Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]=1[OH:26])[CH:21]=O)[CH3:16].[NH2:30][C:31]([NH2:33])=[O:32].Cl>CCO.O>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:21]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:10]3[S:11][CH:12]=[CH:13][CH:14]=3)[NH:33][C:31](=[O:32])[NH:30]2)[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]=1[OH:26])[CH3:16]
Reactant: NC(N)=O
Reactant: O=C(Cc1ccccc1)c1cccs1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3cccs3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 22.9 %

Procedure:
A mixture of 2-phenyl-1-(thiophen-2-yl)ethanone (Intermediate 38) (100 mg, 0.49 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (95 mg, 0.45 mmol), urea (81 mg, 1.35 mmol), and concentrated HCl solution (0.04 mL, 0.45 mmol) in EtOH (5 mL) was refluxed overnight. The mixture was diluted with water, and extracted with EtOAc. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layer was dried over Na2SO4, evaporated in vacuo, and purified by preparative HPLC to give Compound 78 (45 mg, yield 23%). 1H NMR (DMSO-d6 300 MHz): δ 10.22 (s, 1H), 8.61 (s, 1H), 7.47 (s, 1H), 7.34-7.29 (m, 2H), 7.15-7.13 (m, 1H), 7.09-7.06 (m, 3H), 6.99 (s, 1H), 6.87-6.83 (m, 3H), 5.02 (d, J=2.4 Hz, 1H), 3.92 (q, J=7.2 Hz, 2H), 1.22 (t, J=7.2 Hz, 3H); MS (ESI): m/z 438.0 [M+1]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[Br:16]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(#N)C>[Br:16][C:8]1[C:3]([NH:2][CH3:1])=[N:4][CH:5]=[C:6]([C:9]([F:15])([F:14])[C:10]([F:11])([F:12])[F:13])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CNc1ccc(C(F)(F)C(F)(F)F)cn1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CNc1ncc(C(F)(F)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.5 %

Procedure:
To a mixture of methyl-(5-pentafluoroethyl-pyridine-2-yl)-amine (4.6 g) and acetonitrile (70 mL), N-bromosuccinimide (5.0 g) was added under ice-cooling, and stirred at room temperature for 8 hours. Into a mixture, saturated aqueous sodium thiosulfate solution and aqueous sodium hydrogen carbonate solution were poured, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 6.3 g of (3-bromo-5-pentafluoroethyl-pyridine-2-yl)-methyl-amine.
Reaction SMILES: [CH:1]([C@@H:14]1[CH2:19][CH:18]=[CH:17][CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:28])C=1.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH:1]([C@@H:14]1[CH2:19][C@@H:18]2[C@@H:17]([O:28]2)[CH2:16][O:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C1=CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(C(c2ccccc2)[C@@H]2C[C@H]3O[C@H]3CO2)cc1
Reaction time: 20 h
Yield: 50.1 %

Procedure:
To a solution of (2S)-2-benzhydryl-3,6-dihydro-2H-pyran 27a (0.15 g, 0.6 mmol) in CH2Cl2 (20 ml) was added mCPBA (0.3 g, 70%, 1.2 mmol) in a portionwise manner at 0° C. The mixture was brought to room temperature and the reaction mixture was stirred for 20 h under N2. Na2SO3 (20 ml 1.0 M solution) was added to the reaction mixture at 0° C. to quench the reaction. The aqueous phase was extracted with CH2Cl2 (20 ml×2). The combined organic phase was washed in turn with saturated NaHCO3 and brine, then dried over anhydrous Na2SO4. Evaporation of the solvent gave light brown solid residue. The crude products were purified by flash chromatography on silica gel (hexane/ethyl ether=9:1) to give 0.08 g (1S,4S,6R)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane 28a (50.3%, [α]D=(−)60, c=1, MeOH) and 0.065 g 28b (1R,4S,6S)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane (41%, [α]D=(−)76, c=1, MeOH).
Reaction SMILES: [Br:1][C:2]([Br:14])=[CH:3][C:4]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:5]=1[NH2:6].Br[CH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]([Br:14])=[CH:3][C:4]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:5]=1[NH:6][CH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: CCOc1ccc(N)c(C=C(Br)Br)c1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(NCc2cccc(C(=O)OC)c2)c(C=C(Br)Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A suspension of 2-(2,2-dibromovinyl)-4-ethoxyaniline (240 mg), methyl 3-(bromomethyl)benzoate (180 mg) and potassium carbonate (124 mg) in N,N-dimethylformamide (2 mL) was stirred overnight at room temperature. Water was added to the reaction mixture and this resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (258 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][C:5]([N:14]=[C:15]=[O:16])=[C:4]([F:17])[CH:3]=1.[OH:18][CH:19]([C:24]([CH3:26])=[CH2:25])[C:20]([O:22]C)=O.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][C:5]([N:14]2[C:20](=[O:22])[C:19](=[C:24]([CH3:26])[CH3:25])[O:18][C:15]2=[O:16])=[C:4]([F:17])[CH:3]=1
Reactant: O=C=Nc1cc(OC2CCCC2)c(Cl)cc1F
Reactant: C=C(C)C(O)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)=C1OC(=O)N(c2cc(OC3CCCC3)c(Cl)cc2F)C1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
A 20-L stainless steel vessel equipped with a mechanical stirrer and a dropping funnel was charged with a solution of 4-chloro-5-cyclopentyloxy-2-fluorophenylisocyanate (4.00 kg, 15.6 mol) and methyl 2-hydroxy-3-methyl-3-butenoate (2.40 kg; purity=ca. 90%; 18.4 mol) in toluene (10 L). To the solution being cooled in an ice water bath, triethylamine (40 mL) was added dropwise slowly enough to ensure against the increase in the temperature of the solution. The solution was stirred at the same temperature for 3 h until TLC confirmed that the starting materials had disappeared. Subsequently, potassium carbonate (200 g) was added and, with the resulting methanol being removed with a fitted distillator, the mixture was stirred under heating in a water bath (100° C.) for 5 h. After completion of the reaction, the reaction mixture was washed with 1N HCl (10 L), 1N sodium hydroxide (10 L) and again with 1N HCl (10 L). The toluene layer was dried with anhydrous magnesium sulfate and the solvent was distilled off under vacuum; thereafter, hexane was added in an amount about one half of the resulting oil and the mixture was left to stand at room temperature, thereby producing 3N-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)-5-isopropyliden-2,4-oxazolidinedione as whitish yellow solids (4.19 kg, 11.8 mol; yield=75.7%; primary crystal). MP: 104.5°-105.0° C. 1H-NMR(CDCl3,TMS,ppm): δ1.49-1.97(8H,m), 2.03(3H,s), 2.31(3H,s), 4.73(1H,m), 6.88(1H,d,JHF =6.6Hz), 7.33(1H,d,JHF =8.5Hz). IR (KBr disk, cm-1): 2970, 1815, 1740, 1500, 1200.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][C:12](=[O:27])[NH:13][CH2:14][CH2:15][NH:16]C(OCC2C=CC=CC=2)=O)[CH:5]=[C:4]([CH3:28])[C:3]=1[S:29]([NH:32][C@@H:33]([CH2:38][NH:39][C:40]([C:42]1[CH:50]=[C:49]2[C:45]([C:46]([CH2:52][CH2:53][CH2:54][NH:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=3)=[N:47][N:48]2[CH3:51])=[CH:44][CH:43]=1)=[O:41])[C:34]([O:36][CH3:37])=[O:35])(=[O:31])=[O:30].FC(F)(F)C(O)=O>CO.[Pd]>[NH2:16][CH2:15][CH2:14][NH:13][C:12]([CH2:11][CH2:10][CH2:9][O:8][C:6]1[CH:5]=[C:4]([CH3:28])[C:3]([S:29]([NH:32][C@@H:33]([CH2:38][NH:39][C:40]([C:42]2[CH:50]=[C:49]3[C:45]([C:46]([CH2:52][CH2:53][CH2:54][NH:55][C:56]4[CH2:61][CH2:60][CH2:59][CH2:58][N:57]=4)=[N:47][N:48]3[CH3:51])=[CH:44][CH:43]=2)=[O:41])[C:34]([O:36][CH3:37])=[O:35])(=[O:30])=[O:31])=[C:2]([CH3:1])[CH:7]=1)=[O:27]
Reactant: COC(=O)[C@H](CNC(=O)c1ccc2c(CCCNc3ccccn3)nn(C)c2c1)NS(=O)(=O)c1c(C)cc(OCCCC(=O)NCCNC(=O)OCc2ccccc2)cc1C
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CNC(=O)c1ccc2c(CCCNC3=NCCCC3)nn(C)c2c1)NS(=O)(=O)c1c(C)cc(OCCCC(=O)NCCN)cc1C
Reaction time: 7.5 h
Yield: 116.2 %

Procedure:
In a Parr bottle were added 10% Pd/C (50 mg) and methanol (5 mL) under nitrogen. The product of Step A (113 mg, 116 umol) in methanol (5 mL) was added, along with 20 uL of trifluoroacetic acid. The mixture was hydrogenated at 50 psi with shaking for 7.5 hours, filtered through Celite, the Celite rinsed with methanol, and the combined filtrates concentrated. The residue was redissolved in 1:1 acetonitrile/water/0.1% TFA, frozen and lyophilized to afford the product as a white powder (98 mg, 88%).
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[NH:52]1[CH2:57][CH2:56][CH:55]([NH:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[CH3:65])[CH2:54][CH2:53]1>CN(C=O)C.O>[O:18]=[C:16]([N:52]1[CH2:57][CH2:56][CH:55]([NH:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[CH3:65])[CH2:54][CH2:53]1)[CH2:15][NH:14][C:12]([C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:11][N:10]=1)=[O:13]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Cc1ccccc1NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1NC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Reaction time: 16 h
Yield: 94 %

Procedure:
To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.102 g, 0.00042 mol) in DMF (1 mL) was added DIPEA (0.245 g, 0.00190 mol), HOBt (0.056 g, 0.000418 mol) and EDCI.HCl (0.145 g, 0.00076 mol) at ambient temperature. After 2 minutes piperidin-4-yl-o-tolyl-amine dihydrochloride (0.1 g, 0.00038 mol) was added and the resulting mixture was stirred for 16 hours. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.15 g (94% of 5-phenyl-1H-pyrazole-3-carboxylic acid [2-oxo-2-(4-o-tolylamino-piperidin-1-yl)-ethyl]-amide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[OH:11])([O-:3])=[O:2].[H-].[Na+].Br[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].[OH-].[Na+]>CN1CCCN(C)C1=O.C(OCC)(=O)C>[CH3:21][C:15]([O:11][C:5]1[CH:6]=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.9 %

Procedure:
A solution of 2-nitro-4-methylphenol (11.48 g) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (50 ml) was cooled at 5° C. and treated with portions of sodium hydride (55% w/w dispersion in mineral oil, 3.27 g). The mixture was stirred at room temperature for 2 hours, then cooled to 5° C. and treated with ethyl 2-bromo-2-methylpropionate (13.15 g). The mixture was heated at about 100° C. for 18 hours, then cooled to room temperature and poured into a mixture of aqueous sodium hydroxide solution (1M) and ethyl acetate. The organic solution was separated and washed twice with 1M sodium hydroxide solution, then dried (MgSO4) and concentrated. The resulting oil was purified by flash column chromatography, eluting with a mixture of ethyl acetate and hexane, (increasing from 5:95 v/v to 10:90 v/v), to give ethyl 2-methyl-2-(2-nitro-4-methylphenoxy)propionate (4.48 g) as an oil; NMR: 1.25 (3H, t), 1.60(6H, s), 2.35(3H, s), 4.25(2H, q) and 6.8-7.6(3H, m).
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[C:28]([C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[C:28]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([NH:1][C:2]2[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=2)=[O:37])=[CH:39][CH:40]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C(=O)NC2=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (10 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (1.0 g) and triethylamine (0 4 ml), and 4-t-butylbenzoyl chloride (0.9 g) was gradually added thereto and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1.C(OC([N:38]1[CH2:44][CH2:43][CH2:42][C@H:39]1[CH:40]=O)=O)(C)(C)C.[BH4-].[Na+]>CO>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][NH:20][CH2:40][CH:39]2[CH2:42][CH2:43][CH2:44][NH:38]2)=[CH:17][CH:18]=1)[CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1cnc2c(c1)CCCC2N(Cc1ccc(CNCC2CCCN2)cc1)Cc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 54.2 %

Procedure:
To a stirred solution of N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (0.231 g, 0.58 mmol) in dry MeOH (5.5 mL) was added N-(tert-butoxycarbonyl)-L-prolinal (0.116 g, 0.58 mmol) and the mixture was stirred at room temperature for 2.5 h. The reaction mixture was concentrated under reduced pressure and subjected to high vacuum for 1 h. The residue was dissolved in dry MeOH (5 mL) and to the resultant solution was added sodium borohydride (44 mg, 1.16 mmol), which was stirred for 0.5 h (see General Procedures XX). Purification by radial chromatography on a 2 mm TLC grade silica gel plate (CH2Cl2/MeOH/NH4OH, 100:1:1 followed by 50:1:1) afforded the desired product (0.151 g, 45%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.[CH3:50][N:51]1[CH2:56][CH2:55][CH:54]([CH2:57][NH2:58])[CH2:53][CH2:52]1>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([NH:58][CH2:57][CH:54]3[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]3)=[O:26])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reactant: CN1CCC(CN)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN1CCC(CNC(=O)C2CCN(C(=O)c3cc4ccccc4n3Cc3ccc(Cl)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (100 mg, 0.252 mmol), 1-hydroxybenzotriazole (68.1 mg, 0.504 mmol) and EDCI (97 mg, 0.504 mmol) were dissolved in DCM (Volume: 4.0 ml). The suspension was stirred at room temperature for 10 minutes where it turned clear. Hunig'sBase (0.132 ml, 0.756 mmol) and (1-methylpiperidin-4-yl)methanamine (100 mg, 0.780 mmol) were added. The reaction was stirred at room temperature overnight. It was diluted with water and ethyl acetate. The water layer was washed with another portion of ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The resulting crude material was triturated with diethyl ether/ethyl acetate to afford the product as a white solid. (Yield: 83 mg, white solid) 1H-NMR (400 MHz, DMSO-d6) 7.77, 7.62, 7.54, 7.35-7.30, 7.21, 7.13-7.06, 6.72, 5.49, 4.38, 4.02, 2.93, 2.78, 2.42-2.30, 2.17, 1.77, 1.57, 1.45-1.02
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]2[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:7]2[C:6]([CH2:16][CH2:17][C:18](=O)[C:19]([OH:21])=O)=[CH:5][CH:4]=1.C(O)(=O)C.[NH2:27][NH2:28]>C(O)C>[CH3:1][O:2][C:3]1[N:8]2[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:7]2[C:6]([C:16]2[CH2:17][CH2:18][C:19](=[O:21])[NH:27][N:28]=2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(CCC(=O)C(=O)O)c2cc(C(F)(F)F)nn12
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(C2=NNC(=O)CC2)c2cc(C(F)(F)F)nn12
Reaction time: 8 h
Yield: 20.2 %

Procedure:
The compound of Example 207 (616 mg, crude) was dissolved in ethanol (15.0 mL). To this solution, hydrazine monoacetate (428 mg) was added and the mixture was stirred for 8 hours under reflux. Subsequently, the solvent was evaporated and the residue was purified by amino-silica gel column chromatography (ethyl acetate) to afford the title compound as a yellow powder (123 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2([C:9]#[N:10])[CH2:8][CH2:7]2)=[N:2]1.[CH2:11]([OH:13])[CH3:12].C([Cl:17])(=O)C>>[ClH:17].[O:1]1[CH:5]=[CH:4][C:3]([C:6]2([C:9](=[NH:10])[O:13][CH2:11][CH3:12])[CH2:8][CH2:7]2)=[N:2]1
Reactant: CC(=O)Cl
Reactant: CCO
Reactant: N#CC1(c2ccon2)CC1
Product: CCOC(=N)C1(c2ccon2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.9 %

Procedure:
Into an 8 mL vial containing 1-(isoxazol-3-yl)cyclopropanecarbonitrile (243 mg, 1.4 mmol) and ethanol (1.98 mL, 34 mmol) was added acetyl chloride (1.45 mL, 20.4 mmol) at 0° C. The reaction mixture was stirred for 18 h at room temperature. An aliquot was removed and the solvent evaporated; 1H NMR showed the presence of product. 1H NMR (500 MHz, CDCl3) δ 1.44 (t, 3H), 1.74-1.79 (m, 2H), 2.16-2.20 (m, 2H), 4.77 (q, 2H), 6.35 (d, 1H), 8.46 (d, 1H). The reaction mixture was concentrated under reduced pressure to afford the title compound (203 mg). The material was used without further purification.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[O:17])(=O)=O.Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:27])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([CH:28]2[CH2:33][CH2:32][N:31]([CH2:6][CH2:7][N:8]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[NH:10][C:9]3=[O:17])[CH2:30][CH2:29]2)=[O:27])=[CH:24][CH:25]=1
Reactant: CS(=O)(=O)OCCn1c(=O)[nH]c2ccccc21
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3ccccc32)CC1

Procedure:
A mixture of 5.6 parts of 2-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)ethyl methanesulfonate, 4.9 parts of (4-fluorophenyl) (4-piperidinyl) methanone hydrochloride, 8 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 7 hours with water-separator. After cooling, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 4.3 parts of 1-{2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 163.6° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][CH:14]=[C:15]([C:17]([OH:19])=O)[N:16]=2)=[CH:8][CH:7]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[O:13][CH:14]=[C:15]([C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[N:16]=2)=[CH:10][CH:11]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1coc(-c2ccc(OCCCCl)cc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1coc(-c2ccc(OCCCCl)cc2)n1)N1CCOCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
A solution of 2-[4-(3-chloropropoxy)phenyl]-1,3-oxazole-4-carboxylic acid i34 (0.5 g, 1.57 mmol, 1 eq), morpholine (0.15 g, 1.73 mmol, 1.1 eq) and triethylamine (0.44 ml, 3.14 mmol, 2 eq) in dichloromethane (20 ml) is cooled to 0° C. N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.33 g, 1.73 mmol, 1.1 eq) and 1-hydroxybenzotriazole (0.04 g, 0.31 mmol, 0.2 eq) are added to the solution and the mixture is stirred 24 h at room temperature. The mixture is then washed with water and a saturated solution of aqueous ammonium chloride. The organic layer is dried over magnesium sulfate, filtered and concentrated under vacuum to give 0.54 g of 4-({2-[4-(3-chloropropoxy)phenyl]-1,3-oxazol-4-yl}carbonyl)morpholine i35.
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[NH:7][C@H:8]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH:19]([CH2:23][OH:24])[CH2:18]2)=[C:13]([CH3:25])[N:12]([CH2:26][C:27]2[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:30]=[CH:29][C:28]=2[F:37])[C:11]1=[O:38])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Br[CH2:56][C:57]1[O:58][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:60][CH:61]=1>ClCCl>[C:1]([O:5][C:6](=[O:45])[NH:7][C@H:8]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:56][C:57]3[O:58][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:60][CH:61]=3)[CH:19]([CH2:23][OH:24])[CH2:18]2)=[C:13]([CH3:25])[N:12]([CH2:26][C:27]2[C:32]([C:33]([F:35])([F:36])[F:34])=[CH:31][CH:30]=[CH:29][C:28]=2[F:37])[C:11]1=[O:38])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(N2CCNC(CO)C2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Reactant: FC(F)(F)c1ccc(CBr)o1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(N2CCN(Cc3ccc(C(F)(F)F)o3)C(CO)C2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.5 %

Procedure:
To a solution of {(R)-2-[3-(2-fluoro-6-trifluoromethyl-benzyl)-5-(3-hydroxymethyl-piperazin-1-yl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (0.028 mmol) in dichloromethane (2 mL) were added N,N-diisopropylethylamine (10 μl, 0.056 mol) and 2-bromomethyl-5-trifluoromethyl-furan (7.6 mg, 0.034 mmol) in the order, followed by stirring at room temperature for 6 hrs. After concentration of the solution, the residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate/dichloromethane, 1/2/1) and dried in a vacuum to afford 17 mg of a white oil (yield 77%).