Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[O:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1>C1COCC1>[F:9][C:4]1[CH:3]=[C:2]([C:13]2([OH:16])[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: O=C1CCOCC1
Reactant: Fc1cc(F)cc(Br)c1
Solvent: C1CCOC1
Product: OC1(c2cc(F)cc(F)c2)CCOCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
To a solution of 1-bromo-3,5-difluorobenzene (1.6 equiv.) in THF (0.26 M) under Ar was added Mg turnings (1.6 equiv.). A reflux condenser was attached and the solution was submerged in a 90° C. oil bath and refluxed for two hours. The dihydro-2H-pyran-4(3H)-one (1.0 equiv.) was added in THF via syringe. The solution was left stirring at rt under Ar for 5 hrs. The reaction solution was quenched by addition of NH4Cl(sat) and the solution was extracted with EtOAc, washed with NaCl(sat), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography (0-100% EtOAc/n-heptanes gradient) to yield 4-(3,5-difluorophenyl)tetrahydro-2H-pyran-4-ol in 71% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.59-1.68 (m, 3 H), 2.07-2.19 (m, 2 H), 3.87-3.93 (m, 4 H), 6.72 (tt, J=8.75, 2.20 Hz, 1 H), 6.97-7.06 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:1][C:2]2[CH:24]=[CH:23][C:5]3[N:6]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[C:7]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:8][C:4]=3[CH:3]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COc1ccc(-n2c(-c3ccccc3)nc3cc(N)ccc32)cc1
Product: COc1ccc(-n2c(-c3ccccc3)nc3cc(NS(=O)(=O)c4ccc(Cl)cc4)ccc32)cc1

Procedure:
5-Amino-1-(4-methoxyphenyl)-2-phenyl-1H-benzimidazole was reacted with 4-chlorobenzenesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]2[CH3:21])=[CH:4][CH:3]=1.Br[C:23]1[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=[C:27]([Br:29])[CH:28]=1>>[Br:29][C:27]1[CH:28]=[C:23]([NH:1][C:2]2[N:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]3[CH3:21])=[CH:4][CH:3]=2)[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)nc1
Reactant: Cn1cc(Br)cc(Br)c1=O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Yield: 82.4 %

Procedure:
Following the procedures of Example 323c, and starting with 340b (4.0 g, 13.7 mmol) and 3,5-dibromo-1-methylpyridin-2(1H)-one (5.5 g, 20.6 mmol) afforded 340c as a yellow solid (5.4 g, 83%). MS-ESI: [M+H]+ 478
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[CH2:18]([CH2:20][NH2:21])[OH:19]>C(O)C>[C:1]([NH:3][C:4]([NH:21][CH2:20][CH2:18][OH:19])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])#[N:2]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: NCCO
Solvent: CCO
Product: Cc1nc[nH]c1CSCCN=C(NC#N)NCCO

Procedure:
A solution of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (2.7 g) (British Specification No. 1397436) and ethanolamine (1.34 g) in ethanol (50 ml) was heated under reflux for 19 hours. Concentration followed by chromatographic purification on a column of silica gel with chlofrom-methanol (10:1) as eluant and final recrystallisation from isopropyl alcohol-acetonitrile gave the title compound, mp. 146°-7°.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[S:4]([C:7]1[CH:8]=[C:9]([C:14](=[O:17])[CH2:15]Cl)[CH:10]=[CH:11][C:12]=1[Cl:13])(=[O:6])=[O:5])[CH3:2].[CH3:20][NH:21][C:22]([NH:24][CH3:25])=[S:23]>>[ClH:13].[Cl:13][C:12]1[CH:11]=[CH:10][C:9]([C:14]2([OH:17])[CH2:15][S:23][C:22](=[N:21][CH3:20])[N:24]2[CH3:25])=[CH:8][C:7]=1[S:4](=[O:6])(=[O:5])[N:3]([CH2:18][CH3:19])[CH2:1][CH3:2]
Reactant: CNC(=S)NC
Reactant: CCN(CC)S(=O)(=O)c1cc(C(=O)CCl)ccc1Cl
Product: CCN(CC)S(=O)(=O)c1cc(C2(O)CSC(=NC)N2C)ccc1Cl
Product: Cl

Procedure:
4.8g of 3'-diethylsulfamoyl-2,4'-dichloroacetophenone and 1.5 g of 1,3-dimethylthiourea were reacted as prescribed in Example 23 and the crystalline end product was filtered off. Melting point: 165° C. (decomposition).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([N:14]([CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:15][CH2:16][CH3:17])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([N:22]1[CH2:21][CH2:20][CH:19]([CH2:18][N:14]([CH:10]2[CH2:9][CH2:8][C:7]3[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:11]2)[CH2:15][CH2:16][CH3:17])[CH2:24][CH2:23]1)(=[O:34])=[O:33]
Reactant: CCCN(CC1CCNCC1)C1CCc2ccc([N+](=O)[O-])cc2C1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCN(CC1CCN(S(C)(=O)=O)CC1)C1CCc2ccc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.3 %

Procedure:
To an ice-cold solution of (7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-ylmethyl-propyl-amine (420 mg, 1.3 mmol) and pyridine (154 μl, 1.5 mmol, 1.2 eq.) in methylene chloride (30 mL) under an inert atmosphere methanesulfonyl chloride (154 μl, 1.9 mmol, 1.5 eq) was added dropwise. The reaction was allowed to warm to room temperature and stir for 24 h. The reaction was quenched with water and the methylene chloride layer separated, dried (MgSO4), and concentrated to afford (1-methanesulfonyl-piperidin-4-ylmethyl)-(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine as a beige solid (454 mg).
Reaction SMILES: CN([CH:4]=[N:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:10]=1)=[S:7])C.[F:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22](=[O:25])[CH2:23]Br.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([C:23]1[S:7][C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([CH3:18])(=[O:16])=[O:17])[CH:10]=2)=[N:5][CH:4]=1)=[O:25]
Reactant: CN(C)C=NC(=S)Nc1cccc(S(C)(=O)=O)c1
Reactant: O=C(CBr)c1ccccc1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cccc(Nc2ncc(C(=O)c3ccccc3F)s2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.7 %

Procedure:
To a solution of 37 mg (0.13 mmol) 1-Dimethylaminomethylene-3-(3-methanesulfonyl-phenyl)-thiourea in 0.33 ml DMF was added 28 mg (0.13 mmol) 2-Fluorophenacyl bromide and the mixture was allowed to stir at room temperature for 16 h. 17 mg (0.13 mmol) diisopropylethylamine was added and the mixture was subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient to yield 38.5 mg (79%) of the title compound after evaporation of the product fractions.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[C:3]=1[CH:14]=O.[C:16](#[N:19])[CH:17]=[CH2:18].N12CCN(CC1)CC2>C(OCC)(=O)C>[CH3:13][O:12][C:6]1[CH:7]=[CH:8][C:9]2[CH:10]=[CH:11][C:2]3[O:1][CH2:18][C:17]([C:16]#[N:19])=[CH:14][C:3]=3[C:4]=2[CH:5]=1
Reactant: C=CC#N
Reactant: COc1ccc2ccc(O)c(C=O)c2c1
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Product: COc1ccc2ccc3c(c2c1)C=C(C#N)CO3

Procedure:
Under an anhydrous atmosphere, the aldehyde obtained in Step C (2 g: 9.9 mmol) is partially solubilised in acrylonitrile (6.5 ml:49.4 mmol:10 eq.). The solution becomes clear after the addition of 1,4-diazabicyclo[2.2.2]octane (227 mg:2.47 mmol:0.25 eq.) and becomes a red colour when heated at reflux for a period of 18 hours. The reaction medium is then diluted with ethyl acetate and washed in succession with a 1N sodium hydroxide solution (20 ml) and then a 1N hydrochloric acid solution (20 ml). The concentrated organic phases are purified on a flash silica column eluted with an AcOEt/PE mixture (0.1/1).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:28](=S)=[S:29]>C(OCC)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]=[C:28]=[S:29])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: S=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: CC(C)(C)c1ccc(CN=C=S)cc1
Reaction time: 12 h

Procedure:
8.16 g of 4-t-butylbenzylamine was added dropwise at -10° C. with stirring to a mixture of 10.32 g of dicyclohexylcarbodiimide (DCC), 20 ml of carbon disulfide and 100 ml of diethyl ether. The temperature of the mixture was returned to room temperature, and it was left to stand for 12 hours. The reaction solution was filtered, and the residue was washed with diethyl ether. The filtrate was combined with the washing, and the solvent was evaporated under reduced pressure. The resulting oily product was purified by column chromatography silica gel; developing solvent hexane/ethyl acetate (19:1) to give 8.41 g of the desired 4-t-butylbenzyl isothiocyanate.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[C:28]3[CH2:30][NH:31][CH2:32][CH2:33][C:27]3=[N:26][C:25]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:20][CH2:19]1)[C:12]#[N:13].C(N(CC)CC)C.[CH3:45][O:46][CH2:47][C:48](Cl)=[O:49]>C(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:19][CH2:20][N:21]([C:24]2[N:29]=[C:28]3[CH2:30][N:31]([C:48](=[O:49])[CH2:47][O:46][CH3:45])[CH2:32][CH2:33][C:27]3=[N:26][C:25]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:22][CH2:23]1)[C:12]#[N:13].[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: COCC(=O)Cl
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CNCC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COCC(=O)N1CCc2nc(NC(C)C)c(N3CCC(Oc4ccc(C#N)cc4F)CC3)nc2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-fluoro-4-((1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrile 2,2,2-trifluoroacetate (98.6 mg, 0.094 mmol) and triethylamine (0.039 mL, 0.283 mmol) in DCM (1.0 mL) was added methoxyacetyl chloride (0.017 mL, 0.188 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min and then concentrated via rotary evaporation. The crude material was diluted with DMSO, filtered, rinsed with DMSO, and purified by HPLC Method B, with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm was used, using an ACN gradient of 30% to 70% to give the title compound as a TFA salt (2.9 mg, 5.2%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6, mixture of rotamers) δ ppm 1.18 (d, J=6.6 Hz, 6H), 1.87-1.97 (m, 2H), 2.08-2.16 (m, 2H), 2.62 (t, J=5.8 Hz, 0.9H), 2.72 (t, J=6.1 Hz, 1.1H), 2.89-2.97 (m, 2H), 3.22-3.28 (m, 1H), 3.29 (br s, 1.3H), 3.30 (s, 1.7H), 3.64-3.67 (m, 1.1H), 3.72-3.75 (m, 0.9H), 4.10-4.16 (m, 1H), 4.17 (br s, 0.9H), 4.19 (s, 1.1H), 4.36 (br s, 0.9H), 4.41 (s, 1.1H), 4.80-4.86 (m, 1H), 5.58-5.63 (m, 1H), 7.50 (t, J=8.7 Hz, 1H), 7.66-7.70 (m, 1H), 7.87 (dd, J=11.2, 1.9 Hz, 1H); ESI-MS m/z [M+H]+ 483.5.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:35].C(Cl)Cl.CO>ClCCl>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:34](=[O:35])[O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CCCCCCCCOC(=O)Cl
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCOC(=O)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Temperature: 20 °C
Yield: 93.3 %

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmol) were dissolved in 6 ml dichloromethane. 85 μl (2 molar equivalents) of triethylamine and 127 mg (2 molar equivalents) of octyl chloroformate were respectively added. The reaction mixture was maintained at 20° C. for 3 hours. The solvent was then evaporated under reduce pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 95/5 volume ratio) to provide 137 mg (yield=85%) of the desired product (formula below) as an orange powder.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:9]1)C1C=CC=CC=1.[NH:23]1[CH2:28][CH2:27][S:26][CH2:25][CH2:24]1.[F:29][C:30]([F:45])([F:44])[C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:34](Cl)=[O:35]>>[F:29][C:30]([F:45])([F:44])[C:31]1[CH:32]=[C:33]([C:34]([N:8]2[CH2:13][CH2:12][C@H:11]([N:23]3[CH2:28][CH2:27][S:26][CH2:25][CH2:24]3)[C@H:10]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[CH2:9]2)=[O:35])[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1
Reactant: C1CSCCN1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCSCC2)[C@H](c2ccc(Cl)c(Cl)c2)C1

Procedure:
The title compound, MS: m/e=571.0 (M+H+), was prepared in accordance with the general method of example 26 from 1-benzyl-3-(3,4-dichloro-phenyl)-piperidin-4-one, thiomorpholine and 3,5-bistrifluoromethyl-benzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C:28]([CH3:41])([CH3:40])[CH2:29][O:30][CH2:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:37][CH2:36][C:35]1[CH:38]=[CH:39][C:32]([CH2:31][O:30][CH2:29][C:28]([CH3:41])([CH3:40])[CH3:27])=[CH:33][CH:34]=1
Reactant: CC(C)(C)COCc1ccc(CN)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)(C)COCc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 78.7 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (426 mg, 1 mmol) with 4-(2,2-dimethyl-propoxymethyl)-benzylamine (230 mg, 1.1 mmol) in anhydrous toluene (20 mL). Purify the crude mixture by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 4:1 gradient) to obtain 7-chloro-6-[4-(2,2-dimethyl-propoxymethyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (380 mg, 79%). MS (ES+) m/z: 483 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9](Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]([C:14]1[S:15][C:16]2[CH:22]=[C:21]([O:23][CH2:24][F:25])[CH:20]=[CH:19][C:17]=2[N:18]=1)[NH2:13]>>[F:25][CH2:24][O:23][C:21]1[CH:20]=[CH:19][C:17]2[N:18]=[C:14]([NH:12][NH:13][C:9]([C:7]3[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:10])[S:15][C:16]=2[CH:22]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])o1
Reactant: NNc1nc2ccc(OCF)cc2s1
Product: O=C(NNc1nc2ccc(OCF)cc2s1)c1ccc([N+](=O)[O-])o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound 4f was prepared according to above described method by using 5-nitro-2-furancarboxylic acid chloride (430 mg, 1 mmol) and 2-hydrazino-6-fluoromethoxybenzothiazole (274 mg, 1.5 mmol) which stirred for 1 h at 0° C. and stirring continued at 25° C. for 11 h (yield 242 mg, 75%).
Reaction SMILES: [CH:1]1([CH:5]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)O[C:7]=2[CH3:17])[CH2:4][CH2:3][CH2:2]1.[CH3:28][NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33].Cl.C(N=C=NCCCN(C)C)C.[OH2:49].OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([CH:5]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([N:29]([CH3:28])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:24])=[CH:21][CH:20]=2)[C:6]2[CH:10]=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[O:49][C:7]=2[CH3:17])[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1oc(-c2ccccc2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCC1
Reactant: CCOC(=O)CCNC
Reactant: O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1oc(-c2ccccc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
A solution of 4-{[cyclobutyl(2-methyl-5-phenylfuran-3-yl)methyl]amino}benzoic acid (181 mg), ethyl 3-(methylamino)propanoate (79 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg), hydroxybenzotriazole monohydrate (92 mg) and triethylamine (84 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (3 mL), tetrahydrofuran (3 mL) and 1N lithium hydroxide (1.0 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (206 mg, 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11]2)=[CH:4][C:3]=1[N:16]1[C:20](=[O:21])[C:19]2[CH2:22][CH2:23][CH2:24][CH2:25][C:18]=2[C:17]1=[O:26].[CH2:27]([N:29](CC)CC)[CH3:28].[CH:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11]2)=[CH:4][C:3]=1[NH:16][C:17](=[O:26])[C:18]1[CH2:25][CH2:24][CH2:23][CH2:22][C:19]=1[C:20]([NH:29][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:28])=[O:21]
Reactant: c1ccccc1
Reactant: CCN(CC)CC
Reactant: CC1CCC(Oc2cc(N3C(=O)C4=C(CCCC4)C3=O)c(F)cc2Cl)C1
Product: CC1CCC(Oc2cc(NC(=O)C3=C(C(=O)NC(C)c4ccccc4)CCCC3)c(F)cc2Cl)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
N-{2-Fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.65 mmol), R-(+)-1-phenylethylamine (0.530 g, 4.37 mmol), triethylamine (0.340 g, 0.470 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-N'-(1-phenylethyl)-3,4,5,6-tetrahydrophthalamide as white crystals (1.297 g, 98.1% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[N:21][CH:22]=3)[CH:11]=[C:10]([C:25]([O:27]CC)=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+].C1COCC1>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:22]=[N:21][C:20]([CH3:23])=[N:19][CH:18]=3)[CH:11]=[C:10]([C:25]([OH:27])=[O:26])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(C(=O)NCc2cnc(C)nc2)cc(-c2ccc(C)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3cnc(C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of ethyl 4′-methyl-5-((2-methylpyrimidin-5-yl)methylcarbamoyl)-biphenyl-3-carboxylate (275 mg, 0.706 mmol), lithium hydroxide (85 mg, 3.5 mmol), THF (10 mL), and water (1 mL) was stirred at room temperature for 5 h. LC-MS indicated completion of the reaction. The solvent was removed in vacuo and the residue was treated with water and acidified with 1N aq. HCl to pH=4-5. The precipitate was collected by filtration and dried to afford the title compound as a white solid. The filtrate was extracted with EtOAc (100 mL). The organic layer was washed with water and concentrated to afford some additional product.
Reaction SMILES: Cl.C[N:3](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=[C:25]1[C:33]1[N:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([OH:37])=O.N[CH:43]([CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH:44]([OH:48])[C:45]([NH2:47])=[O:46]>ClCCl.CCN(CC)CC>[NH2:47][C:45](=[O:46])[CH:44]([OH:48])[CH:43]([C:40]1[CH:39]=[CH:38][C:34]([C:35]([NH2:3])=[O:37])=[C:33]([C:25]2[NH:24][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=2)[N:41]=1)[CH2:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cccnc1-c1nc2ccccc2[nH]1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(C(Cc2ccccc2)C(O)C(N)=O)nc1-c1nc2ccccc2[nH]1
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
0.2 g N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), 1.04 g 1-hydroxybenzotriazole hydrate and 150 μL triethylamine (Et3N) were successively added to a solution of 2-(1H-benzo[d]imidazol-2-yl)nicotinic acid (0.2 g. 0.836 mmol) and 3-amino-2-hydroxy-4-phenylbutanamide (170 mg, 0.875 mmol) in 40 ml of dichloromethane at 5° C., and the mixture was stirred at 5° C. for about 5 minutes. A pH of 8-9 was adjusted by adding of 50 μl Et3N, the mixture stirred for 1 hour at 5° C. and then overnight at room temperature. For work up the reaction mixture was evaporated to dryness, treated with 50 ml of water, the precipitate filtered off with suction, washed three times with water and dried at 50° C. over night. The crude product was purified by crystallization from 10 ml of 2-propanole yielding 50 mg of the title compound as white amorphous solid.
Reaction SMILES: [N:1]1([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][CH2:5][C:4](=O)[CH2:3][C:2]1=[O:8].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][CH2:23][C:24](=O)[CH3:25].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[C:4]2[CH2:5][CH2:6][N:1]([N:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[C:2](=[O:8])[C:3]=2[C:24]([CH3:25])=[CH:23]1
Reactant: CC(=O)CNc1ccccc1Cl
Reactant: O=C1CCN(N2CCCCC2)C(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cn(-c2ccccc2Cl)c2c1C(=O)N(N1CCCCC1)CC2
Temperature: 25 °C
Yield: 21 %

Procedure:
To a solution of [1,1′]bipiperidinyl-2,4-dione, from Step 4 (2.49 g, 12.7 mmol) in dry toluene (240 ml) at room temperature were added 1-(2-chlorophenylamino)propan-2-one (2.33 mg, 12.7 mmol) from Step 5 followed by a catalytic amount of p-TSA. The reaction mixture was boiled under reflux with a Dean-Stark trap, and 90 ml toluene was collected in the trap. Then 1 molar equivalent of p-TSA was added and the reaction mixture was boiled under reflux overnight. After cooling to room temperature, the reaction mixture was evaporated and purified by flash chromatography (heptane: EtOAc gradient) to give 0.93 g (21%) of the title compound.