Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([C:12]2[NH:17][C:16](=O)[CH:15]=[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:26]>>[Cl:26][C:16]1[CH:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:13]=[C:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:17]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=c1cc(-c2ccccc2)nc(-c2ccccc2)[nH]1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1cc(-c2ccccc2)nc(-c2ccccc2)n1
Yield: 65 %

Procedure:
Phosphorous oxychloride (9.30 mL, 99.8 mmol, 7.5 eq.) was added dropwise to 2,6-diphenyl-3H-pyrimidin-4-one (10) (3.3 g, 13.3 mmol) in a vigorous reaction. To this mixture was added slowly phosphorous pentachloride (2.77 g, 13.3 mmol, 1 eq.) and the reaction mixture was stirred at reflux for 3 hours. The reaction mixture was then quenched by pouring into ice-water, and extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with water and brine, dried (MgSO4) and then concentrated to give a yellow solid. This was recrystallised from hot ethanol to give fine white needles (65%). 1H NMR δ (CDCl3): 8.60-8.18 (m, 5H, Ar), 7.63 (s, 1H, Ar), 7.51-7.57 (m, 5H, Ar).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][N:21]([CH3:29])[C:20]1=[O:30]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][N:21]([CH3:29])[C:20]2=[O:30])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CN1Cc2ccccc2C(N)C1=O
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)N(C)Cc2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure 5-D), the title compound was prepared as a solid having a melting point of 174-175° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9](=O)[C:8]2[CH:7]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[CH:5]=[CH:4][C:3]1=2.[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(CC)CC>C1COCC1.Cl[Ti](Cl)(Cl)Cl>[CH3:16][O:15][C:13]([C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:17])([CH3:1])[CH2:11][CH:10]=[C:9]([S:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[CH:7]=1)=[O:14]
Reactant: Sc1ccccc1
Reactant: COC(=O)c1ccc2c(c1)C(=O)CCC2(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)C(Sc1ccccc1)=CCC2(C)C
Reaction time: 6 h

Procedure:
To a solution of methyl-5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylate (Compound E2, 835.0 mg, 3.60 mmol) in 25.0 mL of THF at room temperature was added TiCl4 (670.0 mg, 3.55 mmol). Thereafter a solution of thiophenol (430.0 mg, 3.90 mmol) and Et3N (730.0 mg, 7.20 mmol) in 10 mL THF was added. The resulting brown mixture was stirred for 6 h before H2 0 was carefully added to quench the reaction. The product was extracted into Et2O and the combined organic layers washed with saturated aqueous NaCl and dried over MgSO4. Removal of the solvents under reduced pressure afforded a solid from which the title compound was isolated as a yellow solid by column chromatography (5% EtOAc-hexanes).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.[C:13](Cl)(=[O:15])[CH3:14]>ClCCCl>[F:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][C:11]=1[C:13](=[O:15])[CH3:14]
Reactant: Oc1cccc(F)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc(O)cc1F
Temperature: 25 °C
Yield: 8.4 %

Procedure:
To a stirred suspension of aluminum chloride (42 g, 312 mmol) in 1,2-dichloroethane (100 ml) was added 3-fluorophenol (31 g, 276 mmol) dropwise at 0° C. After addition, acetyl chloride (24 g, 306 mmol) was added dropwise and then the mixture was heated at reflux temperature for 16 hours. The mixture was cooled down to room temperature, and poured into ice. The whole was extracted with diethylether. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was recystallized with hexane to give title compound (3.57 g, 8% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[CH2:14][S:15]([N:18]=[C:19]=[O:20])(=[O:17])=[O:16])=[O:4].[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25]([NH2:31])[N:24]=1.C(Cl)CCC>C(Cl)Cl>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25]([NH:31][C:19]([NH:18][S:15]([CH2:14][C:6]2[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])(=[O:17])=[O:16])=[O:20])[N:24]=1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CS(=O)(=O)N=C=O
Reactant: COc1cc(OC)nc(N)n1
Solvent: ClCCl
Solvent: CCCCCl
Product: COC(=O)c1cccc([N+](=O)[O-])c1CS(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1

Procedure:
A solution of the sulfonyl isocyanate from Example 6 (approximately 1.2 g) and 0.55 g of 4,6-dimethoxy-2-aminopyrimidine in 5 ml methylene chloride was stirred at room temperature for 4 hours. The reaction mixture was then filtered and the filtrate concentrated in vacuo to give a gummy solid. Trituration with warm n-butyl chloride gave a tan solid which was filtered and washed with ethyl acetate. The yield of 2-[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]methyl-3-nitrobenzoic acid, methyl ester was 1.0 g as a light tan-colored solid, m.p. 177°-181°; IR(nujol): 1730, 1700 cm-1 ; NMR (CDCl3 /DMSO-d6): δ 3.75 (6H, s, OCH3 's), 3.8 (3H, s, CO2CH3), 5.7 (2H, s, --CH2 --), 5.8 (1H, s, heterocyclic ring H), 7.65-8.4 (3H, m).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=O)[CH2:8][CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:6][C:5]=2[NH:4][CH:3]=1.[C:18]([NH:21][NH2:22])([NH2:20])=[NH:19].[ClH:23].Cl.O>C(O)C>[ClH:23].[NH:21]([N:22]=[C:9]1[CH2:8][CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][C:5]2[NH:4][CH:3]=[C:2]([CH3:1])[C:10]1=2)[C:18]([NH2:20])=[NH:19]
Reactant: Cc1c[nH]c2c1C(=O)CC(c1ccccc1)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1c[nH]c2c1C(=NNC(=N)N)CC(c1ccccc1)C2
Yield: 8.9 %

Procedure:
A mixture of 3-methyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.8 g), aminoguanidine hydrochloride (0.41 g), concentrated hydrochloric acid (0.18 ml), water (0.18 ml) and ethanol (50 ml) was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with diethylether. To the mixture was added sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and to the residue was 1N hydrochloric acid (2 ml). The solvent was evaporated, and the residue was recrystallized from ethanol-ethyl acetate to give 4-guanidinoimino-3-methyl-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 2) (0.1 g) as colorless crystals.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:32])[N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34].[N:35]1([CH2:40][CH2:41]O)[CH:39]=[CH:38][N:37]=[CH:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[N:35]1([CH2:40][CH2:41][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](=[O:32])[N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:29])[CH3:30])[CH:20]=[N:21]3)=[CH:16][C:15]=2[O:33][CH3:34])[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Reactant: OCCn1ccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCn1ccnc1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 79.9 %

Procedure:
Diethyl azodicarboxylate (435 mg, 2.5 mmol) was added dropwise to a suspension of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (612 mg, 2 mmol), (prepared as described for the starting material in Example 85), 2-(imidazol-1-yl)ethanol (280 mg, 2.5 mmol), (J. Med. Chem. 1993, 25 4052-4060), and triphenylphosphine (655 mg, 2.5 mmol) in methylene chloride (10 ml) at 5° C. The mixture was stirred for 10 minutes at 5° C. and then 1 hour at ambient temperature. The mixture was poured directly on to a silica column and eluted with methylene chloride/methanol (95/5) to give 7-(2-(imidazol-1-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (640 mg, 80%).
Reaction SMILES: [I-:1].[OH:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N+:11]([CH3:21])([CH3:20])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1.CO.C(=O)([O-])[O-].[K+].[K+].[CH2:30]([N:32]([CH3:36])[C:33](Cl)=[O:34])[CH3:31]>C(O)CO>[I-:1].[CH2:30]([N:32]([CH3:36])[C:33]([O:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N+:11]([CH3:21])([CH3:20])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1)=[O:34])[CH3:31]
Reactant: CCN(C)C(=O)Cl
Reactant: C[C@@H](c1ccccc1)[N+](C)(C)[C@@H](C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: OCCO
Product: CCN(C)C(=O)Oc1cccc([C@H](C)[N+](C)(C)[C@@H](C)c2ccccc2)c1
Temperature: 60 °C

Procedure:
Mix 7.9 g (0.02 mol) of (S)-1-(3-hydroxyphenyl)-N,N-dimethyl-N—((S)-1-phenylethyl)ethanaminium iodide (formula VIII) with 100 ml of methanol, 4.1 g (0.03 mol) of potassium carbonate, 3.6 g (0.03 mol) ethyl(methyl)carbamic chloride and 0.1 g of macrogol 400 at room temperature, heat it to 60° C. and react it for 12 hours. After it is cooled to room temperature, filter it and reduce the pressure to recover the solvent and receive 9.0 g of red-brown liquid to be directly used in the next reaction.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:22][CH3:23])[C:9]2[C:14]([C:15]=1[N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH:13][CH:12]=[C:11]([CH3:21])[N:10]=2)=[O:5])[CH3:2].N1CC[O:28]CC1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:22][CH3:23])[C:9]2[C:14]([C:15]=1[N:16]1[CH2:17][CH2:18][O:28][CH2:19][CH2:20]1)=[CH:13][CH:12]=[C:11]([CH3:21])[N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCCC2)c2ccc(C)nc2n(CC)c1=O
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(N2CCOCC2)c2ccc(C)nc2n(CC)c1=O

Procedure:
A stirred mixture of 0.59 g. (0.002 mole) of 1-ethyl-1,2-dihydro-4-chloro-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (Example 30), 0.17 g. (0.002 mole) of morpholine and 0.2 g. (0.002 mole) of sodium carbonate in 20 ml. of ethanol was heated under reflux for 4 hours. The mixture was filtered and the filtrate was diluted with water to the cloudy point. The precipitate which formed was collected, air dried and was recrystallized from heptane to afford 0.2 g. of product, m.p. 129°-131° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([OH:17])=O)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[C:20]([O:24][C:25]([N:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([NH2:37])[CH:33]=2)[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:20]([O:24][C:25]([N:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([NH:37][C:15]([C:10]3[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:8][CH:7]=4)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:17])[CH:33]=2)[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2C1
Yield: 97.2 %

Procedure:
7.6 g (29 mmol) of 4'-trifluoromethyl-biphenyl-2-carboxylic acid, 7.1 g (29 mmol) of 6-amino-3,4-dihydro-1H-isoquinoline-2-caboxyiic acid tert-butyl ester, 100 mg of DMAP and 6.1 g (32 mmol) of EDCl were mixed in 130 ml of methylene chloride for 12 hrs. Reaction was extracted with 2×150 ml 1N HCl, 2×150 ml 1N NaOH, 150 ml water, brine and concentrated to yield 14 g of a beige foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.[C:15]([C:19]1[CH:35]=[CH:34][C:22]([CH2:23][NH:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:15]([C:19]1[CH:35]=[CH:34][C:22]([CH2:23][N:24]([CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([F:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:21][CH:20]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: O=C(O)c1c(F)c(F)cc2cc[nH]c12
Reactant: Cc1ccc(CCNCc2ccc(C(C)(C)C)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(CCN(Cc2ccc(C(C)(C)C)cc2)C(=O)c2c(F)c(F)cc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 37.5 %

Procedure:
87 mg (0.44 mol) of 5,6-difluoro-1H-indol-7-carboxylic acid, 113 mg (0.40 mmol) of (4-tert-butyl-benzyl)-[2-(4-methyl-phenyl)-ethyl]-amine and 84 mg (0.44 mmol) of EDC.HCl were dissolved in 4 ml DCM. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was purified by column chromatography (20 g silica gel; heptane/EtOAc 4:1) to yield 69 mg (38%) product as a colorless viscous oil. MS (ISP) 461.3 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:20](/B(O)O)=[CH:21]\[CH2:22][CH2:23][CH2:24][CH3:25].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:41].Cl.Cl>CCOCC>[ClH:41].[ClH:41].[CH:20](/[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[CH:21]\[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: Brc1cnc2ccc(NCCCN3CCCC3)nn12
Reactant: CCCC/C=C/B(O)O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCOCC
Product: CCCC/C=C/c1cnc2ccc(NCCCN3CCCC3)nn12
Yield: 36 %

Procedure:
Prepared from the product of step A and (E)-1-hexeneboronic acid according to general procedure 2. The free-base was converted to the dihydrochloride salt with 2N HCl in Et2O to provide the title compound (59 mg, 36%) as a brown solid; 1H NMR (500 MHz, CD3OD) δ 7.97 (s, 1H), 7.92 (d, J=9.9 Hz, 1H), 7.23 (d, J=9.9 Hz, 1H), 6.87-6.85 (m, 1H), 6.72-6.69 (m, 1H), 3.70-3.66 (m, 2H), 3.56 (t, J=6.7 Hz, 2H), 3.37-3.34 (m, 2H), 3.13-3.08 (m, 2H), 2.37-2.33 (m, 2H), 2.22-2.13 (m, 4H), 2.06-2.02 (m, 2H), 1.56-1.50 (m, 2H), 1.47-1.41 (m, 2H), 0.97 (t, J=7.3 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 157.1, 139.2, 133.2, 130.4, 121.3, 120.7, 117.6, 114.2, 55.3, 54.2, 39.7, 34.3, 32.3, 26.0, 24.1, 23.3, 14.3; HPLC tR=12.3 min (Luna), 97.6%; ES-MS: (M+H)=328 m/z.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.C(=O)([O-])[O-].[NH4+:33].[NH4+]>C(Cl)Cl.C(O)C>[ClH:27].[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1)(=[NH:33])[NH2:2]
Reactant: N#Cc1cccc(COc2cccc(OS(=O)(=O)c3ccccc3Cl)c2)c1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: N=C(N)c1cccc(COc2cccc(OS(=O)(=O)c3ccccc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 150 %

Procedure:
5 To a solution of 2-chlorobenzenesulfonic acid 3-[(3-cyanophenyl)methoxy]phenyl ester (280 mg, 0.7 mmol), as prepared in the preceding step, in methylene chloride (10 mL) was added 37% HCl in ethanol (15 mL) at 0° C. The mixture was stirred at room temperature for 2 days. The solvent was evaporated and the residue was co-evaporated with methylene chloride several times. The residue was then dissolved in ethanol (10 nL) and ammonium carbonate (300 mg, 3.0 mmol) was added at 0° C. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride (150 mL), washed with 10% K2CO3 (2×50 mL), and dried over K2CO3. The solvent was removed in vacuo, HCl in methanol (30 mL) was added, and then concentrated in vacuo. The residue was purified by flash chromatography (10% methanol in methylene chloride) to give the title compound as a white foam (238 mg, 75%). 1H-NMR (300 MHz, DMSO-d6) δ 5.15 (s, 2H), 6.67 (d, 1H, J=4.0 Hz), 6.81 (s, 1H), 7.03 (d, 1H, J=4.0 Hz), 7.32 (t, 1H, J=8.3 Hz), 7.58 (t, 1H, J=7.5 Hz), 7.65 (t, 1H, J=7.7 Hz), 7.75-7.94 (m, 6H), 9.27 (br s, 2H), and 9.45 (br s, 2H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C20H17N2ClO4S: 417.1 (M+H), 439.0 (M+Na). Found: 417.4, 439.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[Cl:7][CH2:8][CH2:9]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:9][CH2:8][Cl:7])[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: OCCCl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClCCn1cc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-1H-pyrazole (5 g, 34.02 mmol), 2-chloroethanol (2.7 mL, 40.82 mmol) and PPh3 (10.71 g, 40.82 mmol) and in THF (68 mL) at 0° C. was added DEAD (6.4 mL, 40.8 mmol). The mixture was allowed to warm-up to room temperature and stirred overnight. It was then concentrated under reduced pressure, the residue was treated with ether and the resultant suspension was filtered. The filtrate was collected and concentrated under reduced pressure to afford the title compound 75 which was used in the next step without further purification. MS (m/z). 209.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].C(N(CC)CC)C.[CH3:28][C:29]1([CH2:34][NH2:35])[CH2:33][CH2:32][NH:31][CH2:30]1>C(#N)C>[NH2:35][CH2:34][C:29]1([CH3:28])[CH2:33][CH2:32][N:31]([C:3]2[C:2]([Cl:1])=[C:11]3[C:6]([C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9][N:10]3[CH:12]3[CH2:14][CH2:13]3)=[CH:5][C:4]=2[F:19])[CH2:30]1
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: CC1(CN)CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1(CN)CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)C1
Yield: 95 %

Procedure:
To 1.05 g (3.50 mmol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added 15 ml of acetonitrile, 1.0 g (9.9 mmol) of triethylamine and 0.7 g (6 mmol) of the 3-methyl-3-pyrrolidinemethanamine. The mixture was refluxed 18 hours and cooled. Filtration gave 1.31 g of the title compound, mp 189°-191° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[S:10][CH:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=2)[CH:3]=[N:2]1.[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:11]([C:8]2[CH:7]=[C:6]([C:4]3[CH:5]=[N:1][NH:2][CH:3]=3)[S:10][CH:9]=2)=[O:13])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(O)c1csc(-c2cn[nH]c2)c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)c2csc(-c3cn[nH]c3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
5-(1H-Pyrazol-4-yl)-thiophene-3-carboxylic acid (0.194 g, 1.0 mmol) and [1,4]diazepane-1-carboxylic acid tert-butyl ester (0.25 g, 1.25 mmol) were dissolved in DMF (5 mL) then DIPEA (0.387 g, 3.0 mmol) and HATU (0.46 g, 1.2 mmol) were added and the reaction mixture stirred at room temperature overnight. The solvent was removed by evaporation then the residue was dissolved in DCM and washed with water. The organic phase was washed with 0.5 M HCl then aqueous sodium hydrogen carbonate solution then the organics were evaporated. The crude material was purified by flash chromatography on a 10 g silica II cartridge, eluting with 2% methanol in DCM. The fractions containing the desired product were concentrated under vacuum to give 4-[5-(1H-pyrazol-4-yl)-thiophene-3-carbonyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.29 g) as a white solid. LCMS m/z 377.32 [M+H]+ R.T.=3.00 min (Analytical Method 6).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C[N:11](N=O)[C:12]([NH:14][N+:15]([O-:17])=[O:16])=N.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:12]([NH:14][N+:15]([O-:17])=[O:16])=[NH:11]
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Reactant: NCc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=C(NCc1cccc(F)c1)N[N+](=O)[O-]
Reaction time: 18 h
Yield: 89.2 %

Procedure:
The compound m-fluorobenzylamine (7.5 g, 0.06 mol) is added to a slurry of N-methyl-N-nitroso-N'-nitroguanidine (8.33 g, 0.056 mol) in a 50% aqueous ethanol mixture. The thus-formed mixture is stirred for 18 hours, then treated with 1N NaOH (150 ml), and the mixture filtered. The filtrate is acidified with concentrated HCl, and the reaction mixture is then filtered to obtain the desired fluffy white solid product (10.6 g) having a melting point of 177° C.-179° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([F:12])[CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]([C:18]1[CH:22]=[C:21]([NH2:23])[O:20][N:19]=1)([CH3:17])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:23][C:21]2[O:20][N:19]=[C:18]([C:15]([CH3:17])([CH3:16])[C:14]([F:25])([F:24])[F:13])[CH:22]=2)=[O:11])=[C:4]([F:12])[CH:3]=1
Reactant: CC(C)(c1cc(N)on1)C(F)(F)F
Reactant: O=C(O)Cc1ccc(Br)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(c1cc(NC(=O)Cc2ccc(Br)cc2F)on1)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.2 %

Procedure:
To a mixture of 2-(4-bromo-2-fluorophenyl)acetic acid (360 mg, 1.545 mmol) in DCM (50 mL) was added 3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-amine (300 mg, 1.545 mmol), HATU (881 mg, 2.317 mmol) and triethylamine (0.645 mL, 4.63 mmol). Then the mixture was stirred at 25° C. for 12 h. The mixture was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to yield a yellow oil of 2-(4-bromo-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide (600 mg, 1.1 mmol, 71% yield): 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=6.8 Hz, 1H), 7.34-7.29 (m, 1H), 7.21 (s, 1H), 6.64 (d, J=6.8 Hz, 1H), 6.43 (s, 1H), 3.75 (s, 2H), 1.52 (s, 6H); ES-LCMS m/z 409 (M+H).