Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH2:11])[CH2:8][CH2:9][CH2:10][C:3]1=2.C(Cl)(Cl)[Cl:13].S(Cl)(Cl)(=O)=O.[OH-].[Na+]>O>[Cl:13][C:6]1[S:2][C:3]2[CH2:10][CH2:9][CH2:8][CH:7]([NH2:11])[C:4]=2[CH:5]=1
Reactant: ClC(Cl)Cl
Reactant: NC1CCCc2sccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=S(=O)(Cl)Cl
Product: NC1CCCc2sc(Cl)cc21
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A sample of 11.4 grams of 4,5,6,7-tetrahydrobenzo[b]thien-4-amine hydrochloride is stirred in 150 ml. of chloroform at about 10° C., and 6.1 ml. of sulfuryl chloride is added dropwise. The mixture is stirred for 3.5 hours at room temperature, and then about 20 ml. of 50% sodium hydroxide solution is added gradually to dissolve the suspended solid. The mixture is then poured into water and extracted with chloroform twice. The extracts are dried, evaporated to dryness, and the residue is distilled to give 7.4 grams of 2-chloro-4,5,6,7-tetrahydrobenzo[b]thien-4-amine, boiling point 94° C. to 98° C./0.5 Torr.
Reaction SMILES: [CH2:1]([N:4]([C:19]([O:21][CH2:22][C:23]1C=CC=CC=1)=[O:20])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([F:18])[CH:6]=1)C=C.N1C=CC=CC=1.[I:35]I>C(Cl)(Cl)Cl>[I:35][CH2:23][CH:22]1[O:21][C:19](=[O:20])[N:4]([C:5]2[CH:6]=[C:7]([F:18])[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[C:9]([F:11])[CH:10]=2)[CH2:1]1
Reactant: II
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cc(F)c(-c2cccnc2)c(F)c1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C1OC(CI)CN1c1cc(F)c(-c2cccnc2)c(F)c1
Reaction time: 1.5 h

Procedure:
N-Allyl-N-carbobenzyloxy-4-(3-pyridyl)-3,5-difluoroaniline (PREPARATION 4, 496 mg 1.31 mmol) in chloroform (25 ml), pyridine (1.58 ml, 19.6 mmol, 15 eq) and iodine (4.97 g, 19.6 mmol, 15 eq) are combined. The resulting mixture is placed under an atmosphere of nitrogen and heated to 50° with stirring. After 1.5 hr, the reaction is decanted into chloroform (70 ml). The remaining sludge is rinsed with chloroform (3×15 ml). The combined organics are washed with sodium thiosulfate (20%), then brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to give a solid. This material is purified by silica gel chromatography (100 g) eluting with methanol/chloroform (0.5/99.5 - 11, 1/99, 11). The appropriate fractions are pooled and concentrated to give the title compound, mp 133°-134°; FTIR (mull) cm-1 3130, 1758, 1650, 1414, 1241, 1017 and 846; NMR (CDCl3) 8.72, 8.62, 7.79, 7.43-7.38, 7.32, 4.84-4.72, 4.19, 3.80, 3.51 and 3.39 δ.
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[O:3][C:4]([CH3:8])([C:6]#[CH:7])[CH3:5].[Li]CCCC.CON(C)[C:19](=[O:26])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>C1COCC1>[CH3:5][C:4]([O:3][Si:2]([CH3:10])([CH3:9])[CH3:1])([CH3:8])[C:6]#[C:7][C:19]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[O:26]
Reactant: CON(C)C(=O)c1ccncc1
Reactant: C#CC(C)(C)O[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C#CC(=O)c1ccncc1)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
To a pre-cooled −78° C. stirred solution of trimethyl (2-methylbut-3-yn-2-yloxy) silane (5.0 g, 0.03 mol) in dry THF (150 mL), n-BuLi (23.82 mL, 0.03 mol, 1.6 M in hexane) was added dropwise over a period of 10 minutes under an inert atmosphere. The reactions was stirred for 30 minutes at −78° C. and then a solution of N-methoxy-N-methylisonicotinamide (6.34 g, 0.03 mol) in dry THF (30 mL) was added to the reaction mixture and stirring was continued for an additional 40 min at −78° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and finally concentrated in vacuo to obtain a residue. The residue was purified via silica gel column chromatography eluting with 5% EtOAc in hexanes to afford 4-methyl-1-(pyridin-4-yl)-4-(trimethylsilyloxy) pent-2-yn-1-one (2.2 g, 27%) as oil.
Reaction SMILES: S(O[C:6]1(O)[CH:15]2[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:9][CH2:8][CH2:7]1)(=O)(=O)C.CN(C)C=[O:20].[N-:22]=[N+:23]=[N-:24].[Na+]>O>[N:22]([CH:7]1[CH2:8][CH2:9][CH:10]2[CH:15]([CH2:14][CH2:13][CH:12]([OH:20])[CH2:11]2)[CH2:6]1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC1(O)CCCC2CCCCC21
Reactant: CN(C)C=O
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NC1CCC2CC(O)CCC2C1

Procedure:
24.8 g (0.1 mole) of decalindiol monomesylate (XI) in 1 1 of dimethylformamide were heated together with 65 g (1 mole) of sodium azide and 100 ml of water for 5 hours at 90°-100° C. After cooling, the mixture was poured into 2 1 of water and extracted with methyl tert-butyl ether, and the organic extracts were washed with sodium chloride solution, dried over Na2SO4 and evaporated down under reduced pressure.
Reaction SMILES: C(C1C2N=[N:10][S:11]C=2C(N)=CC=1)#N.[N:13](C1C2CCCCC=2C(C#N)=CC=1)=C=O.[OH:28][C@H:29]1[C@@H:36]2[N:32]([C:33](=[O:50])[N:34]([C:38]3[C:47]4CCCC[C:42]=4[C:41]([C:48]#[N:49])=[CH:40][CH:39]=3)[C:35]2=[O:37])[CH2:31][CH2:30]1>>[OH:28][C@H:29]1[C@H:36]2[N:32]([C:33](=[O:50])[N:34]([C:38]3[C:47]4[C:42](=[N:13][S:11][N:10]=4)[C:41]([C:48]#[N:49])=[CH:40][CH:39]=3)[C:35]2=[O:37])[CH2:31][CH2:30]1
Reactant: N#Cc1ccc(N)c2snnc12
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Reactant: N#Cc1ccc(N=C=O)c2c1CCCC2
Product: N#Cc1ccc(N2C(=O)[C@H]3[C@H](O)CCN3C2=O)c2nsnc12

Procedure:
The title compound (12.2 mg) was prepared from compound 50A by procedures analogous to those described in Experiment 2E and 2F. HPLC: 99% at 1.57 min (retention time) (Conditions: Phenom. Luna. (4.6×50 mm); Eluted with 0% to 100% B, 4 min gradient, 1 min hold. (A=90% H2O—10% MeOH—0.1% TFA and B=10% H2O—90% MeOH—0.1% TFA); Flow rate at 4.0 mL/min UV detection at 220 nm). Chiral HPLC: retention time=22.68 min (98%); Conditions: OD (4.6×250 mm); Eluted with 25% isopropanol in hexane for 30 min at 1 mL/min; MS (ES) m/z 316 [M+1]+.
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2([C:28]([F:31])([F:30])[F:29])[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[C:20]([CH3:27])[CH:19]=3)[CH2:14]2)[CH:9]=[C:10]([Cl:12])[CH:11]=1.O.[OH-].[Na+]>CCOCC>[CH3:1][N:2]([CH3:4])[NH:3][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:18]([C:15]2[CH2:14][C:13]([C:8]3[CH:9]=[C:10]([Cl:12])[CH:11]=[C:6]([Cl:5])[CH:7]=3)([C:28]([F:31])([F:30])[F:29])[O:17][N:16]=2)=[CH:19][C:20]=1[CH3:27]
Reactant: CN(C)N
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NN(C)C
Yield: 71.1 %

Procedure:
To a solution of N,N-dimethyl hydrazine (0.55 g) in ether (46 mL) was added 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoyl chloride (2.00 g) in small portions at 0° C. After 50 min at this temperature, water was added and the pH was adjusted to 7 by addition of NaOH (2 M). The organic layer was separated and the aqueous layer was extracted with ether. Combined organic layers were washed with NaHCO3 solution, dried over Na2SO4 and evaporated to give the title compound (1.50 g, 71%).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH:34]=O)[CH2:9]1)=O)(C)(C)C.[CH:36]([NH2:39])([CH3:38])[CH3:37].[BH4-].[Na+]>C(Cl)Cl.CO>[CH:31]([N:14]([CH2:13][C@H:11]1[C@H:10]([CH2:34][NH:39][CH:36]([CH3:38])[CH3:37])[CH2:9][NH:8][CH2:12]1)[C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=1)([CH3:33])[CH3:32]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1OC
Reactant: CC(C)N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CNC[C@H]2CNC(C)C)C(C)C)ccc1OC

Procedure:
from (3S*,4R*)-3-formyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.75 g, 1.52 mmol), isopropylamine (0.654 mL, 7.61 mmol) and NaBH4 (0.115 g, 3.04 mmol) and purification by flash chromatography on silica gel (CH2Cl2/MeOH 96:4, then CH2Cl2/MeOH (10% NH3 conc.) gradient from 9:1 to 8:2) to give the title compound as colorless oil. MS: 536.4 [M+H]+. tR (HPLC, Nucleosil C18HD column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 4.58 min.
Reaction SMILES: [OH-:1].[Na+].Br[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.N#N.[OH2:19]>>[C:8]1([OH:19])[C:7]([C:10]2[C:15]([OH:1])=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][CH:9]=1
Reactant: [OH-]
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Reactant: O
Agent: N#N
Agent: [Na+]
Product: Oc1ccccc1-c1ccccc1O
Temperature: 300 °C

Procedure:
A 600 ml autoclave was charged with 400 ml of 1N NaOH (0.4 mole), 11.5 g (37 mmole) 4,4'-dibromobiphenyl and 64 mg (0.256 mmole) CuSO4.5H2O as 4 ml of 0.064M solution in H2O. The autoclave was pressure checked with N2 to 1100 psi, vented, flushed with air and resealed. The autoclave was heated to 300° C. at an autogenic pressure of 1168 psi. These conditions were maintained for two hours. After cooling and venting the aqueous reaction product was filtered to remove a grey solid which probably contained catalyst and unreacted starting material. This filter was then removed to a second filter flask. Any starting material remaining was recovered by washing with acetone and stripping the solvent on a rotary evaporator. The filtered aqueous product solution was acidified (pH2) with 25% sulfuric acid. The precipitated crude biphenol (4,4'-dihydroxybiphenyl) was filtered and washed with water (50 ml).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=1.CN(C)C=O.C(Cl)(=O)C([Cl:26])=O>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([Cl:26])=[O:17])=[CH:11][CH:10]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccc(C)c1-c1ccc(C(=O)Cl)cc1

Procedure:
A stirred solution of 2′,6′-dimethyl-1,1′-biphenyl-4-carboxylic acid of Step A (0.790 g, 3.5 mmol) in dichloromethane (15 mL) was treated under nitrogen with a catalytic amount of N,N-dimethylformamide followed by dropwise addition of 2N oxalyl chloride in dichloromethane (2.8 mL). After the gas evolution ceased the mixture was refluxed for 4 hours, cooled, and evaporated. The residue was azeotroped twice with benzene and dried in vacuo to provide 2′,6′-dimethyl-1,1′-biphenyl-4-carboxylic acid chloride. The crude 2′,6′-dimethyl-1,1′-biphenyl-4-carboxylic acid chloride (0.856 g, 3.5 mmol) was dissolved in dichloromethane (7 mL) and added dropwise to a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 12 (0.450 g, 1.41 mmol) in anhydrous tetrahydrofuran 10 mL) containing N,N-diisopropylethyl amine (0.860 mL). The mixture was stirred for 18 hours at room temperature and evaporated to dryness. The residue was dissolved in dichloromethane, the solution washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous potassium carbonate and evaporated. The residue was chromatographed over silica gel Merck-60 eluting with a gradient from 0 to 4% methanol in 1:1 hexane-ethyl acetate to provide the title compound (0.452 g) as a white solid after trituration with hexane, m.p. 216-218° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[CH:5]=1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[C:5]2[CH:47]([OH:51])[C:48]([CH3:50])([CH3:49])[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)[NH:11][C:6]=2[CH:7]=[C:8]([F:10])[CH:9]=1)=[O:20]
Reactant: CC(C)C=O
Reactant: COC(=O)c1cc(F)cc(N=Cc2cccc(Br)c2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)cc2c1C(O)C(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
To a stirred mixture solution of 3-[(3-bromo-benzylidene)-amino]-5-fluoro-benzoic acid methyl ester (51.7 g, 153.8 mmol) and ytterbium(III) triflate hydrate (14.3 g, 23.1 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (14 mL, 153.8 mmol) and water (2.8 mL, 153.8 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-7-fluoro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (63.0 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H19BrFNO3 (M+H)+: 409.27, observed: 390.0 & 392.0.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][CH2:10][C:9](=[O:13])[C:8]=2[CH:7]=[CH:6][C:5]=1[OH:14])(=O)[CH3:2].C(O)(=O)C.[C:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:14][C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[O:13])[CH2:10][O:11][C:12]=2[C:4]=1[CH:1]([N:29]1[CH2:28][CH2:27][N:26]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:31][CH2:30]1)[CH3:2]
Reactant: CC(=O)c1c(O)ccc2c1OCC2=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(c1c(O)ccc2c1OCC2=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
A solution of 7-acetyl-6-hydroxybenzofuran-3(2H)-one (0.60 g, 3.1 mmol) in methylene chloride (25 mL) was added with acetic acid (0.25 mL) and N-Boc-piperazine (0.64 g, 3.4 mmol), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0° C., and then added portionwise with sodium triacetoxyborohydride (0.84 g, 4.1 mmol). After completion of the addition, the ice bath was removed to allow the reaction mixture to warm to room temperature, and the mixture was stirred at the same temperature for 20 hours. The reaction mixture was extracted with methylene chloride, and then the organic layer was successively washed with water, saturated aqueous sodium hydrogencarbonate, and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (100:0→97:3)) to obtain tert-butyl 4-[1-(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)ethyl]piperazine-1-carboxylate (0.74 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][C:46]([N:49]4[CH2:54][CH2:53][NH:52][C:51](=[O:55])[CH2:50]4)=[CH:45][CH:44]=3)=[CH:39][CH:38]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C:23](=[O:25])[N:22](COCC[Si](C)(C)C)[S:21]3(=[O:35])=[O:34])=[CH:16][CH:15]=2)[CH:13]=1.I[CH3:57]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:44]=[CH:45][C:46]([N:49]4[CH2:54][CH2:53][N:52]([CH3:57])[C:51](=[O:55])[CH2:50]4)=[CH:47][CH:48]=3)=[CH:39][CH:38]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C:23](=[O:25])[NH:22][S:21]3(=[O:34])=[O:35])=[CH:16][CH:15]=2)[CH:13]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(N5CCNC(=O)C5)cc4)cc3)cc2)S1(=O)=O
Reactant: CI
Product: CN1CCN(c2ccc(-c3ccc(Cc4nc(-c5ccc(Cl)cc5Cl)cn4-c4ccc(N5CC(=O)NS5(=O)=O)cc4)cc3)cc2)CC1=O

Procedure:
4-[4′-(4-(2,4-Dichloro-phenyl)-1-{-4-[1,1,4-trioxo-5-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-2-yl]-phenyl}-1H-imidazol-2-ylmethyl)-biphenyl-4-yl]-piperazin-2-one (17 mg, 0.02 mmol) was treated as described in general procedure L (using iodomethane) and general procedure W stepwise to give the desired compound 4-(4′-{4-(2,4-dichloro-phenyl)-1-[4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-imidazol-2-ylmethyl}-biphenyl-4-yl)-1-methyl-piperazin-2-one.
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4][CH:5]([C:10]1[S:14][C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[N:12][CH:11]=1)[CH2:6][C:7]([O-:9])=[O:8].[N:23]1[C:32]2[NH:31][CH2:30][CH2:29][CH2:28][C:27]=2[CH:26]=[CH:25][C:24]=1[CH2:33][CH2:34][CH2:35][C:36](=[S:38])[NH2:37].O1CCO[CH2:41][CH2:40]1>>[ClH:1].[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[S:14][C:10]([CH:5]([CH2:4][C:3]3[N:37]=[C:36]([CH2:35][CH2:34][CH2:33][C:24]4[CH:25]=[CH:26][C:27]5[CH2:28][CH2:29][CH2:30][NH:31][C:32]=5[N:23]=4)[S:38][CH:2]=3)[CH2:6][C:7]([O:9][CH2:40][CH3:41])=[O:8])=[CH:11][N:12]=2)=[CH:16][CH:17]=1
Reactant: C1COCCO1
Reactant: NC(=S)CCCc1ccc2c(n1)NCCC2
Reactant: O=C([O-])CC(CC(=O)CCl)c1cnc(-c2ccc(Cl)cc2)s1
Product: CCOC(=O)CC(Cc1csc(CCCc2ccc3c(n2)NCCC3)n1)c1cnc(-c2ccc(Cl)cc2)s1
Product: Cl
Temperature: 120 °C
Yield: 44 %

Procedure:
thyl 6-chloro-3-[2-(4-chlorophenyl)-1,3-thiazol-5-yl]-5-oxohexanoate, Scheme 2, Example A, (230 mg, 0.595 mmol) and 4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanethioamide, Scheme 3, Step 1, (140 mg, 0.595 mmol) was dissolved in 1,4-dioxane (5 mL) and heated to 120° C. for 18 hours. The solvent was removed and the residue purified via reverse phase HPLC to give the product (180 mg, 44%). 1H NMR (DMSO-d6) δ1.10 (t, 3H), 1.77–1.85 (m, 2H), 2.02–2.11 (m, 2H), 2.68–2.90 (m, 6H), 2.95–3.18 (m, 4H), 3.38–3.46 (m, 2H), 3.86–3.95 (m, 2H), 4.00 (q, 2H), 6.55 (d, 1H), 7.18 (s, 1H), 7.48–7.55 (m, 2H), 7.57 (d, 1H), 7.62 (s, 1H), 7.80–7.85 (m, 2H).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15](=[O:28])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].CI>C1COCC1.CCCCCC>[CH3:13][O:14][C:15](=[O:28])[C@:16]1([CH3:1])[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)[C@]1(C)CCCN1C(=O)OC(C)(C)C
Temperature: 78 °C
Reaction time: 0.33 h
Yield: 100400.9 %

Procedure:
To a stirred solution of diisopropylamine (2.02 mL, 0.0144mol) in THF (30 mL) was added dropwise 1.59 M n-hexane solution of n-BuLi (9.06 mL, 0.0144mol) at minus 78° C. for over 5 min. The resulting solution was stirred for 20 min at minus 78° C. To the solution was added dropwise N-tert-butoxycarbonylproline methyl ester (3.00 g, 0.0131 mmol) in THF (30 mL) at minus 78° C. for over 5 min. The resulting solution was stirred for 10 min at minus 78° C. To the solution was added dropwise MeI (0.900 mL, 0.0144 mol) at minus 78° C. The resulting solution was stirred for 30 min at minus 78° C. The solution was quenched by the addition of sat. NH4Cl. The resulting mixture was extracted with CHCl3. The extract was washed with water, dried over Na2SO4, and evaporated in vacuo to afford 3.20 g (q.y.) N-tert-butoxycarbonyl-2-methylproline methyl ester as a yellow syrup. 1H-NMR (CDCl3) δ 1.33 (s, 9H), 1.38 (s, 3H), 1.72–2.20 (m, 4H) 3.27–3.59 (m, 2H) 3.63 (d, J=6.3 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[C:8]2[C:9]3[N:10]([N:13]=[C:14]([CH2:21][CH3:22])[C:15]=3C(OCC)=O)[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31].O>Cl.O1CCCC1>[CH2:21]([C:14]1[CH:15]=[C:9]2[C:8]3[CH:4]([CH2:3][CH2:2][NH:1][C:30](=[O:32])[CH3:31])[CH2:5][CH2:6][C:7]=3[CH:12]=[CH:11][N:10]2[N:13]=1)[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1c(CC)nn2ccc3c(c12)C(CCN)CC3
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1cc2c3c(ccn2n1)CCC3CCNC(C)=O
Temperature: 100 °C
Reaction time: 72 h
Yield: 86.2 %

Procedure:
A mixture of ethyl 9-(2-aminoethyl)-2-ethyl-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridine-1-carboxylate (81.0 mg, 0.269 mmol) in 12M hydrochloric acid (3 mL) was stirred at 100° C. for 3 days, and the mixture was concentrated under reduced pressure. To a mixture of the residue and triethylamine (375 μL, 2.69 mmol) in tetrahydrofuran (2.7 mL) was added acetic anhydride (76.3 μL, 0.807 mmol) under ice-cooling, and the mixture was stirred at room temperature for 15 min. Water (50 μL) was added, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) to give the title compound (62.9 mg, yield 85%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][N:23]1[CH2:27][CH2:26][CH:25]([CH2:28][OH:29])[CH2:24]1.CN(C=O)C.[H-].[Na+]>C(O)(=O)C>[CH3:22][N:23]1[CH2:27][CH2:26][CH:25]([CH2:28][O:29][C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([NH2:17])[C:10]=2[F:16])[CH2:24]1
Reactant: CN1CCC(CO)C1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CN1CCC(COc2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Temperature: 25 °C

Procedure:
To a mixture of 596 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 460 mg of 1-methyl-3-hydroxymethylpyrrolidine and 5 ml of DMF was added 262 mg of 55% sodium hydride while the former was stirred at room temperature. After the resultant mixture was stirred for 1 hour at room temperature, 360 mg of acetic acid was added and DMF was distilled off under reduced pressure. The residue was purified by chromatography on silica gel (chloroform/methanol: 3/1), followed by recrystallization from ethanol. The title compound was obtained as pale green powder (yield: 240 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.[NH2:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][N:31]([C:35]2[C:44]([F:45])=[CH:43][C:42]3[C:46](=[O:52])[C:47]([C:49]([OH:51])=[O:50])=[CH:48][N:40]4[C:41]=3[C:36]=2[CH2:37][CH2:38][N:39]4[CH3:53])[CH2:30]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][N:31]([C:35]2[C:44]([F:45])=[CH:43][C:42]3[C:46](=[O:52])[C:47]([C:49]([OH:51])=[O:50])=[CH:48][N:40]4[C:41]=3[C:36]=2[CH2:37][CH2:38][N:39]4[CH3:53])[CH2:30]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2CCN4C)C[C@H]1N
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2CCN4C)C[C@H]1NC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
350 mg (2 mmol) of N-t-butoxycarbonylglycine and 202 mg (2 mmol) of N-methylmorpholine were added to 6 ml of methylene chloride. The mixture solution was cooled on freezing mixture, and 0.26 ml (2 mmol) of isobutyl chlorocarbonate was added to the solution. After 20 minutes, 716 mg (2 mmol) of the compound (30) obtained in Example 5 (1) was added to the solution, and the solution was stirred at room temperature for 30 minutes. Then, 10 ml of water was added to the solution, and the solution was acidified with by citric acid. The organic layer was separated from the solution and was removed distillation after drying over sodium sulfate. Ethyl acetate--ether was added to the residue, then the product came out of the solution, and the solid was filtered off to obtain 776 mg of the subject compound (84) in a 75% yield. The results of the analysis of this compound were as follows: