Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[O:9]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10]1>>[OH:9][CH2:13][CH2:12][N:11]([CH2:10][P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4])[CH2:14][CH2:15][OH:16]
Reactant: OCCN1CCOC1
Reactant: CCOP([O-])OCC
Product: CCOP(=O)(CN(CCO)CCO)OCC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Diethyl phosphite (2.5 mol, 352/3 g) was added slowly to a mixture of the product from stage (1.1) and Amberlight™ IR120 resin—acid form (available from Aldrich, 100 g) to form a reaction mixture. On completion of the addition, the reaction mixture was stirred at 60° C. for 2 hours and then allowed to cool to a temperature of 25° C. The product was extracted with a 2:1 mixture of diethyl ether and ethyl acetate (5×300 ml), the combined extracts were dried over magnesium sulphate and evaporated to give 354 g of diethyl [bis(2-hydroxyethyl)amino]methylphosphonate in the form of a pale yellow liquid. The product was stored over 4A molecular sieves. This was designated Monomer (1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][CH:15]1[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:25][CH:26]3[CH2:31][O:30]C(C)(C)[O:28][CH2:27]3)[C:16]1=[O:34])=[O:13])=[CH:6]2>C1COCC1>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][CH:15]1[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:25][CH:26]([CH2:27][OH:28])[CH2:31][OH:30])[C:16]1=[O:34])=[O:13])=[CH:6]2
Reactant: CC1(C)OCC(CN2C(=O)C(NC(=O)c3cc4cc(Cl)ccc4[nH]3)Cc3ccccc32)CO1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(NC1Cc2ccccc2N(CC(CO)CO)C1=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 1 h
Yield: 84.8 %

Procedure:
6M aqueous HCl (2.34 mL) was added to 5-chloro-N-{1-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-1H-indole-2-carboxamide (Example 37; 540 mg, 1.16 mmol) in THF (19 mL) and the reaction was stirred for 1 h. The reaction was quenched by addition of triethylamine (1.5 mL) and the reaction was diluted with water (20 mL) and EtOAc (40 mL). The organic layer was separated, dried (MgSO4), filtered and evaporated. The residue was triturated with hot Et2O (15 mL) and after cooling was filtered and dried to afford the title compound (421 mg, 85%) as white solid.
Reaction SMILES: Cl.[CH:2]([C:8]1[CH:9]=[C:10]([C:16]2[O:17]CC(C)(C)N=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15])=[CH:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cl-].[Na+].[OH2:25]>>[CH:2]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:16]([OH:17])=[O:25])=[CH:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O
Reactant: CCCCC=Cc1cc(C2=NC(C)(C)CO2)ccc1OC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: CCCCC=Cc1cc(C(=O)O)ccc1OC
Yield: 35 %

Procedure:
6N Hydrochloric acid (20 ml) was added to 2-[3-(1-hexenyl)-4-methoxyphenyl]-4,4-dimethyl-4,5-dihydrooxazole (583 mg, 2.03 mmol), and the mixture was refluxed under heating for 4 hours. Saturated saturated brine (30 ml) was added to this solution, and the aqueous layer was extracted 3 times with ethyl acetate (50 ml). The organic layers were combined, and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=2/1) to give 3-(1-hexenyl)-4-methoxybenzoic acid (164.3 mg, 35%) as a mixture (colorless crystals) of geometrical isomers (1:1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:17][CH3:18])=[C:8]([O:15][CH3:16])[C:9]=2[O:13][CH3:14])[N:4]=1.[NH:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:14][O:13][C:9]1[C:8]([O:15][CH3:16])=[C:7]([O:17][CH3:18])[CH:6]=[C:5]2[C:10]=1[CH:11]=[CH:12][C:3]([CH2:2][N:19]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:2][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][C:7]([O:17][CH3:18])=[C:8]([O:15][CH3:16])[C:9]=4[O:13][CH3:14])[N:4]=3)[CH2:21][CH2:20]1)=[N:4]2
Reactant: COc1cc2nc(CCl)ccc2c(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc2nc(CN3CCCN(Cc4ccc5c(OC)c(OC)c(OC)cc5n4)CC3)ccc2c(OC)c1OC

Procedure:
2-Chloromethyl-5,6,7-trimethoxyquinoline (400 mg) and homopiperazine (765 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: C1(C[O:8][CH2:9][CH:10]2[S:14][CH2:13][CH:12]([S:15][C:16](=[O:18])[CH3:17])[CH2:11]2)C=CC=CC=1.B(F)(F)F.CCOCC>C(Cl)(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:8][CH2:9][CH:10]1[S:14][CH2:13][CH:12]([S:15][C:16](=[O:18])[CH3:17])[CH2:11]1
Reactant: CC(=O)SC1CSC(COCc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: FB(F)F
Agent: [I-]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CC(=O)SC1CSC(CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
A 0° C. solution, under argon, of 0.123 g of product from Example 139 in 1.0 ml of dry chloroform is treated with 51.1 microliter of boron trifluoride etherate and 0.193 g of tetra n-butylammonium iodide. The reaction mixture is stirred at room temperature overnight and concentrated in vacuo. The residue is purified by chromatography (silica gel: 0-100% ethyl acetate/hexane) to give 0.079 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:17]([CH3:34])[C:18]([CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][N:20]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.[C:38]1([CH2:44][C:45]([N:47]=[C:48]=[S:49])=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CCO.C1(C)C=CC=CC=1>[F:37][C:4]1[CH:3]=[C:2]([NH:1][C:48]([NH:47][C:45](=[O:46])[CH2:44][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[S:49])[CH:36]=[CH:35][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:17]([CH3:34])[C:18]([CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][N:20]=3)[S:15][C:8]=12
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCO
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
To a solution of 46 (375 mg, 0.711 mmol) in a mixture of EtOH (5 mL) and toluene (5 mL) at RT was added phenylacetyl isothiocyanate (189 mg, 1.066 mmol) and the reaction mixture was stirred at RT for 3 hours. The mixture was concentrated to dryness then purified by column chromatography (eluent a gradient of 80% EtOAc in hexane to EtOAc), to afford 47 (400 mg, 80%) as a red solid. MS (m/z): 705.2 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].C([Li])CCC.[Cl:15][C:16]1[C:17]([F:27])=[C:18]([CH:22]=[C:23]([F:26])[C:24]=1[F:25])C(Cl)=O.Cl>O1CCCC1>[Cl:15][C:16]1[C:17]([F:27])=[C:18]([C:6](=[O:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9])[CH:22]=[C:23]([F:26])[C:24]=1[F:25]
Reactant: O=C(Cl)c1cc(F)c(F)c(Cl)c1F
Reactant: CCOC(=O)CC(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Temperature: -5 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a mixture of 2.64 g (20 mmol) of malonic acid monoethyl ester, 0.10 g (catalytic amount) of dipyridyl, and 50 ml of dry tetrahydrofuran at -30° C. is added 13 ml of n-butyllithium (1.55 M, 20.2 mmol) at a rapid rate. When addition is complete, the solution is warmed to -5° C., and another 13 ml of n-butyllithium (1.55 M, 20.2 mmol) is added dropwise until a pale pink color persists for ten minutes. The suspension is then cooled to -78° C. To this mixture is added a solution of 2.3 g (10 mmol) of 3-chloro-2,4,5-trifluorobenzoyl chloride in 3 ml of dry tetrahydrofuran. The reaction mixture is stirred at -78° C. for one hour, then warmed to -35° C. and poured into a mixture of ice (50 g) and 6 N hydrochloric acid (4 ml). This solution is extracted with dichloromethane, and the extracts are washed with water, 5% aqueous sodium bicarbonate, dilute hydrochloric acid, and water. The organic phase is dried over magnesium sulfate, filtered, and concentrated to give 2.5 g of the title compound as an orange solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O-:11].[Na+].C1C2C(=CC=CC=2)C=CC=1O.[C:24](=[O:26])=[O:25].OC1C=CC2C(=CC=CC=2)C=1C(O)=O>O>[OH:11][C:2]1[C:3]([C:24]([OH:26])=[O:25])=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: O=C=O
Reactant: [O-]c1ccc2ccccc2c1
Agent: O=C(O)c1c(O)ccc2ccccc12
Agent: Oc1ccc2ccccc2c1
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc2ccccc2cc1O
Temperature: 100 °C
Reaction time: 4 h
Yield: 0.03 %

Procedure:
An autoclave was charged with 498 g of light oil (boiling at 250°-350° C.) and 166 g of sodium β-naphtholate, and with stirring, 72 g of β-naphthol was added. The mixture was reacted with carbon dioxide under a pressure of 5 kg/cm2.G at a reaction temperature of 270° C. for 4 hours. The reaction mixture was added to 830 ml of water, and heated at 100° C. for 30 minutes to decompose a 2-hydroxynaphthalene-1-carboxylic acid salt. The mixture was then separated into a light oil layer and an aqueous layer at 85° C. From the light oil layer, β-naphthol was extracted as an aqueous solution of sodium β-naphtholate by using an aqueous solution of sodium hydroxide. The pH of the aqueous layer was adjusted to 5.5 with hydrochloric acid, and the tarry layer that sedimented was separated at 85° C., and β-naphthol was recovered from the tarry layer by vacuum distillation. Water (500 ml) was added to the aqueous layer, and the mixture was extracted with 650 ml of toluene at 80° C. From the toluene layer, β-napthol was extracted as an aqueous solution of sodium β-naphtholate by using an aqueous solution of sodium hydroxide. The pH of the aqueous layer was adjusted to 2.0 with hydrochloric acid, and the mixture was cooled to 40° C., followed by filtration. Thus, 79.9 g of 2-hydroxynaphthalene-3-carboxylic acid (melting range 220°-221° C.; purity 99.6%; β-naphthol content 0.03%) was obtained.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)CCl>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:21])(=[O:20])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:4])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: Nc1ccccc1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Solvent: ClCCCl
Product: CN1C(C(=O)Nc2ccccc2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Yield: 69 %

Procedure:
4-Hydroxy-2-methyl-N-phenyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 1 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and aniline. Yield: 69% of theory; m.p. 273°-274° C (decomp.; from ethylene chloride).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].I[C:6]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]2[C:7]=1/[C:8](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:9](=[O:18])[NH:10]2>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.CN(C=O)C.CCN(CC)CC>[OH:4][CH2:1][C:2]#[C:3][C:6]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]2[C:7]=1/[C:8](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:9](=[O:18])[NH:10]2
Reactant: C#CCO
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(C#CCO)c21

Procedure:
Using Method C above, propargyl alcohol (0.11 g, 1.95 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (0.32 g, 0.78 mmol) (Starting Material 2 above) using (Ph3P)2PdCl2 (27.4 mg) and Cul (7.4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 85° C. for 18 h to yield (Z)-1,3-dihydro-4-(3-hydroxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one. (Yield 0.12 g, 46%).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[C:18]([Cl:19])=[C:17]([Cl:20])[C:10]2[S:11][C:12]([C:14](=[O:16])[CH3:15])=[CH:13][C:9]=2[CH:8]=1)C.[OH-].[Na+].Cl.C(OCC)C>C(O)C>[C:14]([C:12]1[S:11][C:10]2[C:17]([Cl:20])=[C:18]([Cl:19])[C:7]([O:6][CH2:5][C:4]([OH:21])=[O:3])=[CH:8][C:9]=2[CH:13]=1)(=[O:16])[CH3:15]
Reactant: CCOC(=O)COc1cc2cc(C(C)=O)sc2c(Cl)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CC(=O)c1cc2cc(OCC(=O)O)c(Cl)c(Cl)c2s1
Reaction time: 2 h
Yield: 46.9 %

Procedure:
To 5.1 g of ethyl[ (6,7-dichloro-2-acetylbenzo[b]thien-5-yl)oxy]acetate in 200 ml of 95% ethanol is added 150 ml of a 6 N sodium hydroxide solution and the mixture is refluxed at 100° for 45 mins. The solvent is removed in vacuo to give a white slurry to which is added 250 ml of a 6 N hydrochloric acid and 200 ml ethyl ether. The mixture is stirred for 2 hrs, filtered and the filter cake is distributed between 6 N hydrochloric acid and ethyl ether. The organic layers are separated and the aqueous layers are extracted with ethyl ether. The combined organic extracts are washed, dried over anhydrous magnesium sulfate, filtered and the solvent is evaporated to give a solid. Recrystallization from acetone-hexane gives 2.2 g of [(2-acetyl-6,7-dichlorobenzo[b]thien-5-yl)oxy]acetic acid, mp 203°-205°.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][O:11]2.C(O)(C(F)(F)F)=O.[K+].[Br-]>C(#N)C.O>[F:35][C:32]([F:33])([F:34])[C:29]1[CH:28]=[CH:27][C:26]([CH2:25][O:24][C:21]2[CH:20]=[CH:19][C:18]([CH2:17][S:16][C:13]3[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:36])=[O:2])=[C:7]4[C:12]=3[O:11][CH2:10][CH2:9][CH2:8]4)=[CH:23][CH:22]=2)=[CH:31][CH:30]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)c2c1CCCO2
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)COc1ccc(SCc2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)c2c1CCCO2

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 83A. mp 143-144° C.; HPLC: area %=96.02, r.t.=3.770 min, γ=214 nm, mobile phase=acetonitrile/water w/0.10% TFA; IR (KBr) cm−1: 3042, 2581, 1739, 1714, 1325, 1116; 400 MHz 1H NMR (DMSO-d6): δ 12.95 (br(s), 1H), 7.66-7.74 (m, 2H), 7.56-7.63 (m, 2H); 7.10-7.17 (m, 2H), 6.92 (d, 1H, J=8.7 Hz), 6.83-6.89 (m, 2H), 6.26 (d, 1H, J=8.5 Hz), 5.13 (s, 2H), 4.58 (s, 2H), 4.08 (t, 2H, J=4.8 Hz), 3.90 (s, 2H), 2.55 (t, 2H, J=6.5 Hz), 1.83 (pentet, 2H); MS m/z 503 (M−1). Anal. Calc'd for C26H23F3O5S: C, 61.90; H, 4.60. found: C, 61.41; H, 4.50.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[N:14]=[C:13]([NH2:26])[N:12]=2)=[CH:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[NH2:26][C:13]1[N:12]=[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][CH:6]=2)[CH:16]=[C:15]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])[N:14]=1
Reactant: COC(=O)c1ccc(Nc2cc(-c3cc(Cl)ccc3OC)nc(N)n2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1-c1cc(Nc2ccc(CO)cc2)nc(N)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a stirred solution of the title compound of Example 9 in tetrahydrofuran (5.0 ml), cooled to 0° C. was added a solution of lithium aluminum hydride in tetrahydrofuran (1.0 M, 0.5 ml). After stirring at 0° C. for 2 hours, aqueous sodium hydroxide solution (1.0 M, 5.0 ml) was added carefully. The mixture was extracted with tetrahydrofuran (2×10 ml). The organic phase was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure provided the title compound (0.031 g, 87% yield) as a white powder. 1H NMR (DMSO-d6) δ 3.88 (s, 3H, CH3), 4.44 (d, 2H, J=5.7 Hz, CH2), 5.06 (t, 1H, J=5.7 Hz, OH), 6.29 (s, 2H, NH2), 6.72 (s, 1H, Ar), 7.17 (d, 1H, J=8.9 Hz, Ar), 7.23 (d, 2H, J=8.5 Hz, Ar), 7.45 (dd, 1H, J=8.9 Hz, J=2.8 Hz, Ar), 7.70 (d, 2H, J=8.5 Hz, Ar), 7.91 (d, 1H, J=2.8 Hz, Ar), 9.20 (s, 1H, NH).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]2[N:8]=[C:9]([NH:11][C:12]3[NH:13][CH2:14][CH2:15][N:16]=3)[NH:10][C:6]=2[CH:5]=1)([O-])=O>CN(C)C=O.[Pd]>[NH2:1][C:4]1[CH:18]=[CH:17][C:7]2[N:8]=[C:9]([NH:11][C:12]3[NH:13][CH2:14][CH2:15][N:16]=3)[NH:10][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2nc(NC3=NCCN3)[nH]c2c1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc2nc(NC3=NCCN3)[nH]c2c1
Yield: 87.8 %

Procedure:
2-(5-Nitrobenzimidazolyl)amino-2-imidazoline (12.80 g,) was dissolved in anhydrous dimethylformamide (200 ml) and hydrogenated at 50 psi and room temperature for 48 hours, over 5% palladium charcoal (500mgs). The filtered reaction mixture was evaporated under reduced pressure to yield 2-(5-aminobenzimidazolyl)amino-2-imidazoline (9.87g), characterised as the dihydrochloride (7.60g) (m.p. 285°C).
Reaction SMILES: [C:1]([CH:4]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6][CH2:5]1)([OH:3])=[O:2].S(Cl)(Cl)=O.CCOCC.[CH2:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:2][C:1]([CH:4]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6][CH2:5]1)=[O:3])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)C1CCCCNC1
Reactant: OCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: O=C(OCc1ccccc1)C1CCCCNC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Suspend 1.15 g 3-carboxyperhydroazepine [P. Krogsgaard-Larsen et al., Acta Chem. Scand., B32, 327 (1978)] in 8 ml benzyl alcohol. Cool the mixture to 0° and add 1 ml thionyl chloride. Stir the mixture at room temperature for 48 hours, then add it dropwise to 300 ml ether with vigorous stirring. Decant the ether and dissolve the residue in H2O. Wash the aqueous solution with ether, then make it to pH 12 and extract with ethyl acetate. Dry the extracts and concentrate in vacuo to obtain 3-benzyloxycarbonylperhydroazepine.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:5][N:6]=1.[Cl-].[NH4+].O1CCCC1.O>C(O)C.[Fe]>[NH2:1][C:2]1[S:3][C:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:5][N:6]=1
Reactant: Nc1ncc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)c2cnc(N)s2)cc1
Yield: 86.6 %

Procedure:
To a mixture of 2-amino-5-(4-nitrophenylsulfonyl)thiazole (4.0 g) and ammonium chloride in a mixture of ethanol (80 ml), tetrahydrofuran (40 ml) and water (30 ml) was portionwise added the iron powder (4 g) at 80° C. with stirring. The mixture was refluxed for 1.5 hours with stirring. The reaction mixture was filtered by suction and the filtrate was concentrated under reduced pressure. The residue was triturated with water and the precipitates were collected by filtration, washed with water and dried in vacuo no give 2-amino-5-(4-aminophenylsulfonyl)thiazole (3.10 g, yield: 86.6%).
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][C:10]2[C:24]([O:25][C:26]3[CH:27]=[N:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=3)=[CH:23][C:13]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21]C=C[N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[NH:36]1C=CC(C=O)=N1>>[C:1]([C:3]1[C:8]([O:9][C:10]2[C:24]([O:25][C:26]3[CH:27]=[N:28][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][CH:31]=3)=[CH:23][C:13]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][NH:36][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: O=Cc1cc[nH]n1
Reactant: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2cccnc2C#N)cn1
Product: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cc[nH]n4)nc3cc2Oc2cccnc2C#N)cn1

Procedure:
The entitled compound was obtained as a colorless solid in the same method as in Example 202 or in accordance with the method or by combining it with an ordinary method but using 4-(2-cyanopyridin-3-yloxy)-5-(6-methanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 218 (step 3) and 1H-pyrazole-3-carboxaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[H-].[Na+].[CH:32]1([CH2:36]Br)[CH2:35][CH2:34][CH2:33]1.[NH4+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]([CH2:36][CH:32]2[CH2:35][CH2:34][CH2:33]2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CCOC(=O)Cc1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Reactant: BrCC1CCC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC1CCC1)c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.6 g, 0.49 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt. in paraffin oil, 0.039 g, 1.69 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and cyclobutylmethyl bromide (0.223 g, 1.49 mmol) was added drop wise at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. and saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO4 The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate (0.25 g) as a colorless liquid.
Reaction SMILES: [C:1]([N:11]([CH3:19])[C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH2:20][C@H:21]([C:34]([NH2:36])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=1.C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([N:11]([CH3:19])[C@H:12]([C:16]([NH:20][C@H:21]([C:34]([NH2:36])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:31])[CH3:32])[CH:24]=1)=[O:18])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Reactant: CC(C)(C)c1cc(C[C@H](N)C(N)=O)ccc1O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)[C@@H](C(=O)N[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 131.9 %

Procedure:
To a solution of 400 mg (1.52 mmol) of Z-N-Me-Val-OH, 300 mg (1.27 mmol) of Tyr(3-tBu)-NH2 and 230 mg (1.52 mmol) of HOBT in 7 ml of DMF, 0.24 ml (1.52 mmol) of DIC was added dropwise under cooling with ice and the mixture was stirred at room temperature for 15 hours and a half. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of methylene chloride, methanol and aqueous ammonia at a ratio of 100:3:1) to give 810 mg of Z-N-Me-Val-Tyr(3-tBu)-NH2.