Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([OH:24])=[O:23])[CH2:10][S:11][CH:12]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[CH2:13][N+:14]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)(=O)C.[Pd]>[NH2:14][CH2:13][CH:12]([S:11][CH2:10][C@@H:9]([C:22]([OH:24])=[O:23])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSC(C[N+](=O)[O-])c1cccs1)C(=O)O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CSC(CN)c1cccs1)C(=O)O
Temperature: 70 °C
Reaction time: 5 h
Yield: 81.8 %

Procedure:
129 g of N-t-butoxycarbonyl-S-[2-nitro-1-(2-thienyl)ethyl]-L-cysteine [produced as described in step (a) above] were dissolved in 1 liter of acetic acid. To the solution were added 100 g of 10% w/w palladium-on-carbon, and the mixture was shaken for 5 hours at 70° C. in an atmosphere containing hydrogen at a partial pressure of 3-4 kg/cm2. The palladium-on-carbon catalyst was then filtered off, and the filtrate was condensed by evaporation under reduced pressure. The remaining acetic acid was then distilled off as an azeotrope with toluene. The residue was dissolved in a mixture of 500 ml of ethyl acetate and 100 ml of water, and the pH of the aqueous layer was adjusted to a value of 6.1, by adding sodium bicarbonate powder, whilst stirring. The organic layer was then separated, and the aqueous layer was extracted with a mixture of ethyl acetate and methylene chloride. The separated organic layer and the extract were combined and the mixture was dried over anhydrous magnesium sulfate, after which the solvent was distilled off. The gummy residue was solidified by the addition of diethyl ether and then recovered by filtration, giving 97.1 g of the title compound as a powder. This compound was used in the reaction of step (c) without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([CH2:15][CH2:16][CH3:17])[CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][CH:8]=1.C(Cl)(=O)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[C:12](=[O:14])[CH2:11][CH:10]([CH2:15][CH2:16][CH3:17])[CH2:9]2
Reactant: CCCC(CC(=O)O)Cc1cccc(OC)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCC1CC(=O)c2ccc(OC)cc2C1
Yield: 82.2 %

Procedure:
3-{[3-(Methyloxy)phenyl]methyl}hexanoic acid (92) (2.76 g, 11.7 mmol) was treated with oxalyl chloride followed by AlCl3 in CH2Cl2 to give 2.10 g (82%) of compound 93 as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ 0.90-1.00 (m, 3H), 1.35-1.50 (m, 4H), 2.10-2.35 (m, 2H), 2.60-2.75 (m, 2H), 2.90-3.00 (m, 1H), 3.85 (s, 3H), 6.65-6.70 (m, 1H), 6.82 (dd, J1=8.7 Hz, J2=1.4 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H). LCMS (ESI): m/z 219 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(OCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=2)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(CNS(C)(=O)=O)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 100 °C
Yield: 12.8 %

Procedure:
To a degassed solution of 1.5 g (5.1 mmol) of material from Example 1, 1.1 g (7.7 mmol) of potassium carbonate and 1.1 g (7.7 mmol) of 4-fluorobenzeneboronic acid in 30 mL of toluene was added 0.2 g (0.3 mmol) of dichlorobis(triphenylphoshine)palladium (II). The mixture was heated to 100° C. for 16 hours and cooled to ambient temperature. The mixture was diluted with 20 mL of ethyl acetate, filtered through diatomaceous earth and concentrated in vacuo. Chromatography (50 g of silica gel, 30% ethyl acetate/hexane) of the residue afforded a white solid which was suspended in ethyl ether, filtered and recrystallized from chlorobutane to afford 0.2 g (12%) of the title compound.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.Cl.[Cl:26][CH2:27][CH2:28][CH2:29][CH:30]([C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[C:37]([F:43])[CH:36]=1)[C:31]([NH:33][NH2:34])=[O:32].[F:44]/[C:45](=[CH:49]\[C:50]1[CH:55]=[CH:54][C:53]([N:56]2[CH:60]=[C:59]([CH3:61])[N:58]=[CH:57]2)=[C:52]([O:62][CH3:63])[CH:51]=1)/[C:46](O)=[O:47].O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[F:44]/[C:45](=[CH:49]\[C:50]1[CH:55]=[CH:54][C:53]([N:56]2[CH:60]=[C:59]([CH3:61])[N:58]=[CH:57]2)=[C:52]([O:62][CH3:63])[CH:51]=1)/[C:46]([NH:34][NH:33][C:31](=[O:32])[CH:30]([C:35]1[CH:36]=[C:37]([F:43])[C:38]([F:42])=[C:39]([F:41])[CH:40]=1)[CH2:29][CH2:28][CH2:27][Cl:26])=[O:47]
Reactant: COc1cc(/C=C(\F)C(=O)O)ccc1-n1cnc(C)c1
Reactant: NNC(=O)C(CCCCl)c1cc(F)c(F)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(/C=C(\F)C(=O)NNC(=O)C(CCCCl)c2cc(F)c(F)c(F)c2)ccc1-n1cnc(C)c1

Procedure:
IPEA (0.14 mL) and BOPCl (100 mg) were added to a solution of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acid hydrazide hydrochloride (83 mg) and (Z)-2-fluoro-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (CAS No. 870838-71-4, 72 mg) in methylene chloride (5 mL), and the reaction solution was stirred at room temperature for 13 hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane:ethyl acetate=1:1->ethyl acetate->ethyl acetate:methanol=9:1) to obtain 84 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][OH:38]>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:36][CH2:37][OH:38])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:7]=1[CH3:8]
Reactant: OCCBr
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccc3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccc3)ccnc2cc1OCCO
Temperature: 70 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
4-(5,6-Dimethyl-2-phenyl-pyridin-3-yloxy)-6-methoxy-quinolin-7-ol (compound 332) (162 mg) was dissolved in N,N-dimethylformamide (3 ml) to prepare a solution. Potassium carbonate (180 mg) and 2-bromoethanol (0.1 ml) were added to the solution, and the mixture was stirred at 70° C. overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (135 mg, yield 76%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=2[CH2:19][CH2:20][CH3:21])=[N:5][N:6]=1.[C:22]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)(=[O:27])[CH2:23][C:24]([O-])=[O:25].C1(N=C=NC2CCCCC2)CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1.C(OCC)(=O)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([CH2:8][S:7][C:4]2[S:3][C:2]([NH:1][C:24](=[O:25])[CH2:23][C:22]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[O:27])=[N:6][N:5]=2)=[C:10]([CH2:19][CH2:20][CH3:21])[C:11]=1[OH:18])(=[O:17])[CH3:16]
Reactant: COc1ccc(COC(=O)CC(=O)[O-])cc1
Reactant: CCCc1c(CSc2nnc(N)s2)ccc(C(C)=O)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCc1c(CSc2nnc(NC(=O)CC(=O)OCc3ccc(OC)cc3)s2)ccc(C(C)=O)c1O
Yield: 17.4 %

Procedure:
To a solution of 0.14 g of 2-amino-5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazole obtained in Example 5 and 0.15 g of mono-p-methoxybenzyl malonate in 3 ml of pyridine were added 0.15 g of dicyclohexylcarbodiimide and a catalytic amount of p-toluenesulfonic acid. The resultant mixture was stirred at room temperature for hours. During the stirring, 0.15 g each of mono-p-methoxybenzyl malonate and dicyclohexylcarbodiimide were supplemented to the system. After completion of the reaction, ethyl acetate was added to the system. After insoluble matters were filtered off, the filtrate was concentrated under reduced pressure The obtained residue was dissolved in chloroform. The solution was washed with, in sequence, 1N hydrochloric acid, water, a saturated aqueous sodium bicarbonate solution and water and then, dried over anhydrous magnesium sulfate The solvent was then removed by distillation. The resultant residue was subjected to silica gel column chromatography followed by elution with a mixture of chloroform-methanol (4:1). The eluate was recrystallized from isopropyl alcohol to give 0.04 g of p-methoxybenzyl 3-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]amino]-3-oxopropionate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=N[CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)[OH:11].[CH:31](Cl)(Cl)Cl>[O-2].[O-2].[Mn+4]>[NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[C:24]([CH:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[CH:31][CH:22]=[CH:21][N:20]=2)=[CH:16][CH:17]=1)=[O:11]
Reactant: ClC(Cl)Cl
Reactant: OC(c1ccc(Oc2nccnc2C2CCOCC2)cc1)c1nc2ncccc2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Product: O=C(c1ccc(Oc2ncccc2C2CCOCC2)cc1)c1nc2ncccc2[nH]1

Procedure:
To a round bottomed flask was added (1H-imidazo[4,5-b]pyridin-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanol (0.992 g, 2.459 mmol) and manganese dioxide (1.069 g, 12.29 mmol) to stir in chloroform (8.20 mL) for 1 hr. Reaction was filtered through celite. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Synergi column, 4 micron, MAX-RP, 80 Å, 150×30 MM, 0.1% TFA in ACN/H2O, gradient 40% to 80% over 18 min to provide (1H-Imidazo[4,5-b]pyridin-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)methanone. MS (ESI, pos. ion) m/z: 401.9 (M+1). IC50 (uM) +++++.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][CH2:8][C:9]#[C:10][C:11]1[CH:16]=[CH:15][C:14]([B:17]([OH:19])[OH:18])=[CH:13][CH:12]=1>C1COCC1>[OH:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([B:17]([OH:19])[OH:18])=[CH:13][CH:12]=1
Reactant: OCC#Cc1ccc(B(O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC/C=C/c1ccc(B(O)O)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65.3 %

Procedure:
Lithium aluminum hydride (1.0 M solution in THF, 19.0 mL, 19.0 mmol) was added dropwise over 10 min to a solution of [4-(3-hydroxy-1-propynyl)phenyl]boronic acid (1.06 mg, 6.02 mmol, prepared as described in Reference Example 235) in THF (50 mL) with vigorous strirring. The resulting suspension was heated to reflux for 3 h, cooled to 0° C., cautiously quenched with water (2 mL), strirred for 10 min, and concentrated to dryness in vacuo. Water (20 mL) was added to the residue, the mixture was cooled to 0° C., acidified with 20% H2SO4 (10 mL), and stirred for 10 min at 0° C. The solids were removed by filtration, washed with water, and allowed to air-dry. Recrystallization from water provided 0.70 g (69%) of the title compound as colorless crystals. MS 177 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([NH2:13])[CH:3]=1.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][C:20](Cl)=[O:21].O>N1C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([NH:13][C:20](=[O:21])[CH2:19][C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)[CH:3]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: CCOc1nc(N)cc(N)c1C#N
Solvent: c1ccncc1
Solvent: O
Product: CCOc1nc(NC(=O)Cc2cccs2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 9.4 %

Procedure:
To 50 mg (0.28 mmol) of 4,6-diamino-2-ethoxy-nicotinonitrile in 1 mL of pyridine was added 150 μL (1.21 mmol) of 2-thiopheneacetyl chloride, dropwise. The mixture was stirred for 5 min at ambient temperature, then 1 mL of water was added. The mixture was stirred for an additional 30 minutes then concentrated under reduced pressure. The residue was taken up in 10 mL of ethyl acetate, extracted with water (2×5 mL), 1M HCl(aq.) (1×5 mL), saturated NaHCO3(aq.) (2×5 mL), and brine (1×5 mL), dried over MgSO4, filtered, and concentrated to an oil. This was partially purified via silica gel chromatography, eluting with 30% ethyl acetate:hexanes to provide a sticky, yellow solid. This was triturated with methanol to provide 8 mg (9%) of a white solid. 1H NMR (300 MHz, d6-DMSO) δ 10.33 (s, 1H), 7.38 (m, 1H), 7.18 (s, 1H), 6.97 (m, 2H), 6.92 (s, 2H), 4.34 (q, 2H, J=7.1 Hz), 3.94 (s, 2H), 1.30 (t, 3H, J=7.1 Hz); MS (ESI) m/e=275 (M−Et+H)+, 303 (M+H)+, 301 (M−H)−.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH3:27])[C:9]([NH:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:13]=1)=[O:10])(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]([CH3:27])[C:9]([NH:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:13]=1)=[O:10]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(Cl)cc(C#Cc2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(N)C(=O)Nc1cc(Cl)cc(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of tert-butylN-[1-[[4-chloro-6-(2-phenylethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]carbamate D3a (20 mg, 0.05 mmol) and DCM:TFA (9:1, 1.8 ml) is stirred at RT for 90 minutes. The mixture is diluted with DCM and extracted with a saturated aqueous solution of NaHCO3. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 14 mg (93%). HPLC-MS: M+H=300; tR=1.92 min (*Method—1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([OH:10])=O.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:34][C:35]1([C:41]2[CH:42]=[C:43]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:44]=[CH:45][CH:46]=2)[CH:40]2[CH:36]1[CH2:37][NH:38][CH2:39]2.C(=O)([O-])O.[Na+]>CN(C)C=O.CO>[CH3:34][C:35]1([C:41]2[CH:42]=[C:43]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:44]=[CH:45][CH:46]=2)[CH:40]2[CH:36]1[CH2:37][N:38]([C:8](=[O:10])[CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:39]2
Reactant: O=C(O)CCc1cccs1
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C(=O)CCc3cccs3)CC21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.1 %

Procedure:
To a solution of 3-(2-thienyl)propanoic acid (200 mg, 1.2 mmol) in N,N-dimethylformamide (25 ml) was added 1-hydroxybenzotriazole monohydrate (200 mg, 1.31 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (340 mg, 1.77 mmol). After stirring at room temperature for 10 min the mixture was treated with the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 400 mg, 1.3 mmol) and sodium hydrogen carbonate (220 mg, 2.6 mmol). The reaction mixture was stirred at room temperature for 3 h before concentrating in vacuo. Water (15 ml) was added and the reaction mixture was extracted with ethyl acetate (1×30 ml and 2×15 ml). The combined organic extracts were washed with water (15 ml) and saturated brine (15 ml), dried (MgSO4), and concentrated in vacuo to give a buff solid. The crude product was sonicated in methanol (5 ml) to afford the title compound as an off-white solid (350 mg, 66%, m.p. 184.5° C.).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([NH2:21])=O)=[CH:15]2)(=[O:8])=[O:7].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19](=[S:31])[NH2:21])=[CH:15]2)(=[O:8])=[O:7]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Solvent: C1CCOC1
Product: NC(=S)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 40 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (0.66 g), Lawesson's reagent (0.88 g) and tetrahydrofuran (20 mL) was stirred at 40° C. overnight. The reaction mixture was concentrated, the obtained residue was subjected to silica gel column chromatography, and the title compound (0.61 g, yield 86%) was obtained as yellow crystals from a fraction eluted with tetrahydrofuran-hexane (3:2, volume ratio). melting point 249-250° C. (decomposition).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[O:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][C@@H:24]1[CH2:32][NH:33][CH3:34]>>[O:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][C@@H:24]1[CH2:32][N:33]([CH3:34])[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:20]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CNC[C@H]1Cc2ccccc2O1
Product: CN(C[C@H]1Cc2ccccc2O1)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)-1-(2,3-dihydrobenzofuran-2-yl)-N-methylmethanamine (1.2 equiv) to give 187 (16.8 mg, M+1 459.1)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:28]=3)=[O:25])[CH2:20][C@@H:19]2[CH2:37][OH:38])=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>ClCCl>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:28]=3)=[O:25])[CH2:20][C@@H:19]2[CH:37]=[O:38])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(OC(=O)N2CC[C@H](c3ccc(F)cc3)[C@@H](CO)C2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(OC(=O)N2CC[C@H](c3ccc(F)cc3)[C@@H](C=O)C2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 0.3 mL of oxalyl chloride in 5 mL of dichloromethane was added dropwise 0.5 mL of DMSO at −78° C., followed by stirring for 10 minutes. To the reaction mixture was added dropwise a solution of 664 mg of 4-(methoxycarbonyl)phenyl rel-(3R,4S)-4-(4-fluorophenyl)-3-(hydroxymethyl)piperidine-1-carboxylate in 5 mL of dichloromethane at −78° C., followed by stirring for 15 min, and a solution of 1.8 mL of diisopropylethylamine in 3 mL of dichloromethane was then added dropwise, followed by elevation to room temperature over 2 hours. The reaction mixture was concentrated under reduced pressure, and to the residue was added diethylether, followed by washing with saturated brine, and drying over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 4-(methoxycarbonyl)phenyl rel-(3R,4S)-4-(4-fluorophenyl)-3-formylpiperidine-1-carboxylate as a crude product. ESI+: 386
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3([OH:22])[CH2:21][CH2:20][C:15]4([O:19][CH2:18][CH2:17][O:16]4)[CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:26][CH:27]1[CH2:29][CH2:28]1.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH:27]1([CH2:26][O:22][C:12]2([C:9]3[S:10][CH:11]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:13][CH2:14][C:15]3([O:16][CH2:17][CH2:18][O:19]3)[CH2:20][CH2:21]2)[CH2:29][CH2:28]1
Reactant: BrCC1CC1
Reactant: OC1(c2nc(-c3ccccc3)cs2)CCC2(CC1)OCCO2
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(-c2csc(C3(OCC4CC4)CCC4(CC3)OCCO4)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.6 %

Procedure:
8.0 g of 8-(4-phenylthiazol-2-yl)-1,4-dioxa-spiro[4.5]decan-8-ol were dissolved in 100 ml of anhydrous DMF and treated with 1.1 g of sodium hydride. The mixture was stirred at room temperature for 15 min, then 6.0 g of bromomethylcyclopropane were added. The mixture was stirred at room temperature for 18 h, then poured onto 400 ml of a saturated aqueous sodium hydrogencarbonate solution and extracted three times with 300 ml each of EA. The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. 8.3 g of the title compound were obtained as a pale yellow oil.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[SH:13].[CH3:14][O:15][C:16]([C:18]1[S:19][C:20]([N+:24]([O-:26])=[O:25])=[C:21](Br)[CH:22]=1)=[O:17]>CN(C=O)C>[CH3:14][O:15][C:16]([C:18]1[S:19][C:20]([N+:24]([O-:26])=[O:25])=[C:21]([S:13][C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:3]=2)[CH:22]=1)=[O:17]
Reactant: Sc1ccc2ccccc2c1
Reactant: COC(=O)c1cc(Br)c([N+](=O)[O-])s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Sc2ccc3ccccc3c2)c([N+](=O)[O-])s1

Procedure:
To a suspension of NaH (30 mg, 1.24 mmol) in DMF was slowly added dropwise naphthalene-2-thiol (199 mg, 1.24 mmol, Aldrich Chemical Company) in DMF at rt. This clear solution was then added dropwise to a solution of 4-bromo-5-nitro-thiophene-2-carboxylic acid methyl ester ((Example 114, step c) 300 mg, 1.27 mmol) in DMF at rt. Aqueous workup resulted in isolation of 4-(naphthalen-2-ylsulfanyl)-5-nitro-thiophene-2-carboxylic acid methyl ester. The procedure as in Example 20: step b was followed using 4-(naphthalen-2-ylsulfanyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (194 mg, 0.56 mmol) and m-CPBA (354.4 mg, 1.2 mmol) resulting in 4-(naphthalene-2-sulfonyl)-5-nitro-thiophene-2-carboxylic acid methyl ester. The procedure as in Example 27: step a was followed using 4-(naphthalene-2-sulfonyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (32 mg, 0.085 mmol) sodium thiomethoxide (7.55 mg, 0.94 mmol) resulting in 5-methylsulfanyl-4-(naphthalene-2-sulfonyl)-thiophene-2-carboxylic acid methyl ester. The procedure as in Example 20: step f was followed using 5-methylsulfanyl-4-(naphthalene-2-sulfonyl)-thiophene-2-carboxylic acid methyl ester (29 mg, 0.77 mmol) and dimethyl aluminum amide (0.39 mL, 0.39 mmol) resulting in the title compound 5-methylsulfanyl-4-(naphthalene-2-sulfonyl)-thiophene-2-carboxamidine triflouroacetate (19 mg, 70%). 1H-NMR (CD3OD): δ: 8.67 (m, 1H), 8.37 (s, 1H), 8.05–8.15 (m, 2H), 7.95–8.01 (d, J=7.21 Hz, 1H), 7.90–7.95 (d of d, J=6.7, 2.0 Hz), 7.65–7.75 (m, 2H), 2.70 (s, 3H).