Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:33])[C@H:5]([CH3:32])[CH2:6][C@H:7]([NH:21][C:22]([C:24]1[S:25][C:26]([C:29](=[O:31])[NH2:30])=[CH:27][CH:28]=1)=[O:23])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+]>C(O)C>[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=[CH:10][C:9]([CH2:8][C@@H:7]([NH:21][C:22]([C:24]2[S:25][C:26]([C:29](=[O:31])[NH2:30])=[CH:27][CH:28]=2)=[O:23])[CH2:6][C@@H:5]([CH3:32])[C:4]([OH:33])=[O:3])=[CH:14][CH:13]=1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(C(N)=O)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(C(N)=O)s1)C(=O)O
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
To a solution of 5-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-butylcarbamoyl)-thiophene-2-carboxylic acid (Example 26: 115 mg, 0.247 mmol) in THF (1 mL) at 0° C. is added diisopropylethylamine (63.8 mg, 0.494 mmol) followed by dropwise addition of a solution of isobutyl chloroformate (33.7 mg, 0.247 mmol) in THF (0.1 mL). The mixture is stirred at 0° C. for 30 minutes then ammonium hydroxide (0.3 mL of 14.8 M solution) is added. The mixture is allowed to warm to room temperature then aqueous 1M HCl (3 mL) is added. Most of the THF is removed under reduced pressure and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure to give (2R,4S)-5-biphenyl-4-yl-4-[(5-carbamoyl-thiophene-2-carbonyl)-amino]-2-methyl-pentanoic acid ethyl ester. MS 465.3 (M+1). Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-[(5-carbamoyl-thiophene-2-carbonyl)-amino]-2-methyl-pentanoic acid ethyl ester (115 mg, 0.248 mmol) in ethanol (8 mL) is added aqueous 1M NaOH (0.866 mL, 0.866 mmol) and the mixture is stirred at 50° C. for 3.5 hours. The ethanol is removed under reduced pressure and water is added to the residue. The resulting solution is acidified with aqueous 1M HCl and the resulting precipitate is filtered and washed with water. The solid is purified by preparative HPLC using 50% MeCN/water to elute the product. The appropriate fractions are lyophilized to give (2R,4S)-5-biphenyl-4-yl-4-[(5-carbamoyl-thiophene-2-carbonyl)-amino]-2-methyl-pentanoic acid. MS 437.2 (M+1); 1H-NMR (400 MHz, DMSO-d6); δ ppm 1.09 (d, J=7.20 Hz, 3H), 1.57 (m, 1H), 1.88 (m, 1H), 2.46 (m, 1H), 2.84 (m, 2H), 4.18 (m, 1H), 7.28 (d, J=8.21 Hz, 1H), 7.33 (t, 1H), 7.44 (t, 1H), 7.57 (d, J=8.21 Hz, 2H), 7.64 (d, J=7.33, 2H), 7.69 (m, 2H), 8.06 (s, 1H), 8.38 (d, J=8.59 Hz, 1H), 12.07 (s, broad, 1H).
Reaction SMILES: [O-]CC.[Na+].Cl.[CH2:6]([NH:13][C:14]([NH2:16])=[NH:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[CH2:25][C:26](OC)=[O:27]>>[ClH:17].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[CH2:25][C:26]([NH:15][C:14]([NH:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[NH:16])=[O:27]
Reactant: COC(=O)Cc1c(Cl)cccc1Cl
Reactant: N=C(N)NCc1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: N=C(NCc1ccccc1)NC(=O)Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 128 %

Procedure:
To sodium ethoxide [prepared by reacting sodium (60 mg, 2.61 mmol) and anhydrous ethanol (5 ml)] benzylguanidine hydrochloride (580 mg, 3.12 mmol) was added and refluxed in an oilbath for 1 hour. The reaction mixture was cooled to room temperature and insoluble materials filtered. Methyl 2,6-dichlorophenylacetate (285 mg, 1.3 mmol) (CH3(C═O)CH2(2,6,-di-ClC6H3) was added to the filtrate and refluxed for 2 hours. After cooling to room temperature the reaction mixture was concentrated and converted to the hydrochloride salt by the addition of hydrogen chloride (1M in ether) to provide 310 mg of N-(2,6-dichlorophenylacetyl)-N′-benzylguanidine hydrochloride as a white solid, purity 89.3% (HPLC); 1H-NMR (CD3OD) δ 4.38 (s, 4H, CH2), 7.32–7.41 (m, 8H, Ar).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH:18]([NH:17][C:15]([C@H:12]1[CH2:13][CH2:14][C@@H:9]([NH:8][C:6]2[CH:7]=[C:2]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:3]=[CH:4][C:5]=2[N+:21]([O-:23])=[O:22])[CH2:10][CH2:11]1)=[O:16])([CH3:20])[CH3:19]
Reactant: C1COCCN1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ccc2[N+](=O)[O-])CC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(N3CCOCC3)ccc2[N+](=O)[O-])CC1

Procedure:
A suspension of cis-4-(5-chloro-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamide (300 mg, 0.883 mmol) in morpholine (2 mL, 22.93 mmol) was irradiated in a microwave reactor for 1 hour at 150° C. The reaction mixture was partitioned between water and DCM. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to a yellow oil. The residue was concentrated, adsorbed onto a plug of silica gel, and purified by column chromatography, eluting with 0-100% EtOAc in DCM, to provide cis-N-isopropyl-4-(5-morpholino-2-nitrophenylamino)cyclohexanecarboxamide as a yellow powder (0.38 g, 110% yield). MS, m/z (C20H30N4O4): calcd, 390.2. found, 390.9 [M+H].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([P:8](=[O:13])([O:11][CH3:12])[O:9][CH3:10])=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.[N:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)=[C:22]=[O:23]>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([P:8](=[O:13])([O:11][CH3:12])[O:9][CH3:10])=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:22]([NH:21][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)=[O:23])=[CH:16][CH:15]=1
Reactant: COP(=O)(OC)c1cnc(N)c(-c2ccc(N)cc2)c1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COP(=O)(OC)c1cnc(N)c(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)c1
Temperature: 25 °C

Procedure:
The reaction mixture of dimethyl (6-amino-5-(4-aminophenyl)pyridin-3-yl)phosphonate (30 mg, 0.10 mmol, 1 eq) and 1-isocyanato-3-(trifluoromethyl)benzene (0.018 mL, 1.2 eq) in anhydrous DMF (0.5 mL) under anhydrous nitrogen atmosphere was stirred at room temperature for an hour. It was then diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, brine, and lastly dried with anhydrous sodium sulfate. The upper clear solution was decanted, concentrated, and the solid residue was subject to a gradient column chromatography (EtOAc-Hex 2:1 to MeOH-EtOAc 1:20) to yield dimethyl (6-amino-5-(4-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)pyridin-3-yl)phosphonate as a white solid in amount of 41 mg.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:6][CH:7]=1)[CH:19]=[CH2:18]
Reactant: CCC(=O)c1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C(=O)CC)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.4 %

Procedure:
To 1-(4-hydroxy-phenyl)-propan-1-one (4.6 g, 30 mmol) and K2CO3 (5 g, 36 mmol) in DMF (10 mL) was added allylbromide (7.26 g, 60 mmol) dropwise with violent stirring. The reaction mixture was stirred at room temperature for 12 h and filtered to remove salt. The filtrate was concentrated to yield the titled compound (5.5 g, 97%) as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ 7.94 (d, 2H, J=9.0 Hz), 7.05 (d, 2H, J=9.0 Hz), 6.05 (m, 1H), 5.44, 5.38, 5.30, 5.26 (4d, 2H, J=3.0 Hz), 4.66 (d, 2H, J=6.0 Hz), 2.98 (q, 2H, J=7.5 Hz), 1.07 (t, 3H, J=7.5 Hz). MS (ESI) m/e 191 (M+H)+; 189 (M−H)−.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([N:11]([C:20]2[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=2)[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)[CH:7]=[CH:8][C:9]=1[CH3:10].[CH3:28]OCCOC>[Br-].C[P+](C)(C)C.C(O)C>[CH3:3][C:4]1[CH:5]=[C:6]([N:11]([C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[CH2:28])=[CH:22][CH:21]=2)[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: COCCOC
Reactant: Cc1ccc(N(c2ccc(C=O)cc2)c2ccc(C)c(C)c2)cc1C
Agent: C[P+](C)(C)C
Agent: [Br-]
Agent: [H-]
Solvent: CCO
Product: C=Cc1ccc(N(c2ccc(C)c(C)c2)c2ccc(C)c(C)c2)cc1
Temperature: 25 °C

Procedure:
12.1 g of sodium hydride and 580 mL of 1,2-dimethoxyethane were placed in a three-neck flask. While stirring at room temperature, 108.5 g of tetramethylphosphonium bromide was added. After adding one drop of anhydrous ethanol, the mixture was reacted for 4 hours at 70° C. 100 g of 4-[N,N-bis-(3,4-dimethylphenyl)amino]benzaldehyde was added to the reaction mixture. The mixture was reacted for 5 hours at 70° C. The reaction solution was filtered, and an ether extract of filtered cake and filtrate were washed in water. The ether solution was dehydrated with calcium chloride, the ether was removed, and a reaction mixture was obtained. This mixture was recrystallized twice with ethanol, and a needle-form 4-[N,N-bis-(3,4-dimethylphenyl)amino]styrene was obtained. The yield was 84.5 g (yield rate of 85.0%).
Reaction SMILES: [OH-].[Na+].Cl.[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:5]=1.[Br:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[CH:18][NH:19]2>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Br:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[CH:18][N:19]2[S:10]([C:6]1[CH:5]=[N:4][CH:9]=[CH:8][CH:7]=1)(=[O:12])=[O:11]
Reactant: Brc1cccc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Product: O=S(=O)(c1cccnc1)n1ccc2c(Br)cccc21
Reaction time: 0.75 h
Yield: 94.5 %

Procedure:
Aq. 2M NaOH (1 mL) was added to a stirred mixture of pyridine-3-sulfonyl chloride hydrochloride (240 mg, 1.12 mmol; Intermediate 23), 4-bromoindole (200 mg, 1.02 mmol) and tetrabutylammonium hydrogen sulfate (35 mg, 0.10 mmol). The reaction was stirred 45 min. and the layers were allowed to separate. The organic layer was washed twice with diluted aq. NaOH, dried and concentrated to get the title compound (325 mg, 95%) as an off white solid. MS (ESI+) for C13H9BrN2O2S m/z 337 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].[CH3:13][O:14][CH2:15][CH2:16]O>>[N:1]1[CH:6]=[C:5]([C:7]([O:9][CH2:16][CH2:15][O:14][CH3:13])=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([O:12][CH2:16][CH2:15][O:14][CH3:13])=[O:11]
Reactant: COCCO
Reactant: O=C(O)c1ccc(C(=O)O)nc1
Product: COCCOC(=O)c1ccc(C(=O)OCCOC)nc1

Procedure:
Analogously to Example 26, 10 g of pyridine-2,5-dicarboxylic acid are converted into the acid chloride and this is reacted with 9.1 g of ethylene glycol monomethyl ether. Working up is carried out in accordance with Example 26. The product is obtained as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]([CH3:32])([C:15]([N:17]1[CH2:31][CH2:30][CH2:29][C@H:18]1[C:19]([O:21]CC1C=CC=CC=1)=[O:20])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].O[Li].O>O1CCOCC1.O>[CH2:1]([O:3][C:4]([NH:6][C:7]([CH3:32])([C:15]([N:17]1[CH2:31][CH2:30][CH2:29][C@H:18]1[C:19]([OH:21])=[O:20])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)NC(C)(Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)NC(C)(Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 2.5 h
Yield: 102.4 %

Procedure:
To a stirring solution of EtOCO-D,L-Phe(αMe)-Pro-OBzl (13.2 g, 30 mmol) in p-dioxane (250 mL) was added a solution of LiOH.H2O (6.3 g, 151 mmol) in water (125 mL). After stirring for 2.5 h, the solvent was removed in vacuo and the residue was diluted with water and washed three times with diethyl ether. The aqueous phase was then taken to pH 2 with conc. HCl and extracted three times with ethyl acetate. The combined ethyl acetate extracts were dried (Na2SO4), filtered and concentrated in vacuo to give 10.7 g of a white solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.[CH:11]([Sn](CCCC)(CCCC)CCCC)=[CH2:12]>C1(C)C=CC=CC=1>[F:10][C:4]1[CH:3]=[C:2]([CH:11]=[CH2:12])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1ccc(Br)cc1F
Solvent: Cc1ccccc1
Product: C=Cc1ccc(C#N)c(F)c1

Procedure:
A solution of 4-bromo-2-fluorobenzonitrile (4.92 g, 0.0246 mol), vinyltributyltin (0.78 g, 0.246 mol), and tetrakistriphenylphosphine (0.67 g, 0.58 mmol) in 250 mL of toluene was refluxed under nitrogen overnight. The solvent was evaporated and the residue was flash chromatographed on silica gel with heptane:CH2Cl2 (1:1) to pure CH2Cl2. A colourless oil was obtained that crystallised. Yield: 3.0 g (82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:17][CH3:18])[C:11]=1[N:12]([CH3:16])[C:13](=[O:15])[CH3:14])[C:6]([OH:8])=[O:7].Cl.[CH3:20]O>>[CH3:20][O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:17][CH3:18])[C:11]([N:12]([CH3:16])[C:13](=[O:15])[CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CO
Reactant: COc1cc(C(=O)O)cc(OC)c1N(C)C(C)=O
Agent: Cl
Product: COC(=O)c1cc(OC)c(N(C)C(C)=O)c(OC)c1
Reaction time: 20 h

Procedure:
A suspension of 35.8 g. of 3,5-dimethoxy-4-(N-methyl-acetamido)-benzoic acid in 500 ml. of absolute methanol was saturated with dry hydrogen chloride, whereby a solution gradually formed. After standing at room temperature for 20 hours, the solution was evaporated to dryness under vacuum. The residue was treated with 200 ml. of ice-water and with a concentrated sodium hydroxide solution until a strongly alkaline reaction was achieved and the resulting emulsion was extracted with two 500 ml. portions of ethyl acetate. The ethyl acetate extracts were washed with two 100 ml. portions of water, combined, dried over magnesium sulfate, filtered and evaporated under vacuum. After recrystallization from ethyl acetate/cyclohexane, the residue yielded 3,5-dimethoxy-4-(N-methylacetamido)-benzoic acid methyl ester having a melting point of 115°-116° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][CH2:11][N:12]2[C:16](=[O:17])[CH2:15][CH2:14][C:13]2=[O:18])[CH:5]=[CH:4][N+:3]=1[O-].C(O)C.[C:23]([O:26]C(=O)C)(=[O:25])[CH3:24]>>[C:23]([O:26][CH2:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][CH2:11][N:12]2[C:16](=[O:17])[CH2:15][CH2:14][C:13]2=[O:18])[CH:5]=[CH:4][N:3]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(OCCN2C(=O)CCC2=O)cc[n+]([O-])c1C
Solvent: CCO
Product: CC(=O)OCc1nccc(OCCN2C(=O)CCC2=O)c1C
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
0.12 g of 2,3-dimethyl-4-(2-succinimidoethoxy)pyridine N-oxide was dissolved in 5 ml of acetic anhydride to obtain a solution. This solution was stirred at 100° C. for 0.5 hour and cooled, followed by the addition of 30 ml of ethanol. The obtained mixture was stirred at a room temperature for 0.5 hour and distilled to remove the solvent. Thus, 0.14 g of crude 2-acetoxymethyl-3-methyl-4-(2-succinimidoethoxy)pyridine was obtained as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]=[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)[CH:9]([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2].[CH:20]([Mg]Br)=[CH2:21].[NH4+].[Cl-]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)([CH:9]([F:10])[F:11])[CH:20]=[CH2:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N=C(c1cccc(Br)c1)C(F)F
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: C=CC(NC(=O)OC(C)(C)C)(c1cccc(Br)c1)C(F)F
Temperature: -20 °C
Reaction time: 1.25 h

Procedure:
[1-(3-Bromo-phenyl)-2,2-difluoro-ethylidene]-carbamic acid tert-butyl ester (9.09 g, 27.2 mmol) was dissolved in toluene and cooled to −20° C. under N2. Using a syringe pump, vinylmagnesiumbromide (42.5 ml, 34.0 mmol) was added (1 eq. per hour). After 1.25 hrs no starting material was left and 218 ml half-saturated NH4Cl solution was added to the reaction. The product was extracted with TBME. The organic phases were washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by automated column chromatography (cyclohexane/TBME) to yield the title compound as a yellowish oil. 1H-NMR (600 MHz, DMSO-d6): 7.81 (br, 1H, NH), 7.52 (m, 2H), 7.35 (m, 2H), 6.48 (t, 1H, CHF2), 5.45 (d, 1H), 5.15 (d, 1H), 1.32 (s, 9H); MS: 362 [(M+H)+].
Reaction SMILES: CS(C)=O.Cl[S:6]([C:9]1[N:20]=[C:12]2[C:13]([O:18][CH3:19])=[CH:14][CH:15]=[C:16]([Cl:17])[N:11]2[N:10]=1)(=[O:8])=[O:7].[F:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:23]=1[NH2:24].N1C=CC=CC=1>C(#N)C.O.ClCCl>[F:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:23]=1[NH:24][S:6]([C:9]1[N:20]=[C:12]2[C:13]([O:18][CH3:19])=[CH:14][CH:15]=[C:16]([Cl:17])[N:11]2[N:10]=1)(=[O:8])=[O:7]
Reactant: COc1ccc(Cl)n2nc(S(=O)(=O)Cl)nc12
Reactant: Nc1c(F)cccc1F
Solvent: CC#N
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccc(Cl)n2nc(S(=O)(=O)Nc3c(F)cccc3F)nc12
Reaction time: 0.33 h
Yield: 62.3 %

Procedure:
Dimethyl sulfoxide (90 microliters, 94 micrograms, 1.2 mmol) was added with stirring to a solution of 2-chlorosulfonyl-5-chloro-8-methoxy[1,2,4]triazolo[1,5-a]pyridine (1.7 g, 6 mmol), 2,6-difluoroaniline (1.6 g, 12 mmol) and pyridine (0.5 g, 6 mmol) in acetonitrile (20 mL) at ambient temperature. The reaction was complete in about 20 min. Dichloromethane and water were added and the solid that separated was collected by filtration. The organic layer was concentrated by evaporation and the residue obtained was washed with water and combined with the earlier obtained solid. The combined solids were then washed with ether and hexane and dried to obtain 1.4 g of the title compound as an off-white powder melting at 190°-191° C. (d).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].CC([O-])=O.[Na+].Br[CH2:11][C:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)=O>C(O)C>[NH2:1][C:2]1[S:3][CH:11]=[C:12]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[N:4]=1
Reactant: NC(N)=S
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(-c2ccc(C(=O)O)cc2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.47 g (6.2 mmol) of thiourea and NaOAc (1.5 g, 6.2 mmol) were combined in 35 mL of ethanol. To this suspension was added 4-(2-bromo-acetyl)-benzoic acid (1.5 g, 6.2 mmol). Reaction mixture was stirred at room temperature overnight. It was evaporated to dryness to yield 4-(2-amino-thiazol-4-yl)-benzoic acid which was used in the next step without any further purification. MS: 221.0 (M+H+).
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.CO.Cl[C:9]1[CH:14]=[C:13]([C:15]([O:17]C)=[O:16])[CH:12]=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=1.Cl>CC(N(C)C)=O>[CH3:1][O:2][C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=1
Reactant: C[O-]
Reactant: COC(=O)c1cc(Cl)nc(-c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CO
Product: COc1cc(C(=O)O)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
25% NaOMe/methanol solution (92 μL) was added to an MeOH (2 mL) solution of methyl 2-chloro-6-phenylpyridine-4-carboxylate (1100 mg), and stirred at room temperature for 2 hours. Further, 25% NaOMe/methanol solution (92 μL) was added to it, and stirred under heat with refluxing for 2 hours and 30 minutes. DMA (3 mL) was added to it, and stirred overnight at 130° C., then 25% NaOMe/methanol solution (92 μL) was added to it, and stirred at 130° C. for 7 hours. With cooling with ice, diluted hydrochloric acid was added to it, the formed precipitate was taken out through filtration, washed with water, dried, and purified through reversed-phase high-performance liquid chromatography [acetonitrile/water+0.11% trifluoroacetic acid] to obtain the title compound as a white powder.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([O:9][CH3:10])=[O:8].[Al+3].[Cl-].[Cl-].[Cl-].[Br:15]Br.O>C(Cl)(Cl)Cl>[Br:15][C:4]1[CH:3]=[C:2]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[S:1][CH:5]=1
Reactant: BrBr
Reactant: COC(=O)Cc1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)Cc1cc(Br)cs1
Temperature: 25 °C
Yield: 41.2 %

Procedure:
To a solution of methyl 2-(thiophen-2-yl)acetate (5 g, 32 m mol) and anhydrous AlCl3 (10.7 g, 80 mmol) in CHCl3 (50 ml) was added dropwise bromine (1.8 ml, 34 mmol) at 0˜5° C. over 30 min. When the addition was complete, the mixture was allowed to warm to room temperature overnight. Then it was poured into icy water (50 ml), extracted with EtOAc (30 ml×3). The combined organic phase was dried over Na2SO4, filtered and concentrated. Purification by column chromatography (PE/EtOAc=10/1) gave the product (3.1 g, 41%) as light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:43])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([N:20]2[CH2:24][CH2:23][CH2:22][CH:21]2[CH2:25][N:26]([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][C:29]=2[N+:38]([O-])=O)[CH3:27])=[O:19])=[CH:13][C:12]=1[O:41][CH3:42]>CO.[Pd]>[NH2:38][C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][C:28]=1[N:26]([CH2:25][CH:21]1[CH2:22][CH2:23][CH2:24][N:20]1[C:18](=[O:19])[CH2:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[O:43])=[C:12]([O:41][CH3:42])[CH:13]=1)[CH3:27])[C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)c1ccc(N(C)CC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3F)c(OC)c2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(N(C)CC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3F)c(OC)c2)c(N)c1
Yield: 33.2 %

Procedure:
A stirred solution of methyl 4-[N-[1-[4-[N′-(2-fluorophenyl)ureido]-3-methoxy-phenylacetyl]-2-pyrrolidinylmethyl]-N-methylamino]-3-nitrobenzoate (901.0 mg, 1.518 mmol) in MeOH (18.0 mL) was hydrogenated over 5% Pd—C (1.35 g) at 45 psi overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was made basic with 1 N NaOH solution and extracted with CHCl3. The extract was washed with brine, dried over Na2SO4, and the solvent was removed under a reduced pressure. The residue was chromatographed on silica-gel with CHCl3-MeOH (24:1, v/v) as eluent to afford 283.7 mg (48%) methyl 3-amino-4-[N-[1-[4[-N′-(2-fluorophenyl)ureido]-3-methoxy-phenylacetyl]-2-pyrrolidinylmethyl]-N-methylamino]benzoate as a brownish amorphous solid, which was used to the subsequent reaction without further purification.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Cl:5][C:6]1[CH:7]=[C:8]2[C:16](=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1F)[NH:15][C:14]1[CH:13]=[N:12][CH:11]=[CH:10][C:9]2=1.Cl>CS(C)=O.O>[Cl:5][C:6]1[CH:7]=[C:8]2[C:16](=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1[O:1][CH2:2][CH3:3])[NH:15][C:14]1[CH:13]=[N:12][CH:11]=[CH:10][C:9]2=1
Reactant: CC[O-]
Reactant: O=[N+]([O-])c1c(F)c(Cl)cc2c1[nH]c1cnccc12
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1c(Cl)cc2c([nH]c3cnccc32)c1[N+](=O)[O-]
Reaction time: 8 h
Yield: 40 %

Procedure:
Sodium ethoxide (232 mg, 3.4 mmol) was added to a solution of 6-chloro-7-fluoro-8-nitro-9H-β-carboline (200 mg, 0.76 mmol) in DMSO (4 ml) and the reaction mixture allowed to stir overnight. The reaction mixture was diluted with water and the pH of the solution was adjusted to about 4 by adding 1N HCl. The aqueous solution was extracted (3×) with EtOAc. The combined EtOAc layers were dried and evaporated. The crude product was purified by flash chromatography to give the desired product in 40-60% yield. 1H-NMR (300 MHz, DMSO-d6): δ 1.44 (t, 3H), 4.24 (q, 2H), 8.21 (d, 1H), 8.46 (d, 1H), 8.91 (s, 1H), 9.02 (s, 1H). Retention Time (LC, method: ammonium acetate standard): 2.37 min. MS (M+H+): 291.9.