Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:26][CH3:27])[CH:22]=[CH:23][C:24]#[N:25])[C:11](=[O:28])[C@@H:10]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H][H]>CCO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:26][CH3:27])[CH2:22][CH2:23][C:24]#[N:25])[C:11](=[O:28])[C@@H:10]([CH2:29][C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](C=CC#N)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC[C@@H](CCC#N)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 56 mg (0.106 mmol) of tert-butyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyanopent-1-en-3-yl)-2-oxopiperidin-3-yl)acetate (Example 30, Step A) in 3.5 mL of EtOH) was added 10% palladium on activated carbon (11.30 mg, 10.62 μmol). Then the reaction mixture was subjected to regular hydrogenation with hydrogen. After being stirred under a hydrogen atmosphere at rt for 2 h, the catalyst was filtered using a short plug of silica gel. The plug was washed several times with EtOAc. The combined filtrates were concentrated under reduced pressure to provide the crude title compound as a colorless film which was used in the subsequent reaction without further purification. MS (ESI) 529.2 [M+H]+.
Reaction SMILES: CS([N:5]1[C:9]([CH3:10])=[CH:8][C:7]([NH:11][C:12]2[N:13]=[C:14]([CH2:24]OS(C)(=O)=O)[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([O:22][CH3:23])=[CH:17][CH:16]=3)=[N:6]1)(=O)=O.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CCO>[CH3:23][O:22][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[C:14]([CH2:24][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[N:13][C:12]([NH:11][C:7]1[CH:8]=[C:9]([CH3:10])[NH:5][N:6]=1)=[CH:21]2
Reactant: COc1ccc2c(COS(C)(=O)=O)nc(Nc3cc(C)n(S(C)(=O)=O)n3)cc2c1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2c(CN3CCCCC3)nc(Nc3cc(C)[nH]n3)cc2c1
Temperature: 120 °C
Yield: 12.5 %

Procedure:
A 2.0˜5.0 mL process vial was charged with 50 mg methanesulfonic acid 3-(1-methanesulfonyl-5-methyl-1H-pyrazol-3-ylamino)-6-methoxy-isoquinolin-1-ylmethyl ester, 50 mg piperidine, 75 mg K2CO3 in 3 mL THF/EtOH(1:1). The vial was heated at 120° C. for 30 min under microwave irradiation. After cooling, the reaction mixture was filtered through a short silica gel column, and the solvent was removed under reduced pressure. The residue in MeOH was sent to prep-HPLC to get 5 mg of (6-Methoxy-1-piperidin-1-ylmethyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine as a yellow solid. LC-MS m/e 352 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][NH:7][CH2:8][CH2:9][C:10]=2[N:11]=1.C(=O)([O-])[O-].[K+].[K+].[Br:18][C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[CH:21]=[CH:22][CH2:23]Br.C(OC(C)C)(C)C>CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:23][CH:22]=[CH:21][C:20]3[CH:25]=[CH:26][CH:27]=[CH:28][C:19]=3[Br:18])[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: BrCC=Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: Nc1nc2c(s1)CCN(CC=Cc1ccccc1Br)CC2
Yield: 42 %

Procedure:
Prepared analogously to Example 1 from 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine, potassium carbonate and 2-bromo-cinnamyl bromide in anhydrous dimethylformamide for 2 hours at 20° C. Yield: 42% of theory, Melting point: 103°-106° C. (diisopropylether).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([OH:9])[C:6]([CH3:10])=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1([C:21]2[N:25]=[C:24](S(C3C=CC(C)=CC=3)(=O)=O)[S:23][N:22]=2)[CH2:20][CH2:19]1>C(#N)C>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:24]2[S:23][N:22]=[C:21]([C:18]3([Cl:17])[CH2:20][CH2:19]3)[N:25]=2)[C:6]([CH3:10])=[CH:5][C:3]=1[NH2:4]
Reactant: Cc1ccc(S(=O)(=O)c2nc(C3(Cl)CC3)ns2)cc1
Reactant: Cc1cc(N)c(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(N)c(Cl)cc1Oc1nc(C2(Cl)CC2)ns1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
3.00 g (19.04 mmol) of 2-chloro-4-hydroxy-5-methylaniline are introduced into 50 ml of acetonitrile, treated at ambient temperature with 3.16 g (22.84 mmol) of potassium carbonate and stirred at ambient temperature for 30 min. Subsequently, 6.26 g (19.04 mmol) of 3-(1-chlorocyclopropyl)-5-[(4-methylphenyl]sulphonyl]-1,2,4-thiadiazole are added and the reaction mixture is stirred at 50° C. for 12 h. After cooling, the mixture is concentrated on a rotary evaporator, the residue is taken up in dichloromethane and the solution is extracted twice with water, dried over Na2SO4 and freed from solvent under vacuum. The residue is purified by column chromatography. 3.18 g of product are obtained (93.3% purity, 49.4% yield, log P (pH 2.3)=3.50).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:17]([CH2:20][OH:21])[CH2:18][NH2:19]>>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[N:7]=[C:2]([NH:19][CH2:18][CH2:17][CH2:20][OH:21])[CH:3]=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: NCCCO
Reactant: COc1ccc(Nc2cccc(Cl)n2)cc1
Product: COc1ccc(Nc2cccc(NCCCO)n2)cc1
Yield: 64 %

Procedure:
95 mg of 6-chloro-N-(4-methoxyphenyl)pyridin-2-amine were mixed with 244 mg of n-propanolamine and the mixture obtained was treated in a vial analogously to the method as set out in Example 16b. 3-(6-(4-Methoxyphenylamino)pyridin-2-ylamino)propan-1-ol was obtained in the form of a brown oil.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:7](=[O:19])[CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C.Cl.ClCCl>O1CCOCC1>[O:3]=[CH:4][CH2:5][N:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:7](=[O:19])[CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(CN(CCCCCOCCc1ccccc1)C(=O)CCOCCc1ccccc1)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=CCN(CCCCCOCCc1ccccc1)C(=O)CCOCCc1ccccc1

Procedure:
N-(2,2-Diethoxyethyl)-3-phenethyloxy-N-(5-phenethyloxypentyl)propanamide (Example 9b), 0.18 g) was dissolved in anhydrous dioxane (5 mL) and treated with concentrated hydrochloric acid (5 mL) at room temperature. The resultant solution was stirred for 1 hour and then poured into dichloromethane (10 mL), washed with water (2×10 mL) and brine (10 mL). The organic layer was isolated, dried over anhydrous magnesium sulphate, filtered and concentrated to give the sub-titled compound (0.12 g) as a viscous oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[N:8](COC)[C:7]=2[CH:19]=1.Cl>O1CCCC1>[Cl:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[NH:8][C:7]=2[CH:19]=1
Reactant: COCN1c2cc(CCl)ccc2Sc2nccnc21
Agent: Cl
Solvent: C1CCOC1
Product: ClCc1ccc2c(c1)Nc1nccnc1S2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
6 g of 8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine was dissolved in 50 ml of tetrahydrofuran and 20 ml of 6 N hydrochloric acid was added thereto at 0° C. After stirring at room temperature for 30 minutes, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crystals precipitating in the course of the concentration were taken up by filtration and washed with diethyl ether to thereby give 4.8 g of the title compound as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].Br[C:25]([C:27]([F:30])([F:29])[F:28])=[CH2:26].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.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>[Cl:14][C:6]1[CH:5]=[C:4]([C:25]([C:27]([F:30])([F:29])[F:28])=[CH2:26])[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][CH2:9][C:10]([F:11])([F:12])[F:13]
Reactant: CC1(C)OB(c2cc(Cl)c(OCC(F)(F)F)c(Cl)c2)OC1(C)C
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)c(OCC(F)(F)F)c(Cl)c1)C(F)(F)F
Temperature: 80 °C
Yield: 74.2 %

Procedure:
A mixture of 2-(3,5-dichloro-4-(2,2,2-trifluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (530 mg, 1.43 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (275 mg, 1.57 mmol), K2CO3 (395 mg, 2.86 mmol) and Pd(PPh3)2Cl2 (20 mg, 0.029 mmol) in THF (3 mL) and H2O (3 mL) was heated at 80° C. in a sealed tube for 3 h. The mixture was cooled to rt and partitioned between EA (50 mL) and H2O (50 mL). The aqueous layer was extracted with EA (50 mL) and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel elute with PE to give 1,3-dichloro-2-(2,2,2-trifluoroethoxy)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (360 mg; yield 74%) as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH3:15])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH3:16][O:17][C:18]([C:20]1[S:24][N:23]=[C:22](O)[CH:21]=1)=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:16][O:17][C:18]([C:20]1[S:24][N:23]=[C:22]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:15])[CH:21]=1)=[O:19]
Reactant: COC(=O)c1cc(O)ns1
Reactant: Cc1onc(-c2ccc(F)cn2)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)ns1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
To a solution of [3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-methanol (458 mg, 2.2 mmol) in THF (10 mL) was added 3-hydroxy-isothiazole-5-carboxylic acid methyl ester (350 mg, 1.9 mmol) and triphenylphosphine (692 mg, 2.6 mmol) at 0° C. under an argon atmosphere. Then diethyl azodicarboxylate (˜40% in toluene, 1.05 mL, 2.4 mmol) was added and the reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (silica, heptane:ethyl acetate=4:1 to 0:1) afforded the title compound (488 mg, 64%) as a white solid. MS: m/e=350.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([Cl:15])[CH:10]=2)[C:5]([N+:16]([O-])=O)=[CH:4][CH:3]=1.[Cl-].[NH4+]>CO.C1COCC1.[Zn]>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([Cl:15])[CH:10]=2)[C:5]([NH2:16])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)nc1Nc1ccnc(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Br)nc1Nc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(6-Bromo-3-nitro-pyridin-2-yl)-(2-chloro-pyridin-4-yl)amine (step 1) (1 eq, 0.303 mmol, 100 mg) is dissolved in MeOH/THF (6 ml of a 1:1 mixture) and stirred for 5 minutes at RT. Zinc (22 eq, 6.6 mmol 350 mg) is added and the reaction mixture is stirred for a further 20 minutes. Saturated aqueous ammonium chloride (0.8 ml) is added to the reaction mixture and stirring continued at room temperature for 30 minutes. The mixture is filtered through CELITE® and the filtrate is diluted with water (10 ml) and extracted with EtOAc (2×10 ml). The organic portions are combined, dried (MgSO4) and concentrated in vacuo to afford the title compound; [M+H]+300.
Reaction SMILES: C[O:2][C:3](=[O:30])[C@H:4]([NH:6][C:7]([C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH3:27])[C:14]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:15][C:11]=2[CH:10]=1)=[O:8])[CH3:5].[OH-].[Li+]>>[Cl:26][C:24]1[CH:23]=[CH:22][C:20]2[N:21]=[C:17]([NH:16][C:14]3[N:13]([CH3:27])[C:12]4[CH:28]=[CH:29][C:9]([C:7]([NH:6][C@H:4]([CH3:5])[C:3]([OH:30])=[O:2])=[O:8])=[CH:10][C:11]=4[N:15]=3)[S:18][C:19]=2[CH:25]=1
Reactant: COC(=O)[C@@H](C)NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C
Agent: [Li+]
Agent: [OH-]
Product: C[C@@H](NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C)C(=O)O
Yield: 74.1 %

Procedure:
(R)-2-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-propionic acid (341 mg) was prepared by following General Procedure E starting from (R)-2-{[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-propionic acid methyl ester (475 mg) and lithium hydroxide (180 mg).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[N:16]1([CH2:20][C@@H:21]([NH2:32])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH:29]([F:31])[F:30])[CH:23]=2)[CH2:19][CH2:18][CH2:17]1>>[N:16]1([CH2:20][C@@H:21]([NH:32][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH:29]([F:30])[F:31])[CH:23]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: N[C@H](CN1CCC1)c1ccc(F)c(C(F)F)c1
Agent: Cl
Product: NC(=O)c1ccnc2c(N[C@H](CN3CCC3)c3ccc(F)c(C(F)F)c3)ncnc12

Procedure:
Compound 48 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with (S)-2-Azetidin-1-yl-1-(3-difluoromethyl-4-fluoro-phenyl)-ethylamine hydrochloride to give the title compound as a white solid. LC/MS [409 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.09 (d, 1H), 9.02 (d, 1H), 8.55 (s, 1H), 8.39 (d, 1H), 8.18 (s, 1H), 7.58 (t, 1H), 7.52 (d, 1H), 7.45 (d, 1H), 7.29 (s, 1H), 7.16 (s, 1H), 7.02 (s, 1H), 5.34 (dd, 1H), 3.20-3.02 (m, 4H), 2.84 (dd, 2H), 1.99-1.85 (m, 2H).
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].Br[C:9]([C:15]1[N:16]=[C:17]([CH3:20])[O:18][CH:19]=1)([CH3:14])[C:10]([O:12][CH3:13])=[O:11]>CN(C=O)C>[C:5]([CH:4]([C:3]#[N:7])[C:9]([CH3:14])([C:15]1[N:16]=[C:17]([CH3:20])[O:18][CH:19]=1)[C:10]([O:12][CH3:13])=[O:11])#[N:6]
Reactant: COC(=O)C(C)(Br)c1coc(C)n1
Reactant: N#CCC#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(c1coc(C)n1)C(C#N)C#N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To NaH (60%, 0.293 g, 7.32 mmol) in 10 mL of DMF at room temperature was added dropwise malononitrile (0.483 g, 7.32 mmol) in 5 mL of DMF. After stirring at room temperature for 15 minutes, the intermediate from Step C (1.82 g, 7.32 mmol) in 10 mL of DMF was added. The resulting mixture was stirred for 2 hours and then quenched with water. The mixture was extracted with EtOAc, dried with MgSO4, and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated compound (a pale yellow oil). 1H NMR (CDCl3, 500 MHz) δ 7.66 (1H, s), 4.88 (1H, s), 3.87 (3H, s), 2.49 (3H, s), 1.92 (3H, s). m/z=234 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:27]C(=O)OC(C)(C)C)[C:10](=[O:26])[NH:11][C:12]2[CH:13]=[C:14]3[C:24](=[O:25])[NH:23][N:22]=[CH:21][C:16]4=[CH:17][NH:18][C:19]([CH:20]=2)=[C:15]34)=[CH:4][CH:3]=1.[ClH:35]>O1CCOCC1>[ClH:35].[NH2:27][C@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[C:10]([NH:11][C:12]1[CH:13]=[C:14]2[C:24](=[O:25])[NH:23][N:22]=[CH:21][C:16]3=[CH:17][NH:18][C:19]([CH:20]=1)=[C:15]23)=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(O)cc1)C(=O)Nc1cc2c3c(c[nH]c3c1)C=NNC2=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](Cc1ccc(O)cc1)C(=O)Nc1cc2c3c(c[nH]c3c1)C=NNC2=O
Yield: 72 %

Procedure:
Preparation of example 178 from the title compound of Example 155 (90 mg, 0.194 mmol) and 4M HCl in dioxane (10 mL) was carried out analogously to Example 91. Isolation, also in an analogous manner afforded the title compound (56 mg, 0.140 mmol) as an orange/yellow powder in 72% yield.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([OH:12])[CH:3]=1.Cl.[CH3:14]O>>[CH3:14][O:12][C:4]1[CH:3]=[C:2]([OH:1])[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: Oc1cc(O)c2ccccc2c1
Reactant: CO
Agent: Cl
Product: COc1cc(O)c2ccccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
To a stirring solution of 1,3-dihydroxynaphthalene (2.31 g, 14.4 mmol) in methanol (150 mL) at 0° C., hydrochloride gas was bubbed for 10 min. The resulting solution was continued stirring at room temperature for 24 hrs. A residue was obtained after evaporation of methanol and purified by silica gel column chromatography eluted with chloroform to provide the title compound as purple crystals (1.42 g, 57%). 1H NMR(300 MHz CDCl3) δ8.08(d, 1H), 7.70(d, 1H), 7.46(t, 1H), 7.34(t, 1H), 6.78 (s, 1H), 6.54 (s, 1H), 5.61(s, 1H), 3.90(s, 3H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17](=[O:28])[C:18](=[CH:24]OCC)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([F:29])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH:30]1([NH2:33])[CH2:32][CH2:31]1>C(OCC)C>[C:1]([N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17](=[O:28])[C:18](=[CH:24][NH:33][CH:30]3[CH2:32][CH2:31]3)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([F:29])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: NC1CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(C2=CCN(C(C)=O)CC2)cc1F
Solvent: CCOCC
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(C2=CCN(C(C)=O)CC2)cc1F
Reaction time: 22 h

Procedure:
A solution of 4.50 g (11.06 mmol) of ethyl 4-(1-acetyl-1,2,3,6-tetrahydro-4-pyridyl)-α-(ethoxymethylene)-2,5-difluoro-β-oxobenzenepropionate in 50 ml of ethyl ether was treated with 0.77 g (13.5 mmol) of cyclopropylamine and stirred for 22 hours. The title compound was isolated as a syrup after evaporation under vacuum.
Reaction SMILES: [CH:1]1([C:7]2[N:12]=[N:11][C:10]([C:13]3[CH:54]=[CH:53][C:16]([CH2:17][C:18]4[N:19]([C:31]5[CH:32]=[C:33]([N:37]6[S:41](=[O:43])(=[O:42])[N:40](COCC[Si](C)(C)C)[C:39](=[O:52])[CH2:38]6)[CH:34]=[CH:35][CH:36]=5)[CH:20]=[C:21]([C:23]5[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=5[Cl:30])[N:22]=4)=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH:1]1([C:7]2[N:12]=[N:11][C:10]([C:13]3[CH:54]=[CH:53][C:16]([CH2:17][C:18]4[N:19]([C:31]5[CH:32]=[C:33]([N:37]6[S:41](=[O:43])(=[O:42])[NH:40][C:39](=[O:52])[CH2:38]6)[CH:34]=[CH:35][CH:36]=5)[CH:20]=[C:21]([C:23]5[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=5[Cl:30])[N:22]=4)=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(C5CCCCC5)nn4)cc3)c2)S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(C5CCCCC5)nn4)cc3)c2)S(=O)(=O)N1

Procedure:
5-{3-[2-[4-(6-Cyclohexyl-pyridazin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (16 mg, 0.02 mmol) was treated as described in general procedure W using tetrabutylammonium fluoride (26 mg, 0.1 mmol) to give 5-{3-[2-[4-(6-cyclohexyl-pyridazin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=1)=[O:8].[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:32]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:33])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:17])([CH3:18])[CH3:19])[CH:13]=[C:12]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=1)=[O:8]
Reactant: CC(C)(C)c1cc(NC(=O)c2cc(Br)ccc2O)cc(C(C)(C)C)c1
Reactant: O=C(Cl)N1CCOCC1
Product: CC(C)(C)c1cc(NC(=O)c2cc(Br)ccc2OC(=O)N2CCOCC2)cc(C(C)(C)C)c1
Yield: 93.6 %

Procedure:
Using 5-bromo-N-{3,5-bis[(1,1-dimethyl)ethyl]phenyl}-2-hydroxybenzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the example 71 gave the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][SH:21])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:30]=[C:31]([NH:34][CH2:35][CH:36]3[CH2:38][CH2:37]3)[S:32][CH:33]=2)=[CH:25][CH:24]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(N(C(C)C)CC)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][S:21][C:23]3[CH:24]=[CH:25][C:26]([C:29]4[N:30]=[C:31]([NH:34][CH2:35][CH:36]5[CH2:37][CH2:38]5)[S:32][CH:33]=4)=[CH:27][CH:28]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CS)c2CC1
Reactant: Brc1ccc(-c2csc(NCC3CC3)n2)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3ccc(-c4csc(NCC5CC5)n4)cc3)c2CC1
Temperature: 100 °C
Yield: 97.6 %

Procedure:
To a solution of 3-tert-butoxycarbonyl-7-chloro-6-mercaptomethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.051 g, 0.155 mmol) in dry dioxane (0.7 mL) add N-[4-(4-bromo-phenyl)-thiazol-2-yl]-cyclopropylmethylamine (0.043 g, 0.14 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.2 mg, 0.0035 mmol), Xantphos (4.1 mg, 0.014 mmol) and diisopropylethylamine (0.049 mL, 0.28 mmol) at room temperature. Purge the reaction mixture with nitrogen and heat the mixture at 100° C. overnight. Cool the reaction mixture to room temperature, dilute with DCM (50 mL) and filter through Celite®. Concentrate the filtrate in vacuo. Dissolve the residue in DCM, load the solution on to a RediSep® column (40 g) and purify the crude mixture by preparative liquid chromatography (0:100 to 25:75 EtOAc/hexane over 33 min; 35 mL/min) to afford 3-tert-butoxycarbonyl-7-chloro-6-{4-[2-(cyclopropylmethyl-amino)-thiazol-4-yl]-phenylthiomethyl}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.076 g, 97%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15](OC)=[O:16])=[CH:4][C:3]=1[F:19].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][C:3]=1[F:19]
Reactant: COC(=O)CCc1cnoc1-c1ccc(Cl)c(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1cnoc1-c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a solution of methyl 3-[5-(4-chloro-3-fluorophenyl)-4-isoxazolyl]propionate (3.30 g) in tetrahydrofuran (30 ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution, 25 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[5-(4-chloro-3-fluorophenyl)-4-isoxazolyl]propan-1-ol (2.79 g, yield 94%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 51–52° C.