Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[Cl:22])=[O:4].[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([Cl:22])[CH:10]=1)[N:7]=[C:6]([N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1c(Cl)nc2c(Cl)cc(Cl)cc2c1-c1ccccc1
Reactant: CCNCC
Product: CCN(CC)c1nc2c(Cl)cc(Cl)cc2c(-c2ccccc2)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 21 step D from 2,6,8-trichloro-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 21 step C) and diethylamine. Brown foam. MS (ESI): 389.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[N:11]([CH2:16][CH2:17][OH:18])[CH:10]=[C:9]([C:19]([O:21]CC)=[O:20])[C:8]2=[O:24].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.C1COCC1>[Cl:1][C:2]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[N:11]([CH2:16][CH2:17][OH:18])[CH:10]=[C:9]([C:19]([OH:21])=[O:20])[C:8]2=[O:24]
Reactant: CCOC(=O)c1cn(CCO)c2c(F)cc(Cc3cccc(Cl)c3Cl)cc2c1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cn(CCO)c2c(F)cc(Cc3cccc(Cl)c3Cl)cc2c1=O
Temperature: 60 °C
Yield: 94.8 %

Procedure:
Ethyl 6-(2,3-dichlorobenzyl)-1,4-dihydro-8-fluoro-1-(2-hydroxyethyl)-4-oxo-3-quinolinecarboxylate (80 mg, 0.18 mmol) obtained in Step 6 was dissolved in a mixture of ethanol (2 ml) and THF (1 ml), and 1N aqueous sodium hydroxide solution (1 ml, 1.0 mmol) was added. The mixture was stirred with heating at 60° C. for 1 hr. After allowing the mixture to cool, 10% aqueous citric acid solution was added to the reaction solution. The precipitate was collected by filtration, washed with 30% aqueous ethanol and vacuum-dried to give an object product (70 mg, yield 93%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][CH:10]([F:12])[F:11])[C:5]([OH:8])=[N:6][CH:7]=1.[CH3:13]I>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH:10]([F:12])[F:11])[C:5]([O:8][CH3:13])=[N:6][CH:7]=1
Reactant: Oc1ncc(Br)cc1OC(F)F
Reactant: CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1ncc(Br)cc1OC(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
As shown in step 3-v of Scheme 3, 5-bromo-3-(difluoromethoxy)pyridin-2-ol (300 mg; 1.25 mmol) was dissolved in 5 mL of chloroform. Silver carbonate (690 mg; 2.5 mmol) and methyl iodide (780 μL; 1.77 g; 12.5 mmol) were added and the mixture stirred at RT overnight. The reaction mixture was filtered through diatomaceous earth, which was washed with additional CHCl3. The filtrates were concentrated under reduced pressure to yield an oil which was purified by silica gel chromatography to yield 5-bromo-3-(difluoromethoxy)-2-methoxypyridine as a white solid (Compound 1010, 250 mg, 78% yield): ESMS (M+H) 254/256; 1H NMR (CDCl3) δ 8.08 (d, 1H, J=2.1 Hz), 7.56 (d, 1H, J=2.1 Hz), 6.60 (t, 1H, J=75 Hz), 3.98 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)[CH3:2].[Cl:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19](Cl)[N:18]=[CH:17][N:16]=1>>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:19]2[C:20]([N+:21]([O-:23])=[O:22])=[C:15]([Cl:14])[N:16]=[CH:17][N:18]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Product: CCOC(=O)Cc1ccc(Nc2ncnc(Cl)c2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Aminophenylacetic acid ethyl ester (0.93 g, 5.2 mmol) is added to a solution of 4,6-dichloro-5-nitropyrimidine (2 g, 10.4 mmol, 2 equiv). The resulting mixture is stirred for 2 h at rt and 4-aminophenylacetic acid ethyl ester (0.47 g, 2.6 mmol, 0.5 equiv) is added. The reaction mixture is stirred for 15 min and filtered. The filtrate is concentrated. The residue is dissolved in EtOAc and a saturated aqueous solution of sodium bicarbonate. The layers are separated. The aqueous phase is extracted with EtOAc. The combined organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the residue by silica gel column chromatography (Hexane/EtOAc, 4:1) provides the title compound as a yellow solid: ES-MS: 335.0/337.0 [M-H]−; single peak at tR=4.73 min (System 1); Rf=0.22 (Hexane/EtOAc, 4:1).
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si](CC(C)C)(C)C)[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[CH3:39][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:37][CH:38]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccc(O[Si](C)(C)CC(C)C)c2)=CCC3(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccc(O)c2)=CCC3(C)C)cc1
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(3-((2,2-dimethylethyl)-dimethylsiloxy)-phenyl)-2-naphthalenyl)ethynyl]benzoate (Compound H) 60.0 mg (0.114 mmol) in 1.0 ml of THF at room temperature was added 91.5 mg (0.35 ml, 0.35 mmol) of tetrabutylamonium flouride (1M solution in THF). After stirring overnight, the solution was diluted with EtOAc and washed with H2O and saturated aqueous NaCl, before being dried over MgSO4. Removal of the solvents under reduced pressure, followed by column chromatography (4: 1, Hexanes:EtOAc) afforded the title compound as a colorless solid. 1H NMR (CDCl3): δ7.98 (2H, d, J=7.8 Hz), 7.52 (2H, d, J=8.3 Hz), 7.39-7.21 (4H, m), 6.93 (1H, d, J=7.5 Hz), 6.84 (1H, d, 7.1 Hz), 6.83 (1H, s), 6.01 1H, t, J=4.7 Hz), 4.91 (1H, s), 4.39 (2H, q, J=7.1 Hz), 2.35 (2H, d, J=4.7 Hz), 1.39 (3H, t, J=7.1 Hz), 1.34 (6H, s).
Reaction SMILES: [C:1]([C:3](=[C:8]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[CH3:18])SC)[C:4]([O:6]C)=O)#[N:2].Cl.[CH:20]1([CH2:26][C:27]([NH2:29])=[NH:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:20]1([CH2:26][C:27]2[NH:29][C:4](=[O:6])[C:3]([C:1]#[N:2])=[C:8]([NH:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:17]=3[CH3:18])[N:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: N=C(N)CC1CCCCC1
Reactant: COC(=O)C(C#N)=C(Nc1cnccc1C)SC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccncc1Nc1nc(CC2CCCCC2)[nH]c(=O)c1C#N
Temperature: 90 °C

Procedure:
0.4 g (1.51 mmol) of methyl 2-cyano-3-[(4-methyl-3-pyridinyl)amino]-3-(methylsulfanyl)-2-propenoate are dissolved with 0.29 g (1.67 mmol) of 2-cyclohexylethanamidine hydrochloride and 0.46 g (3.3 mmol) of potassium carbonate in 5 ml of DMF and heated at 90° C. for 7 days. After cooling and filtration, the product is purified by preparative HPLC (YMC Gel ODS-AQ S 5/15 μm; eluent A; water, eluent B: acetonitrile, gradient: 0 min 30% B, 5 min 30% B, 50 min 95% B) purified. 433 mg (88% of theory) of the product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1.[H-].[Na+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:34])(=O)=O)=CC=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]([S:12]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:13])=[O:14])([F:34])[CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COC(=O)C(C1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(F)(C1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 29.1 %

Procedure:
To a stirred solution of 10 g (0.032 mol) of benzenesulfonyl-(3-oxo-cyclohexyl)-acetic acid methyl ester in 110 mL of DMF at 0° C., 1.42 g (0.035 mol, 1.1 eq) of NaH (60%) were added. The reaction mixture was stirred at this temperature for one hour, and 15.71 g (0.048 mol, 1.5 eq) of N-fluorobenzenesulfonimide were added. After 2 hours at RT, the reaction mixture was poured into water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. The resulting two diastereomers were separated by column chromatography on silica gel with heptane/EtOAc 2:1, yielding 3.06 g (27%) of (RS,SR)-benzenesulfonyl-fluoro-(3-oxo-cyclohexyl)-acetic acid methyl ester as a white solid, MS: 329 (MH+) and 3.2 g (28%) of (RR,SS)-benzenesulfonyl-fluoro-(3-oxo-cyclohexyl)-acetic acid methyl ester as a white solid, MS: 329 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([N+:24]([O-:26])=[O:25])=[C:18]([S:20](Cl)(=[O:22])=[O:21])[CH:19]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([N+:24]([O-:26])=[O:25])=[C:18]([S:20]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:21])=[O:22])[CH:19]=1
Reactant: COc1ccc([N+](=O)[O-])c(S(=O)(=O)Cl)c1
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc([N+](=O)[O-])c(S(=O)(=O)Nc2cccc3cccnc23)c1
Yield: 29.1 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (950 mg, 6.59 mmol), 5-methoxy-2-nitro-benzenesulfonyl chloride (Intermediate 447) (2.15 g, 8.57 mmol), pyridine (4 ml), DMAP (cat.) and DCM (8 ml) gave the title compound (690 mg, 30%) after purification by column chromatography with n-hexane/EtOAc (80:20) as the eluent.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].N1C=CC=CC=1.Cl[C:20](=[O:25])[C:21]([O:23][CH3:24])=[O:22]>C1(C)C=CC=CC=1>[C:20]([O:8][C:7]1[C:2]([F:1])=[C:3]([F:12])[C:4]([F:11])=[C:5]([F:10])[C:6]=1[F:9])(=[O:25])[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C(=O)Cl
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
In 35 ml of toluene, 10 g (54 mmol) of pentafluorophenol and 5 ml (61 mmol) of pyridine were dissolved. To the solution, 7.2 g (59 mmol) of methyl chloroglyoxylate were added dropwise under an ice bath for the reaction. After 1 hour stirring at room temperature, the reaction mixture was filtered and concentrated. The thus obtained crude product was purified by distillation to obtain 10.1 g of pentafluorophenyl methyl oxalate. The compound had a melting point of 34 to 35° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:34])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=4)[CH2:23][C:22](=[O:34])[NH:21][C:9]=3[CH:10]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1ccnc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)ccn1

Procedure:
Prepared from {3-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-4′-fluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K63) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as an orange solid (23 mg).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][C:11]([F:16])=[C:12]([CH3:15])[CH:13]=3)[C:8]([C:17](Cl)=[O:18])=[C:7]2[C:20]2[CH:25]=[CH:24][C:23]([S:26](=[O:35])(=[O:34])[NH:27][C@@H:28]([CH3:33])[C:29]([F:32])([F:31])[F:30])=[CH:22][N:21]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][NH2:37].C1COCC1>C(OCC)(=O)C>[CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][C:11]([F:16])=[C:12]([CH3:15])[CH:13]=3)[C:8]([C:17]([NH:37][CH3:36])=[O:18])=[C:7]2[C:20]2[CH:25]=[CH:24][C:23]([S:26](=[O:35])(=[O:34])[NH:27][C@@H:28]([CH3:33])[C:29]([F:32])([F:31])[F:30])=[CH:22][N:21]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc2c(cc1F)c(C(=O)Cl)c(-c1ccc(S(=O)(=O)N[C@@H](C)C(F)(F)F)cn1)n2C1CCCC1
Reactant: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(S(=O)(=O)N[C@@H](C)C(F)(F)F)cn2)n(C2CCCC2)c2cc(C)c(F)cc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67 %

Procedure:
A mixture of (S)-1-cyclopentyl-5-fluoro-6-methyl-2-(5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-1H-indole-3-carboxylic acid (300 mg, 0.58 mmol) in SOCl2 (4 mL) was stirred at 66° C. for 2 h. Volatiles were removed by a stream of nitrogen followed by vacuum to give (S)-1-cyclopentyl-5-fluoro-6-methyl-2-(5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-1H-indole-3-carbonyl chloride as a solid. The above prepared (S)-1-cyclopentyl-5-fluoro-6-methyl-2-(5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-1H-indole-3-carbonyl chloride (100 mg, 0.188 mmol) was treated with a solution of methylamine in THF (2.0 M, 5 mL, 10 mmol) and stirred at room temperature for 5 min. The mixture was then treated with ethyl acetate, washed with water and brine, dried over Na2SO4 and evaporated to give (S)-1-cyclopentyl-5-fluoro-N,6-dimethyl-2-(5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-1H-indole-3-carboxamide (66 mg, 67%). MS m/z 527.3 M+H+; 1H NMR (500 MHz, CDCl3): δ 9.18 (1H, br s), 8.30 (1H, dd, J=8.0 Hz, J=2.0 Hz), 7.73 (1H, d, J=8.5 Hz), 7.66 (1H, d, J=10.5 Hz), 7.28 (1H, br s), 6.26 (1H, br s), 5.91 (1H, d, J=9.5 Hz), 4.51-4.40 (1H, m), 4.15-4.10 (1H, m), 2.84 (3H, s), 2.43 (3H, d, J=1.5 Hz), 2.30-2.23 (2H, m), 2.10-1.90 (4H, m), 1.68-1.62 (2H, m), 1.42 (3H, d, J=8.5 Hz).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[C@H:10]([C:11]([OH:13])=[O:12])[CH2:9][CH:8]2[CH2:14][O:15][CH2:16][CH:7]12)=[O:5])[CH3:3].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26](=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:20][CH:19]=1.C([BH3-])#N.[Na+]>C(O)C>[C:27]([CH:26]([NH:1][C@H:2]([C:4]([N:6]1[C@H:10]([C:11]([OH:13])=[O:12])[CH2:9][CH:8]2[CH2:14][O:15][CH2:16][CH:7]12)=[O:5])[CH3:3])[CH2:25][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=1)([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)C(=O)CCc1ccc(Cl)cc1
Reactant: C[C@H](N)C(=O)N1C2COCC2C[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCc1ccc(Cl)cc1)N[C@@H](C)C(=O)N1C2COCC2C[C@H]1C(=O)O

Procedure:
Treat 1-[(S)-alanyl]hexahydrofuro[3,4-b]pyrrole-2-(S)-carboxylic acid (prepared as described in Example 47) and ethyl 4-(p-chlorophenyl)-2-oxobutyrate with sodium cyanoborohydride as described in Example 47D (ethanol solvent) to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:12]=2[NH:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:12]=2[NH:11][C:10](=[S:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)Nc2cc(F)ccc2C1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(=S)Nc2cc(F)ccc2C1
Temperature: 90 °C
Yield: 137.8 %

Procedure:
To a solution of 8-fluoro-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (3.24 g, 11.57 mmol) in toluene (50 mL), was added Lawesson's reagent (2.33 g, 5.78 mmol) at r.t. The reaction mixture was heated at 90° C. for 30-40 min. After completion of reaction, as confirmed by TLC, distilled water (50 mL) was added and the crude compound was extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4. The solvents were removed in vacuo to afford the crude compound, which was purified by column chromatography (silica gel, 2:8 EtOAc:Pet. ether) to afford pure 8-fluoro-2-thioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert butyl ester (2.36 g, 69%) as light Yellow solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:7]([CH2:14][CH3:15])[CH2:8][CH2:9][O:10][CH2:11][CH2:12]O)[CH3:6]>C1C=CC=CC=1>[CH2:5]([N:7]([CH2:14][CH3:15])[CH2:8][CH2:9][O:10][CH2:11][CH2:12][Cl:3])[CH3:6]
Reactant: CCN(CC)CCOCCO
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCN(CC)CCOCCCl

Procedure:
A modification of the procedure described in J. Am. Chem. Soc. 76:3163 (1954) was used to obtain this compound, beginning with the dropwise addition of thionyl chloride (17.02 mL, 233.42 mmol) to a solution of 2-(2-di-ethylaminoethoxy)-ethanol in benzene (100 mL). The reaction mixture was stirred at reflux for 1.5 hours and the volatiles were removedunder diminished pressure. The oily residue crystallized in ether, was nearly homogeneous by TLC, and was used without further purification. The HCl salt obtained in this reaction was very hygroscopic. Attempts at purification of the free base via distillation resulted in decomposition. CIMS 180 m/z (M+1), 183 m/z (M+3).
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.[CH3:21][CH:22]([CH3:25])[CH:23]=[CH2:24]>>[CH3:21][CH:22]([CH3:25])[CH2:23][CH2:24][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: C=CC(C)C
Reactant: CCOC(=O)C1=Cc2ccc(I)cc2OC1C(F)(F)F
Product: CCOC(=O)C1=Cc2ccc(CCC(C)C)cc2OC1C(F)(F)F

Procedure:
The ester from Example 9a, Step 2 was coupled and using a similar protocol as described in Example 611d, Step 1 using the appropriate substitution of 3-methylbut-1-ene (77%): ESLRMS m/z 343.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:22])[CH:4]=[C:5]([CH2:10][NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])(=[O:14])=[O:13])[O:6][C:7]=1[CH2:8][OH:9].[CH2:23](OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1CO)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:1][C:2]1[C:3](=[O:22])[CH:4]=[C:5]([CH2:10][NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])(=[O:14])=[O:13])[O:6][C:7]=1[CH2:8][OH:9])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(O)c(CO)o1
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2)oc(CO)c1OCc1ccccc1
Product: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(OCc2ccccc2)c(CO)o1
Yield: 40.85 %

Procedure:
N-(5-Benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-2-methyl-benzenesulfonamide (10-02) (4.7 g, 40.85%) was synthesized as a white solid from N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-2-methyl-benzenesulfonamide (9-02) (9.0 g, 27.69 mmol) following the procedure described for N-(5-benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (10-01).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(CN3CCOCC3)cc2)CC1
Reaction time: 3 h

Procedure:
A solution of 4-(4-formyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (2.06 g) in methanol (100 mL) was treated with morpholine (4 mL) and NaBH(OAc)3 (6.98 g, in portions over 1 h). After 3 h, the mixture was diluted with saturated aquoues NaHCO3 and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (SiO2) to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:13][CH:12]=2)=[C:6]([N+:25]([O-])=O)[CH:5]=1.[NH4+].[Cl-]>CCO.O(C(C)C)C(C)C.[Fe]>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[CH:15][CH:16]=2)=[C:6]([NH2:25])[CH:5]=1
Reactant: COC(=O)c1ccc(Oc2ccc(NC(=O)OC(C)(C)C)cc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: COC(=O)c1ccc(Oc2ccc(NC(=O)OC(C)(C)C)cc2)c(N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
A suspension of 4-(4-tert-butoxycarbonylamino-phenoxy)-3-nitro-benzoic acid methyl ester (18.0 g, 46 mmol), Fe powder (13.5 g, 232 mmol) and NH4Cl (12.4 g, 232 mmol) in aqueous EtOH [prepared from EtOH (180 mL) and H2O (180 mL)] was gradually heated to reflux and refluxed for 1.5 hours. The reaction mixture was filtrated through celite pad and the filtrate was evaporated. The aqueous residue was portioned between AcOEt and 5% NaHCO3 and then filtered through celite pad. The organic layer was separated, washed H2O and brine, dried over MgSO4 and evaporated to give pale brown oil, which was diluted with i-Pr2O (100 mL) and stirred at room temperature for 1 hour. The resulting crystal was collected by filtration, washed with i-Pr2O, and dried at 40° C. overnight under reduced pressure to give the title compound as colorless crystal (10.5 g, 63%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:6]=[C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[CH:10][CH2:9][CH2:8]1>C(O)C>[O:6]=[C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][CH:9]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:8]1
Reactant: C1CCNC1
Reactant: O=C1CCC=Cc2ccccc21
Solvent: CCO
Product: O=C1CC(N2CCCC2)CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
A solution of 7.1 g of pyrrolidine in 30 ml of ethanol was added to a solution of 7.9 g of 5-oxo-6,7-dihydro [5H] benzocycloheptene in 30 ml of ethanol and the mixture was stirred at room temperature for 30 minutes and was evaporated to dryness to obtain 11.5 g of 5-oxo-7-(Pyrrolidin-1-yl)-6,7,8,9-tetrahydro [5H] benzocycloheptene.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH:3]=[CH:2]1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:40](=[NH:42])[NH2:41])[CH:36]=2)[CH:31]=1)(=O)=O.C(OCC)C>N1C=CC=CC=1>[CH:1]1([CH2:6][C:7]([O:9][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([C:40](=[NH:41])[NH2:42])[CH:36]=3)[CH:31]=2)=[O:8])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: O=C(O)CC1C=CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: N=C(N)c1ccc2cc(OC(=O)CC3C=CCC3)ccc2c1
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
To a solution of 2.2 g of 2-cyclopentene-1-acetic acid in 50 ml of anhydrous pyridine, while being cooled in ice and stirred, was added 4.4 g of DCC. After 30 minutes, 5.0 g of 6-amidino-2-naphthol methanesulfonate was added to the mixture and stirred for 24 hours at room temperature. The precipitate formed by the addition of ethyl ether was collected by filtration, admixed with dimethylformamide, and filtered to remove the insolubles. Ethyl ether was added to the filtrate and the precipitate which was formed was collected by filtration and recrystallized from a dimethyl formamide-ethyl ether mixture to yield 2.1 g of a white powder of 6-amidino-2-naphthyl 2-cyclopenteneacetate methanesulfonate.