)(O)O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([N+:24]([O-:26])=[O:25])=[C:18]([CH3:22])[NH:17][C:16]2=[O:23])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)[nH]1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 1.50 g of isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4methyl-2,6-dioxo-1-(2H)-pyrimidinyl]-benzoate in 30 ml of methylene chloride at room temperature is treated with stirring with 2.0 ml of 100% nitric acid. The solution is then treated with 5 drops of concentrated sulphuric acid and stirred for 48 hours at room temperature. The reaction mixture is poured into 150 ml of ice/water, diluted with 100 ml of ethyl acetate and washed four times with 150 ml of water. The organic phase is dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is recrystallized from diethyl ether. Isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4-methyl-5-nitro-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 202°-205° C., is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[C:9]([NH:11][C@H:12]([CH:16]=O)[CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[N:32][CH:33]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[C:9]([NH:11][C@H:12]([CH2:16][NH:27][C:28]2[CH:33]=[N:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH:13]([CH3:14])[CH3:15])=[O:10])=[CH:4][CH:3]=1
Reactant: COc1ccc(N)cn1
Reactant: CC(C)[C@@H](C=O)NC(=O)[C@@H](CC(=O)N1CCOCC1)c1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(NC[C@@H](NC(=O)[C@@H](CC(=O)N2CCOCC2)c2ccc(F)cc2)C(C)C)cn1

Procedure:
2-(S)-(4-Fluoro-phenyl)-N-(1-(S)-formyl-2-methyl-propyl)-4-morpholin-4-yl-4-oxo-butyramide (350 mg, 0.96 mmol, 1.0 eq.) and 5-Amino-2-methoxy-pyridine (240 μL, 1.92 mmol, 2.0 eq.) dissolved in MeOH (2.5 mL) and acetic acid (106 mL, 1.92 mmol, 2.0 eq.) added via syringe at room temperature. Sodium cyanoborohydride (121 mg, 1.92 mmol, 2.0 eq.) added in portion and the reaction monitored the reaction by LC/MS. Upon completion, solvents were evaporated and dissolved in EtOAc (100 mL) washed with brine, dried over MgSO4, filtered and evaporated. Purification by preparative mass-directed HPLC provided the title compound as a white solid after evaporation and lyophilization (2.6 mg, 5.6 □mol, 0.6%). HPLC-MS calcd. for C25H33FN4O4 (M+H+) 473.3, found 473.5.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:26])[C:13]([CH3:25])([S:15]([CH2:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)(=[O:17])=[O:16])[CH3:14])[O:8][N:7]=1)([CH3:5])[CH3:4].[H-].[Na+].[CH3:29]I>C1COCC1>[CH3:29][O:1][CH2:2][C:3]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:26])[C:13]([CH3:14])([S:15]([CH2:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)(=[O:17])=[O:16])[CH3:25])[O:8][N:7]=1)([CH3:5])[CH3:4]
Reactant: CC(C)(CO)c1cc(NC(=O)C(C)(C)S(=O)(=O)CC2CCOCC2)on1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)CC2CCOCC2)on1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
To a solution of 70 mg (0.18 mmol) of N-[3-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-2-methyl-2-(tetrahydro-pyran-4-ylmethanesulfonyl)-propionamide in anhydrous THF (2 mL) at 5° C. are added 9 mg (0.36 mmol) of sodium hydride (60% dispersion in mineral oil). The reaction mixture is stirred for 0.5 h and then 32 μL (0.54 mmol) of methyl iodide are added. The reaction is stirred at room temperature for 18 h and is then warmed to 35° C. for 6 h. The reaction is quenched by addition of methanol and concentrated under reduced pressure. The residue is dissolved in DCM and washed with water, saturated aqueous NaHCO3 solution and brine. The organic layer is dried over Na2SO4, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography (silica, eluent: DCM, 10% ethyl acetate) followed by preparative HPLC (neutral conditions) to afford 20 mg of N-[3-(2-methoxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-2-methyl-2-(tetrahydro-pyran-4-ylmethanesulfonyl)-propionamide. Yield: 28%, ES-MS: m/z 403 [M+H]
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:25])[CH2:21][C:22](O)=[O:23])[C:15]2[CH:26]=[CH:27][CH:28]=[CH:29][C:14]=2[C:13]2[CH:30]=[CH:31][CH:32]=[CH:33][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:34][C:35]([F:40])([F:39])[CH2:36][CH2:37][NH2:38]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:25])[CH2:21][C:22]([NH:38][CH2:37][CH2:36][C:35]([F:40])([F:39])[F:34])=[O:23])[C:15]2[CH:26]=[CH:27][CH:28]=[CH:29][C:14]=2[C:13]2[CH:30]=[CH:31][CH:32]=[CH:33][C:12]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCC(F)(F)F
Reactant: O=C(O)CC(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Product: O=C(CC(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21)NCCC(F)(F)F

Procedure:
Using N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-malonamic acid and 3,3,3-trifluoropropylamine, the title compound was prepared in the same manner as described for example 1c. Colorless, waxy solid (90%). MS: m/e=540(M+H+).