Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([N:14]2[CH2:18][C@@H:17]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@@:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:15]2[C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=2[F:41])=[O:13])=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.CO>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([C@@H:15]2[C@:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:17]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:18][N:14]2[C:12]([NH:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:42])=[O:2])=[CH:9][CH:8]=2)=[O:13])=[C:35]([F:41])[CH:36]=1
Reactant: COC(=O)c1ccc(CNC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2ccc(Cl)cc2F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C[C@@H]1CN(C(=O)NCc2ccc(C(=O)O)cc2)[C@H](c2ccc(Cl)cc2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To a mixture of rac-4-({[(2S,3S,4S)-2,3-bis-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-benzoic acid methyl ester (105.0 mg, 0.17 mmol) in THF/MeOH (1.8 mL/0.6 mL) was added 4 N LiOH (0.6 mL), and the reaction mixture was stirred at rt for 2 hrs. The reaction mixture was concentrated and quenched with 2 N H2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated and purified by RP-HPLC to give rac-4-({[(2S,3S,4S)-2,3-bis-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-benzoic acid (100.1 mg, 97.6%). HRMS (ES+) m/z Calcd for C31H29Cl2F2N3O3+H [(M+H): 600.1627; Found: 600.1628.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20].[Br:24]N1C(=O)CCC1=O>C(#N)C>[Br:24][C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1)([CH3:23])[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(C)c1ccccn1
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: COC(=O)C(C)(Br)c1ccccn1
Reaction time: 8 h

Procedure:
Magnesium perchlorate (0.46 g, 2.08 mmol) was added to an acetonitrile (18 mL) solution containing the intermediate from Step A (1.04 g, 6.30 mmol). After stirring for 5 minutes N-bromosuccinimide (1.35 g, 7.55 mmol) was added and the reaction solution was stirred overnight. The solution was then partitioned between EtOAc and 1N NaHCO3 aq. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product. 1H NMR (400 MHz, CH3CN-d3): δ 8.48 (d, J=4.8 Hz, 1H); 7.85-736 (m, 2H); 7.32-7.26 (m, 1H); 3.72 (s, 3H); 2.24 (s, 3H). m/z=244.4 (M+H).
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH2:12]C)[CH2:6][CH2:5]1.Br[C:38]1[CH:43]=[C:42]([CH3:44])[N:41]([CH3:45])[C:40](=[O:46])[CH:39]=1>>[CH3:45][N:41]1[C:42]([CH3:44])=[CH:43][C:38]([C:17]2[CH:16]=[CH:15][C:14]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:36])([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:19][CH:18]=2)=[CH:39][C:40]1=[O:46]
Reactant: CC[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cc1cc(Br)cc(=O)n1C
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc(=O)n1C

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-one and 4-bromo-1,6-dimethylpyridin-2(1H)-one following a procedure analogous to that described in Example 6 Step 1. LC-MS Method 2 tR=1.173 min, m/z=475.2; 1H NMR (CDCl3) 1.10 (s, 3H), 1.16 (s, 3H), 1.51 (d, 3H), 2.18 (m, 3H), 2.21 (m, 1H), 2.42 (m, 4H), 2.86 (m, 1H), 3.54 (s, 3H), 5.66 (m, 1H), 6.21 (s, 1H), 6.60 (s, 1H), 6.97 (m, 2H), 7.23-7.34 (m, 7H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][C:30]=2[S:35]([N:38]([C:47]2[C:52]([O:53][CH3:54])=[N:51][C:50]([CH3:55])=[CH:49][N:48]=2)COCC[Si](C)(C)C)(=[O:37])=[O:36])=[CH:25][CH:24]=1)[CH:20]([CH3:22])[CH3:21]>C1COCC1.O>[CH2:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][C:30]=2[S:35]([NH:38][C:47]2[C:52]([O:53][CH3:54])=[N:51][C:50]([CH3:55])=[CH:49][N:48]=2)(=[O:37])=[O:36])=[CH:25][CH:24]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: COc1nc(C)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cnccc1-c1ccc(CC(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(C)cnc1NS(=O)(=O)c1cnccc1-c1ccc(CC(C)C)cc1
Reaction time: 2 h
Yield: 9 %

Procedure:
Tetrabutylammonium fluoride (0.45 ml of a 1.0M solution in THF) was added to a solution of 4-(4-isobutylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)-N-[2-(trimethylsilyl)ethoxymethyl]pyridine-3-sulphonamide (0.205 g) in dry THF (2 ml) and the solution was heated under reflux for 40 minutes. More tetrabutylammonium fluoride solution (0.95 ml) was added and heating was continued for 2 hours. The reaction mixture was diluted with water (15 ml) and extracted with ether (2×30 ml). The organic extracts were washed with water and saturated sodium chloride solution and then dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with 40-50% ethyl acetate/hexane through a silica gel Mega Bond Elut column followed by recrystallisation from ethyl acetate/hexane to give 4-(4-isobutylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.014 g), m.p. 232-233° C.; 1H NMR (d6-DMSO): 0.9 (d, 6H), 1.8 (br m, 1H), 2.1-2.5 (br m, 5H), 3.8 (s, 3H), 7.1-7.3 (m, 4H), 7.35 (d, 1H), 7.5 (s, 1H), 8.75 (d, 1H), 9.1 (s, 1H), 10.4 (s, 1H); mass spectrum (+ve ESP): 413 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[N:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[N:26][C:21]2=[N:20][CH:19]=1)CCC>>[CH:8]1([C:4]2[N:3]=[C:2]([C:18]3[N:22]4[CH:23]=[CH:24][C:25]([C:27]([F:28])([F:29])[F:30])=[N:26][C:21]4=[N:20][CH:19]=3)[CH:7]=[CH:6][CH:5]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: Brc1cccc(C2CCCC2)n1
Product: FC(F)(F)c1ccn2c(-c3cccc(C4CCCC4)n3)cnc2n1
Yield: 10.5 %

Procedure:
2-Bromo-6-cyclopentylpyridine (479 mg, 2.1 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.4 mmol) by the method of Example 1 to give 3-(6-cyclopentylpyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (49 mg) as a white solid: δH (400 MHz, DMSO) 1.70-1.87 (6H, m), 2.10-2.16 (2H, m), 7.29 (1H, d, J 7.4), 7.80 (1H, d, J 7.0), 7.87 (1H, t, J 7.8), 7.95-7.97 (1H, m), 8.84 (1H, s), 10.50 (1H, d, J 6.7); m/z (ES+) 332 (M++H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:20]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:19]([CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:18][CH:10]1[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:55])C=1>ClCCl>[CH2:1]([O:8][C@@H:9]1[C@@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:20]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C@@H:19]([CH2:38][O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[O:18][CH:10]1[S:11](=[O:55])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(COC[C@H]2OC(Sc3ccccc3)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Solvent: ClCCl
Product: O=S(c1ccccc1)C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -30 °C
Yield: 97.9 %

Procedure:
To a stirred cooled (-78° C.) solution of 3 (130 g, 0.2 mol) in dichloromethane (400 mL) is added dropwise over a period of 20 min a solution of mCPBA (74%, 58.31 g, 0.25 mol) in dichloromethane (300 mL). The mixture is stirred and allowed to warm up to -30° C. The mixture is then filtered. The filtrate is washed with saturated aqueous sodium bisulfite (2×300 mL), sodium bicarbonate (2×400 mL), brine (400 mL) and water (2×400 mL). The organic layer is dried (Na2SO4) and concentrated. Flash chromatography (CH2Cl2 :EtOAC=9:1) of the residue furnishes sulfoxide mixture 4 (127 g, 95%) as a white solid (mp 120°-122° C.). TLC Rf =0.3 (solvent--EtOH:CH2Cl2 =1:9). IR (KBr): 3060, 3030, 2910, 2867, 1495, 1450, 1360, 1210, 1136, 1092, 1049 cm-1. 1H NMR (CDCl3): 7.72-7.14 (m, 25H), 5.12-4.42 (m, 9H), 4.40-3.30 (m, 6H). Anal. Calc. for C40H40O6S: C, 74.04; H, 6.22; S, 4.93. Found: C, 74.10; H, 6.26; S, 4.99.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)[N:4]=1.[C:19]1([C:25]2[N:26]=[C:27]([C:30]3([CH2:36][NH2:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[S:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:19]1([C:25]2[N:26]=[C:27]([C:30]3([CH2:36][NH:37][C:11](=[O:13])[C:10]4[CH:14]=[CH:15][CH:16]=[C:8]([C:5]5[N:4]=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=5)[CH:9]=4)[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[S:28][CH:29]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: O=C(NCC1(c2nc(-c3ccccc3)cs2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid (52 mg, 0.202 mmole), (4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine (50 mg, 0.184 mmole), and EDCI (38.5 mg, 0.202 mmole) in CH2Cl2 (2 ml) was stirred at room temperature for 8 h. The reaction mixture was then diluted with methylene chloride (10 ml), washed with water (5 ml), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by ISCO (silica gel, elute: 2% methanol in CH2Cl2) to give N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide as a white solid product (59 mg, 62% yield): 1H NMR (CDCl3, 500 MHz): 8.49 (s, 1H), 8.22 (d, J=7.5 Hz, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.88 (d, J=8 Hz, 2H), 7.56-7.53 (m, 2H), 7.52 (s, 1H), 7.369-7.31 (m, 3H), 3.97-3.93 (m, 2H), 3.91 (d, J=5.5 Hz, 2H), 3.77-3.74 (m, 2H), 2.36-2.28 (m, 2H), 2.06-2.04 (m, 2H). MS (ESI) m/z: Calculated for C25H21F3N4O3S: 514.13. found: 515.1 (M−H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[C:17](=[O:31])[NH:18][C:19](=O)[C:20]=2[C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)=[CH:8]1>C(OCC)C.C1COCC1>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[C:17](=[O:31])[NH:18][CH2:19][C:20]=2[C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)=[CH:8]1
Reactant: O=C1NC(=O)C(c2c[nH]c3ccccc23)=C1c1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1NCC(c2c[nH]c3ccccc23)=C1c1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 18 h
Yield: 18.3 %

Procedure:
20 ml of a 1M solution of LiAlH4 in diethyl ether was added to a solution of 1.0 g of 3,4-bis(3-indolyl)-1H-pyrrole-2,5-dione in 140 ml of THF. The mixture was stirred for 18 hours under nitrogen. The mixture was cooled to 0° C., quenched with 50 ml of water, then acidified to pH 2 with 2M hydrochloric acid and extracted with ethyl acetate. The organic extracts were washed with saturated sodium bicarbonate solution, dried and evaporated. The residue was purified on silica gel with 5-10% methanol in dichloromethane. The first product eluted was triturated with ethyl acetate/hexane to give 175 mg of 3,4-bis(3-indolyl)-3-pyrrolin-2-one, m.p. 290°-293° C. (decomposition). The second product eluted was crystallized from ethyl acetate/chloroform to give 490 mg of 5-hydroxy-3,4-bis(3-indolyl)-3-pyrrolin-2-one, m.p. above 250° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH2:16]([O:18][CH2:19][C:20](Cl)=[O:21])[CH3:17]>CC(C)=O>[CH2:16]([O:18][CH2:19][C:20]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:21])[CH3:17]
Reactant: CCOCC(=O)Cl
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: CC(C)=O
Product: CCOCC(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Yield: 51.2 %

Procedure:
20.3 g (0.1 mole) of 6-(p-aminophenyl)-4,5-dihydro5-methyl-3(2H)-pyridazinone were stirred with 14.7 g (0.12 mole) of ethoxyacetyl chloride and 400 ml of absolute acetone for 10 hours at room temperature. The product was filtered off under suction at 10° C., washed with cold acetone and dried at 70° C. under reduced pressure. 14.8 g (51%) of 6-[p-(ethoxyacetylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone were obtained. Mp.: 195°-197° C.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>O1CCOCC1.C(N(CC)CC)C>[CH:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9]
Reactant: [H][H]
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=CNc1ccccc1
Yield: 98 %

Procedure:
A solution of phenyl isocyanate (1.2 g.; 0.01 mole in 100 ml. anhydrous 1,4-dioxane containing two drops of anhydrous triethylamine was mixed with 500 mg. of 10% Pd-on-carbon and shaken at a pressure of 50 p.s.i. of hydrogen on a Parr low pressure hydrogenator. The uptake of hydrogen was complete in 5 minutes. The catalyst was collected and washed with 50 ml. of 1,4-dioxane. The solvent was evaporated to give 1.2 g. (98% yield) of slightly yellow oil which slowly crystallized. The product was confirmed to be formanilide by ir, nmr and glc analyses.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH:4]([C:27]1[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[CH2:22][CH2:21][CH2:20][NH:19][C:18]=3[N:17]=2)[C:10]1=[O:26].O.[OH-].[Li+]>O1CCCC1.O>[CH3:34][O:33][C:30]1[N:29]=[CH:28][C:27]([CH:4]([CH2:5][CH2:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[CH2:22][CH2:21][CH2:20][NH:19][C:18]=4[N:17]=3)[C:10]2=[O:26])[C:3]([OH:35])=[O:2])=[CH:32][CH:31]=1
Reactant: COC(=O)C(CCCCN1CC[C@H](CCc2ccc3c(n2)NCCC3)C1=O)c1ccc(OC)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(CCCCN2CC[C@H](CCc3ccc4c(n3)NCCC4)C2=O)C(=O)O)cn1
Reaction time: 16 h

Procedure:
To a stirred solution of 2-3b (55 mg) in tetrahydrofuran (3 mL) was added lithium hydroxide monohydrate (20 mg) in water (3 mL) and the mixture was stirred for 16 h. The reaction mixture was then concentrated at reduced pressure and resulting oil was purified by flash column chromatography (silica gel, 30:3:3 to 50:5:5% ethanol/ammonium hydroxide/water in ethyl acetate) to give 2-4b.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:14][C:15]([NH2:17])=[NH:16])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[C:18]([O:22][C:23]([C:25]1[C:30]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:29]([OH:39])N=C(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)N=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[CH2:32]([O:31][C:30]1[C:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])=[N:16][C:15]([CH2:14][C:9]2([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=3)[CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:17][C:29]=1[OH:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: N=C(N)CC1(c2cccc(Cl)c2)CCCC1
Agent: Cl
Product: CC(C)(C)OC(=O)c1nc(CC2(c3cccc(Cl)c3)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
tert-butyl 5-(benzyloxy)-2-((1-(3-chlorophenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-carboxylate (500) was synthesized as a white solid from 2-(1-(3-chlorophenyl)-cyclopentyl)-acetamidine hydrochloride (499) following the procedure described for 5-benzyloxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (243).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl.Cl.[CH2:14]([NH:16][CH:17]([CH3:21])[CH2:18][CH2:19][NH2:20])[CH3:15]>C(Cl)Cl.[OH-].[Na+]>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([N:16]([CH2:14][CH3:15])[CH:17]([CH3:21])[CH2:18][CH2:19][NH:20][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CCNC(C)CCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCN(C(C)CCNS(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 14 h
Yield: 39.4 %

Procedure:
A solution of p-toluenesulfonyl chloride (17.01 g, 89.2 mmol) in CH2Cl2 (300 mL) was added to a solution of II (8.89 g, 47.0 mmol) in 1N NaOH (300 mL) which had been cooled to 0° C. After addition was complete, the biphasic mixture was stirred for 14 hours (0° C. to room temperature). The layers were separated and the aqueous portion was extracted with CH2Cl2 (2×50 mL). The combined organic phase was washed with 1N HCl (2×100 mL) and H2O (100 mL) and evaporated in vacuo. Column chromatography on silica gel eluting with 3% EtOH/CHCl3 produced 7.46 g (39%) of III. NMR δ 0.77 (d, 3H, J=7), 1.15 (t, 3H, J=7), 1.45-1.76 (m, 2H), 2.40 (s, 6H), 2.79-3.25 (m, 4H), 3.70-4.08 (m, 1H), 5.47 (t, 1H, J=7), 7.13-7.81 (m, 8H). Anal. calcd. for C20H28N2O4S2 : C, 56.58; H, 6.65; N, 6.60. Found: C, 56.60; H, 6.64; N, 6.65.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2].Br[CH2:22][C:23]1[C:27]2[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=2[S:25][N:24]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:22][C:23]2[C:27]3[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=3[S:25][N:24]=2)[C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: Cc1cc(C)c2c(CBr)nsc2c1
Reactant: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(CC(=O)OCC)n1c(=O)n(Cc2nsc3cc(C)cc(C)c23)c2ccccc21
Yield: 55 %

Procedure:
To a solution of 3-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-hexanoic acid ethyl ester (50 mg, 0.18 mmol) in DMF (10 mL) were added 3-Bromomethyl-4,6-dimethyl-benzo[d]isothiazole, CAS: 3-Bromomethyl-4,6-dimethyl-1,2-benzisothiazole (69.5 mg, 0.27 mmol) and K2CO3 (50 mg, 0.36 mmol) at room temperature under nitrogen atmosphere. The solution was heated to 100 C for 2 hours. The solution was cooled down and water was added. The solution was extracted with EtOAc and the combined organic layer was dried with MgSO4. The solution was filtered and the filtrate was concentrated. The residue was purified by CombiFlash with 20% EtOAc in Hexane as the eluent to afford the desirable product 3-[3-(4,6-Dimethyl-1,2-benzisothiazol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (45 mg, 55%) as colorless foam.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:13])[CH2:9][C:10]([CH3:12])=[O:11])([CH3:6])([CH3:5])[CH3:4].[Li]CCCC.CCCCCC.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl>O1CCCC1>[Cl:25][C:26]1[CH:27]=[C:28]([CH2:29][CH2:12][C:10](=[O:11])[CH2:9][C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:13])[CH:31]=[CH:32][CH:33]=1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: ClCc1cccc(Cl)c1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)CCc1cccc(Cl)c1
Yield: 86.6 %

Procedure:
Sodium hydride (5.43 g, 0.11 mol, 50% as an oil suspension) is placed in a 500 ml 3-neck flask (equipped with a thermometer, an addition funnel, and a rubber septum) under nitrogen and washed 2×100 ml hexanes to remove the oil. Then 230 ml dry THF (tetrahydrofuran) is introduced and the sodium hydride suspension is cooled to 4° and magnetically stirred. t-butylacetoacetate (16.5 ml, 0.1 mol) is added with a rate which is controlled so that the gas evolution is not too vigorous and the temperature is maintained at less than 10°. Stirring is continued until gas evolution ceases (1 hr). Then 62 ml of 1.7 M BuLi in hexane (0.105 mol) is added via syringe at a rate such that the temperature does not rise above 10°. The initial orange color becomes red during addition, but turns into pink after addition is complete. A fine solid also separates from solution. The resulting mixture is stirred for an additional 15 min. before 15.0 ml m-chlorobenzyl chloride (20.0 g, 0.125 mol) in 20 ml dry THF is added dropwise at a rate such that the temperature is maintained between 9° and 12°. When addition is complete, the cooling bath is removed and the reaction is stirred for an additional 1 hr. The reaction mixture is then poured into a 2 l Erlenmeyer flask and 300 ml diethyl ether is added followed by the addition of 130 ml cold 3 N aqueous HCl with stirring. The mixture is stirred for 15 min, and the layers are separated, and the acid layer is washed twice with 150 ml diethyl ether. The combined organic layers are then washed twice with 200 ml of water, 2×100 ml of aqueous 1% Citric acid (pH 4.5), and finally with 100 ml saturated aqueous brine. The organic layer is dried with anhydrous sodium sulfate and the solvent removed to give 24.5 g of t-butyl 5-(m-chlorophenyl)-3-oxo-pentanoate.
Reaction SMILES: [N:1]#[C:2]Br.[CH:4]1[C:14]2[C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][NH:10][CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1>C(Cl)(Cl)Cl>[CH:4]1[C:14]2[C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][N:10]([C:2]#[N:1])[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: c1ccc2c(c1)CNCc1ccccc1-2
Reactant: N#CBr
Solvent: ClC(Cl)Cl
Product: N#CN1Cc2ccccc2-c2ccccc2C1
Reaction time: 1 h

Procedure:
A solution of 1.91 g of cyanogen bromide in 20 ml of chloroform is added dropwise at 5°-10° C. within 25 minutes to a solution, cooled to 5° C., of 7 g of 6,7-dihydro-5H-dibenz[c,e]azepine in 50 ml of chloroform. The reaction mixture is stirred for a further 1 hour and then a small amount of the hydrobromide salt of the still unreacted azepine is filtered off. The filtrate is washed three times with water, dried over anhydrous sodium sulphate and evaporated. There is obtained solid 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile, m.p. 123°-126° C.