Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[Br:28][CH2:29][C:30](Cl)=[O:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:28][CH2:29][C:30]([O:10][C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[CH2:8][C:7]1[C:6]([Cl:26])=[CH:5][N+:4]([O-:27])=[CH:3][C:2]=1[Cl:1])=[O:31]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: O=C(Cl)CBr
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CBr)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (500 mg, 1.2 mmol) is dissolved in CH2Cl2 (15 ml), DMAP (180 mg, 1.8 mmol) and 2-bromoacetyl chloride (243 mg, 1.55 mmol) are added. The mixture is stirred at RT for 2 hours, then is diluted with CH2Cl2 (50 ml) and quenched with HCl 1N aqueous solution (50 ml). The two phases are separated, and the organic phase is washed with HCl 1N aqueous solution (2×50 ml), dried over Na2SO4 and evaporated under vacuum. The crude contains a mixture of the title compound (bromoacetoxy-derivative) and an undesired compound (chloroacetoxy-derivative), in a cumulative amount of 550 mg. The compound undergoes the next step without any further purification. MS/ESI+ 541.17 [MH]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([F:25])[CH:19]=1>O1CCCC1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=2[OH:1])=[C:20]([F:25])[CH:19]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1ccc(C(=O)O)c(O)c1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(=O)Nc2ccc(Cl)cc2F)c(O)c1

Procedure:
To a solution of 2-hydroxy-4-methoxybenzoic acid (1.68 g, 10 mmole) in tetrahydrofuran (40 mL) was added thionyl chloride (2.5 mL, 35 mmole) and refluxed 3 hr. The mixture was steamed (110° C.) by Dean-Stark. The residue was directly reacted with 4-chloro-2-fluorobenzenamine (1.1 mL, 10 mmole) in THF (40 mL) for 14 hr. The reaction mixture was concentrated and extracted with ethyl acetate, dried over anhydrous magnesium sulfate. Recrystallization of desired products from hot dichloromethane afforded the compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-].CCOC(C)=O>CO.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)C1CCN(c2ccc(N)cc2)CC1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of compound 54a (15 g, 51 mmol) in MeOH (100 mL) was added saturated NH4Cl solution (100 mL) followed by Fe(s) (9.1 g, 160 mmol). The resulting mixture was stirred for 5 h at 80° C. and then 200 mL of EtOAc was added. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:5 v/v)) to obtain compound 54b as a black solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C14H20N2O2: 249.2 (M+H). Found 249.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:28][C:29]1[CH:30]=[C:31]([CH2:35][CH2:36][C:37](=O)[CH3:38])[CH:32]=[CH:33][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][CH:37]([CH3:38])[CH2:36][CH2:35][C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([F:28])[CH:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: CC(=O)CCc1cccc(F)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4cccc(F)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 8, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-(3-fluoro-phenyl)-butan-2-one.
Reaction SMILES: [OH-].[K+].C([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]3[N:19]([CH:20]=2)[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[S:16]3)=[CH:9][CH:8]=1)(=O)C.C(O)(=O)C>CO>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]3[N:19]([CH:20]=2)[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[S:16]3)=[CH:11][CH:12]=1
Reactant: CC(=O)Oc1ccc(-c2cn3c(n2)sc2ccccc23)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Oc1ccc(-c2cn3c(n2)sc2ccccc23)cc1
Reaction time: 1 h
Yield: 86.8 %

Procedure:
In a solution of 2.5 g of potassium hydroxide in 90% methanol was suspended 2 g of 2-(p-acetoxyphenyl)imidazo-[2,1-b]benzothiazole and the suspension was stirred for one hour at 40°-50° C., thereby the additive was completely dissolved. Then, 3 ml of acetic acid was gradually added dropwise to the reaction mixture with stirring, thereby crystals precipitated. The crystals were recovered by filtration, washed with water and then methanol, and dried to provide 1.5 g of 2-(p-hydroxyphenyl)imidazo[2,1-b]benzothiazole.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[CH2:25][C@@H:24]2[C@:11]([CH3:29])([CH2:12][C@H:13]([OH:28])[C@H:14]3[C@H:23]2[CH2:22][CH2:21][C:20]2[C@:15]3([CH3:27])[CH2:16][CH2:17][C:18](=[O:26])[CH:19]=2)[C@@:6]1([OH:30])[C:7](=[O:10])[CH2:8][Cl:9])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:39])C=1>ClCCl>[Cl:9][CH2:8][C:7](=[O:10])[C@:6]1([OH:30])[C@:11]2([CH3:29])[C@H:24]([C@H:23]3[C@H:14]([C@@H:13]([OH:28])[CH2:12]2)[C@:15]2([CH3:27])[C:20](=[CH:19][C:18](=[O:26])[CH2:17][CH2:16]2)[CH2:21][CH2:22]3)[CH2:25][C@H:5]1[O:4][CH2:1][CH:2]1[CH2:3][O:39]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CCl
Solvent: ClCCl
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](OCC1CO1)[C@]2(O)C(=O)CCl

Procedure:
A solution of 16α-allyloxy-21-chloro-11β,17-dihydroxypregn-4-ene-3,20-dione (3.8 mmoles) in 50 ml of dichloromethane is stirred with 0.76 g of m-chloroperbenzoic acid for 19 hours at room temperature. The resulting solution is washed with a mixture of 10% potassium carbonate solution and 10% sodium sulfite solution, dried, and evaporated in vacuo to yield the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][CH:10]([C:12]([OH:14])=O)[CH2:9][S:8]2)[CH:2]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(N(CC)CC)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][CH:10]([C:12]([N:24]3[CH2:25][CH2:26][N:21]([C:16]4[N:15]=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:22][CH2:23]3)=[O:14])[CH2:9][S:8]2)[CH:2]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(C1CSC(c2cccnc2)N1)N1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3-pyridyl)thiazolidine-4-carboxylic acid 2.1 g, 1-(2-pyrimidinyl)piperazine.2 hydrochyloride 2.2 g, triethylamine 1.8 g, 1-hydroxybenzotriazole 1.5 g and N,N-dimethylformamide 30 ml was added dicyclohexylcarbodiimide 2.0 g under cooling and the mixture was stirred overnight at room temperature. The resultant dicyclohexylurea was distilled off, ethyl acetate 100 ml and water 50 ml were added to the filtrate and the solution was basified by addition of potassium carbonate. The organic layer was separated and the aqueous layer extracted with ethyl acetate. The organic layer and extract were combined, washed successively with water and saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethanol to give 0.8 g of 1-[2-(3-pyridyl)thiazolidine-4-ylcarbonyl]-4-(2-pyrimidinyl)piperazine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:24]2[C:25]([F:37])=[C:26]([NH:30]C(=O)OCC=C)[CH:27]=[CH:28][CH:29]=2)[CH:5]=[CH:4][N:3]=1.C([SnH](CCCC)CCCC)CCC.O>ClCCl>[NH2:30][C:26]1[C:25]([F:37])=[C:24]([C:9]2[N:10]=[C:11]([C:13]([NH:16][C:17](=[O:18])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(C(C)(C)NC(=O)OC(C)(C)C)sc2-c2ccnc(Cl)n2)c1F
Agent: CCCC[SnH](CCCC)CCCC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
To a solution of 2-propen-1-yl (3-{5-(2-chloro-4-pyrimidinyl)-2-[1-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-methylethyl]-1,3-thiazol-4-yl}-2-fluorophenyl)carbamate (1.28 g, 2.336 mmol). tri-n-butyltin hydride (0.624 mL, 2.336 mmol) in dichloromethane (DCM) (50 mL) was added tetrakis(triphenyl-phosphine)palladium(0) (0.135 g, 0.117 mmol) followed by water (0.2 mL). After 30 min, the reaction was concentrated. The residue was purified via chromatography on silica gel to obtain the title compound (0.81 g 74% yield). MS (ESI): 464.1 [M+H]+
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([C:8](=[O:27])[CH2:9][NH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=3[Cl:20])[NH:13][C:12]=2[C:22]([O:24]CC)=[O:23])=[CH:6][CH:5]=1)([O-:3])=[O:2].O1CCCC1.O.[OH-].[Li+].Cl>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8](=[O:27])[CH2:9][NH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=3[Cl:20])[NH:13][C:12]=2[C:22]([OH:24])=[O:23])=[CH:28][CH:29]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CNc1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
Mix 3-[(4-nitrophenacyl)amino]-2-carbethoxy-4,6-dichloroindole (161 mg, 0.381 mmol), tetrahydrofuran (20 ml) and water (20 mL). Add lithium hydroxide monohydrate (64 mg, 1.52 mmol) and stir overnight. Heat at reflux for 4 hours, cool to room temperature and pour onto 1N hydrochloricacid (100 mL). Collect the resulting solid by filtration and air dry to give the title compound (148 mg, 99%); mp 270°-72° C.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:23]=[CH:22][C:13]([CH2:14][CH:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.CN(C=O)C.Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>O>[O:20]=[C:18]1[N:17]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:16](=[O:21])[CH:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:10]([N:7]3[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]3)=[CH:23][CH:22]=2)[S:19]1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1C(=O)SC(Cc2ccc(N3CCC(=O)CC3)cc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
Sodium hydride (60% in mineral oil, 66 mg, 1.65 mmol) was added into a mixture of 5-[4-(4-oxo-1-piperidineyl)benzyl]-1,3-thiazolidine-2,4-dione (500 mg, 1.65 mmol) (which was obtained in Example 38) and DMF. The mixture was stirred for one hour at room temperature, and then ethyl bromoacetate (0.27 mL, 2.47 mmol) was added. The new mixture was stirred for 30 minutes, poured into water, and extracted with ethyl acetate. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/ethyl acetate 2/1) gave a viscous oil (295 mg, 46% yield); 1H NMR (300 MHz, DMSO-d6) δ 1.20 (t, J=7.16 Hz, 3H), 2.40 (m, 4H), 2.95-3.00 (m, 1H), 3.4 (m, 1H), 3.60 (m, 2H), 4.10 (q, J=7.16 Hz, 2H), 4.30 (s, 2H), 6.97 (m, 2H), 7.16 (m, 2H); MS (ES) m/z: 391 (MH+);
Reaction SMILES: O[Li].O.O.[C:5]([O:9][C:10]([N:12]([CH3:51])[C@@H:13]([CH3:50])[C:14]([NH:16][C@H:17]1[CH2:23][O:22][C:21]2[C:24]([C:28]([O:30]C)=[O:29])=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:32][C:33]2[C:42]3[C:37](=[CH:38][C:39]([C:43]([O:45]C)=[O:44])=[CH:40][CH:41]=3)[CH:36]=[CH:35][C:34]=2[O:47][CH3:48])[C:18]1=[O:49])=[O:15])=[O:11])([CH3:8])([CH3:7])[CH3:6]>CO>[C:5]([O:9][C:10]([N:12]([CH3:51])[C@@H:13]([CH3:50])[C:14]([NH:16][C@H:17]1[CH2:23][O:22][C:21]2[C:24]([C:28]([OH:30])=[O:29])=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:32][C:33]2[C:42]3[C:37](=[CH:38][C:39]([C:43]([OH:45])=[O:44])=[CH:40][CH:41]=3)[CH:36]=[CH:35][C:34]=2[O:47][CH3:48])[C:18]1=[O:49])=[O:15])=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: COC(=O)c1ccc2c(CN3C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc4c(C(=O)OC)cccc43)c(OC)ccc2c1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: COc1ccc2cc(C(=O)O)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc2c(C(=O)O)cccc21
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 28.9 %

Procedure:
LiOH.H2O (22.0 mg, 523 μmol, Eq: 2.00) and H2O (0.5 mL) was added to a solution of (S)-methyl 3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-5-((2-methoxy-6-(methoxycarbonyl)naphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carboxylate (170 mg, 262 μmol, Eq: 1.00) in MeOH (5 mL). The mixture was heated to 50° C. After 3.5 h, LiOH.H2O (44 mg, 1.04 mmol) was added and temperature increased to 60° C. After 1.5 h, the MeOH was removed under vacuum, the aqueous mixture diluted with water and extracted with Et2O. The aqueous mixture was acidified to pH 2.0 with 1 N HCl and extracted with EtOAc. The combined organic extracts were washed brine and concentrated to give a residue that was triturated with Et2O to afford (S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-5-((6-carboxy-2-methoxynaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carboxylic acid (47 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][NH:9][CH2:8][C:7](=[O:11])[N:6]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([N:21]=[C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:14]=1)=[O:4].CCN(C(C)C)C(C)C.[Cl:44][C:45]1[CH:46]=[CH:47][C:48]2[CH:52]=[C:51]([S:53](Cl)(=[O:55])=[O:54])[S:50][C:49]=2[CH:57]=1>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([S:53]([C:51]2[S:50][C:49]3[CH:57]=[C:45]([Cl:44])[CH:46]=[CH:47][C:48]=3[CH:52]=2)(=[O:55])=[O:54])[CH2:8][C:7](=[O:11])[N:6]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([N:21]=[C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:14]=1)=[O:4]
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Reactant: COC(=O)C1CNCC(=O)N1Cc1ccc(C#N)c(N=C(c2ccccc2)c2ccccc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC(=O)N1Cc1ccc(C#N)c(N=C(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 73.2 %

Procedure:
A solution containing (±)-1-[3-(benzhydrylidene-amino)-4-cyano-benzyl]-6-oxo-piperazine-2-carboxylic acid methyl ester (55 mg, 0.12 mmol) in CH2Cl2 (1 mL) is cooled to 0° C. DIPEA (24 mg, 0.18 mmol) is then added followed by the addition of 6-chloro-benzo[b]thiophene-2-sulfonyl chloride (32 mg, 0.12 mmol), EXAMPLE 1. The reaction mixture is warmed to ambient temperature. After 16 h, the reaction mixture is absorbed directly onto silica gel and chromatographed (CH2Cl2 to 2% MeOH/CH2Cl2) to provide 60 mg (73%) of the title compound. 1H NMR (300 MHz, CDCl3) δ2.77 (dd, J=12.3, 3.4 Hz, 1H), 3.50-3.72 (m, 3H), 3.79 (s, 3H), 4.15 (dd, J=12.3, 1.4 Hz, 1H), 4.24 (d, J=16.9 Hz, 1H), 5.41 (d, J=15.3 Hz, 1H), 6.50 (s, 1H), 6.76 (dd, J=7.9, 1.4 Hz, 1H), 7.11-7.86 (m, 15H) ppm; MS (ISP loop): m/z 683 (M+H).
Reaction SMILES: Cl.O(CC)CC.[Cl:7][C:8]1[CH:9]=[C:10]([C:15]2([CH2:21][CH2:22][CH2:23][O:24]C3CCOCC3)[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]2)[CH:11]=[CH:12][C:13]=1[Cl:14]>CO>[Cl:7][C:8]1[CH:9]=[C:10]([C:15]2([CH2:21][CH2:22][CH2:23][OH:24])[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]2)[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: Clc1ccc(C2(CCCOC3CCOCC3)CCCNC2)cc1Cl
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: OCCCC1(c2ccc(Cl)c(Cl)c2)CCCNC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
A solution of dry HCl.OEt2 was added to a solution of piperidine (7) (20.2 g, 54.36 mmol) in MeOH (200 mL) until pH˜1. The mixture was stirred at room temperature for 30 minutes. Solvent was evaporated, the residue was dissolved in CH2Cl2 (300 mL) and stirred with 1N NaOH (100 mL) for 15 minutes. The solvent was separated, washed with NaHCO3, and dried over MaSO4. The crude oil was purified by flash chromatography (CH2Cl2-MeOH(saturated with NH3)/95:5) to give a white solid (13.25 g, 84.6%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH:18]1([CH2:21][NH2:22])[CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[CH:18]1([CH2:21][NH:22][CH:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][N:2]=[CH:3]4)[CH2:12][CH2:13]2)[CH2:20][CH2:19]1
Reactant: NCC1CC1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1cc2[nH]ncc2cc1NC1CCC(NCC2CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.4 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and cyclopropylmethylamine (54 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (13 mg) and a syn-form compound (7 mg).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C:10]([C:11](=[O:25])[N:12]([CH:22]2[CH2:24][CH2:23]2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[C:9]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][C:36]3[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:43])=[CH:28][CH:27]=2)[CH2:8][CH2:7][N:6]1[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][C@@H:5]1[C:10]([C:11](=[O:25])[N:12]([CH:22]2[CH2:24][CH2:23]2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[C:9]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][C:36]3[C:37]([Cl:43])=[CH:38][CH:39]=[CH:40][C:41]=3[Cl:42])=[CH:28][CH:27]=2)[CH2:8][CH2:7][N:6]1[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOc3c(Cl)cccc3Cl)cc2)=C(C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)[C@H]1CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOc3c(Cl)cccc3Cl)cc2)=C(C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)[C@H]1CN
Yield: 18 %

Procedure:
Into a 10 mL round bottom flask was added 19C (200 mg, 302 μmol) and THF (3 mL). Triphenylphosphine (166 mg, 634 μmol) and water (112 mg, 6.22 mmol) was added and the flask was fitted with a reflux condenser and nitrogen inlet. The mixture was refluxed for three hours. Solvent was removed under vacuum and the residue was purified by preparatory LCMS to give 19D (40 mg, 21%). ESI-MS:m/z 734.2 (M+H)+.
Reaction SMILES: [NH:1]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[C@H:2]([C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][C:19]([NH:21][C@H:22]([C:30]([NH:32][C@H:33]([C:38]([NH:40][C@H:41]([C:54]([N:56]1[CH2:67][CH2:66][CH2:65][C@H:57]1[C:58]([O:60]C(C)(C)C)=[O:59])=[O:55])[CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[O:39])[CH2:34][CH2:35][S:36][CH3:37])=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])=[O:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CN(C=O)C>C(O)(C(F)(F)F)=O>[NH:1]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[C@H:2]([C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][C:19]([NH:21][C@H:22]([C:30]([NH:32][C@H:33]([C:38]([NH:40][C@H:41]([C:54]([N:56]1[CH2:67][CH2:66][CH2:65][C@H:57]1[C:58]([OH:60])=[O:59])=[O:55])[CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[O:39])[CH2:34][CH2:35][S:36][CH3:37])=[O:31])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:20])=[O:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 8 ml of TFA were dissolved 800 mg of Boc-Tyr-Gly-Gly-Phe-Met-Lys(Boc)-Pro-OBut, and the solution, after shaking at room temperature for 60 minutes, was concentrated. To the concentrate was added diethyl ether, followed by recovering the resulting precipitates by filtration and drying. The precipitates were dissolved in 10 ml of DMF, and 0.34 ml of TEA and 440 mg of Boc-ONB were added to the solution followed by stirring at 0° C. for 2 hours and at room temperature for 10 hours. The solution was evaporated under reduced pressure to dryness. To the residue was added diethyl ether. The resulting precipitates were recovered by filtration and then placed on a column (2.5×115 cm) of Sephadex LH-20. Elution was conducted with MeOH and fractions of 195 to 225 ml were collected, then the solvent was evaporated to dryness under reduced pressure. To the concentrate was added diethyl ether, and the mixture was subjected to filtration to give the product. Yield 680 mg (90.9%); m.p. 151° C. (decomp.); [α]D24 -28.0° (c=0.52, DMF); Rf1 =0.25, Rf2 =0.64.
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1.[Br:29]C1C=CC2SC(I)=NC=2C=1>>[Br:29][C:28]1[CH:2]=[CH:3][C:4]2[S:8][C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)=[N:6][C:5]=2[CH:27]=1
Reactant: Brc1ccc2sc(I)nc2c1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2cc(Br)ccc2s1

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 5-bromo-2-iodo-1,3-benzothiazole in place of 2-chloro-6-fluorobenzothiazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.11-2.30 (m, 4H), 3.11 (q, J=11.0 Hz, 2H), 3.41 (d, J=12.8 Hz, 2H), 4.47-4.56 (m, 1H), 7.74 (dd, J=8.6, 2.0 Hz, 1H), 8.03-8.08 (m, 2H), 8.34 (br. s., 1H), 8.39 (s, 1H), 8.51 (d, J=1.4 Hz, 1H), 8.54 (d, J=2.2 Hz, 1H). MS (ES+): m/z=455.02/457.00 [MH+]. HPLC: tR=2.19 min (ZQ2, polar—5 min).