Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH:13]1[C:23]2[CH:22]=[CH:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[CH:18]([C:28]#[N:29])[C:17]=2[CH:16]=[CH:15][CH:14]=1.Br[CH2:31][CH2:32][CH2:33][C:34]#[N:35]>C1COCC1>[C:34]([CH2:33][CH2:32][CH2:31][C:18]1([C:28]#[N:29])[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:23]=2[CH:22]=[CH:21][C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]1=2)#[N:35]
Reactant: N#CC1c2ccccc2C=Cc2ccccc21
Reactant: N#CCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#CCCCC1(C#N)c2ccccc2C=Cc2ccccc21
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 78.1 %

Procedure:
To a −5° C. solution of diisopropylamine (0.143 ml, 1 mmol) in THF (1 ml) was added dropwise nBuLi (0.67 ml, 1.06 mmol, 1.6 M in hexane). After 20 minutes stirring at −5° C., a solution of 5H-dibenzo[a,d]cycloheptene-5-carbonitrile (prepared according to: Regnier G. J. et al. J. Med. Chem. 1992, 35, 2481-2496) (0.2 g, 0.9 mmol) in THF (1 ml) was added dropwise. After 15 minutes at −5° C., a solution of 4-bromobutyronitrile (0.1 ml, 1 mmol) in THF (1 ml) was added slowly. The reaction mixture was allowed to warm up slowly to room temperature, stirred overnight and quenched with water and ether. Aqueous phase was extracted with ether and the combined organic phases were washed with water, dried with Na2SO4 and concentrated in vacuo. The residue was chromatographed over silica gel (hexane-ethylacetate 9:1) to provide 5-(3-cyano-propyl)-5H-dibenzo[a,d]cycloheptene-5-carbonitrile (0.2 g, 76%) as a colorless oil, MS: m/e=284 (M+).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH:3]1OC.C[Si]([C:24]#[N:25])(C)C.B(F)(F)F.CCOCC>C(Cl)Cl>[C:24]([CH:3]1[C:2]([CH3:19])([CH3:1])[CH2:6][CH2:5][N:4]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])#[N:25]
Reactant: COC1N(C(=O)OCc2ccccc2)CCC1(C)C
Reactant: C[Si](C)(C)C#N
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(C)CCN(C(=O)OCc2ccccc2)C1C#N
Temperature: -78 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
In a 500 ml flask was dissolved phenylmethyl 3,3-dimethyl-2-(methyloxy)-1-pyrrolidinecarboxylate (0.0426 mol, 11.2 g) in 200 ml methylene chloride under argon. After the solution was cooled to −78° C., trimethylsilyl cyanide (0.0640 mol, 6.32 g) was added followed by boron triflouride etherate (0.0640 mol, 9.09 g). After 1 hr of stirring, the reaction was quenched with saturated aqueous sodium bicarbonate and allowed to warm to 20° C. After 2 hr of vigorous stirring, the aqueous phase was separated and extracted with methylene chloride (2×100 ml). All organics were combined, dried over MgSO4, filtered and concentrated yielding 10.8 g (98%) of phenylmethyl 2-cyano-3,3-dimethyl-1-pyrrolidinecarboxylate as a clear oil which was used without further purification. LCMS (ESI+)=259 m/z (MH+). 1H NMR (400 MHz, CDCl3)— rotamers δ 7.44-7.35 (m, 5H), 5.21 and 5.20 (s, 2H), 4.26 and 4.17 (s, 1H), 3.64-3.51 (m, 2H), 2.01-1.95 (m, 1H), 1.80-1.74 (m, 1H), 1.36 (s, 3H), 1.16 (s, 3H).
Reaction SMILES: [O-]CC.[Na+].[OH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][OH:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[CH2:15]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][OH:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: OCCc1ccccc1O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: OCCc1ccccc1OCc1ccccc1
Yield: 82.3 %

Procedure:
To a solution of sodium ethoxide (10.8 g) in ethanol (500 ml), 2-(2-hydroxyphenyl)ethanol (20.0 g) and benzyl bromide (24.8 g) were added and the mixture was refluxed under heating for 2 hours. The solvent was distilled away under reduced pressure, water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a 2M aqueous potassium hydroxide solution and a saturated brine and dried over sodium sulfate. The solvent was distilled away under reduced pressure and the residue was subjected to silica gel chromatography (eluent; hexane-ethyl acetate=8:1) to give the subject compound (27.2 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:6].[N-:26]=[N+]=[N-].[Na+].[I-].[K+]>CN(C=O)C>[NH2:26][CH2:2][CH2:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:6]
Reactant: O=C(CCCCl)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NCCCC(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
8.9 g (24.9 mmol) 1-(4-chlorobutyryl)-4-diphenylmethylpiperazine, 4.8 g (73.8 mmol) sodium azide, 1 g potassium iodide and 1 g molecular sieve 4A are stirred in 70 ml DMF for five hours at 70° C. After cooling, the reaction mixture is filtered and the filtrate is concentrated under vacuum. The accumulated crude product is dissolved in methanol and mixed with a spatula tip of palladium-carbon (10%). The mixture is stirred for two days at RT under hydrogen atmosphere. The mixture is filtered from the catalyst and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH/TEA (90/10/5): yield 5.2 g (62%) as a colorless amorphous solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[CH3:2].S(Cl)(Cl)=O.[CH3:16]O>>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:16])=[O:8])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(=O)O)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCc1ccc(C(=O)OC)cc1
Reaction time: 3 h

Procedure:
A mixture of 4-ethylbenzoic acid (5.12 g), thionyl chloride (3.0 ml) and methanol (150 ml) was heated and refluxed. After 3 hours, the mixture was concentrated under reduced pressure to give methyl 4-ethylbenzoate (5.59 g). this product was used in the subsequent step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=O)[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8].[S:14]1[CH2:20][C:18](=[O:19])[NH:17][C:15]1=[S:16].C(O)(=O)C.C([O-])(=O)C.[Na+]>O>[C:7]([C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:12]=[C:20]1[S:14][C:15](=[S:16])[NH:17][C:18]1=[O:19])([OH:9])=[O:8]
Reactant: COc1ccc(C(=O)O)c(C=O)c1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C(=O)O)c(C=C2SC(=S)NC2=O)c1

Procedure:
To a stirred hot solution of 4.23 g. (23.5 mM) of 4-methoxyphthalaldehydic acid and 3.13 g. (23.5 mM) of rhodanine in 16.5 ml. of acetic acid is added 6.33 g. (77.2 mM) of anhydrous sodium acetate. The resulting hot solution is refluxed for 0.5 hour, whereupon a solid yellow mass forms. The mixture is cooled, poured into water, to yield 5-(2-carboxy-5-methoxybenzylidene)rhodanine.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:11]2([C:28]([F:31])([F:30])[F:29])[CH2:15][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C:21]3([CH2:27][NH:26][CH2:25]3)[O:20][CH2:19]4)=[N:13][CH2:12]2)[CH:6]=[C:7]([Cl:10])[C:8]=1[Cl:9].CCN(C(C)C)C(C)C.[CH3:41][S:42]([CH2:45][C:46](O)=[O:47])(=[O:44])=[O:43].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[CH3:41][S:42]([CH2:45][C:46]([N:26]1[CH2:25][C:21]2([C:22]3[C:18](=[CH:17][C:16]([C:14]4[CH2:15][C:11]([C:5]5[CH:4]=[C:3]([Cl:2])[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=5)([C:28]([F:30])([F:29])[F:31])[CH2:12][N:13]=4)=[CH:24][CH:23]=3)[CH2:19][O:20]2)[CH2:27]1)=[O:47])(=[O:44])=[O:43]
Reactant: FC(F)(F)C1(c2cc(Cl)c(Cl)c(Cl)c2)CN=C(c2ccc3c(c2)COC32CNC2)C1
Reactant: CS(=O)(=O)CC(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)CC(=O)N1CC2(C1)OCc1cc(C3=NCC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.5 %

Procedure:
To a stirred solution of 5′-(3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]hydrochloride (Preparation 5, 900 mg, 1.77 mmol) in THF (20 mL) was added DIPEA (3.01 mL, 17.65 mmol), methanesulfonyl acetic acid (488 mg, 3.53 mmol) followed by addition of T3P (5.12 mL, 8.82 mmol, 50% solution in ethyl acetate) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours. Reaction was monitored by TLC, after complete consumption of staring material reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3×25 mL). Combined organic layer was washed with NaHCO3 solution (30 mL) & brine (30 mL), dried over sodium sulphate and concentrated to get crude sticky solid 1 g. The crude was purified by column chromatography using 100-200 mesh silica gel. Desired compound was eluted in 0.5% MeOH in DCM to get desired compound as pale green solid 490 mg, 46.6%. 1H NMR (400 MHz, DMSO-d6) δ: 3.14 (s, 3H), 3.75 (d, J=18.04 Hz, 1H), 3.88 (d, J=18.52 Hz, 1H), 4.23 (d, J=10.36 Hz, 4H), 4.44 (d, J=17.6 Hz, 1H), 4.57 (s, 2H), 4.82 (d, J=17.4 Hz, 1H), 5.10 (s, 2H), 7.66 (d, J=7.96 Hz, 1H), 7.80 (s, 2H), 7.86 (s, 1H), 7.95 (d, J=7.96 Hz, 1H). LC-MS (m/z): 594.8 (M+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:2]1.CN(C)C=O.C(Cl)(=O)C([Cl:19])=O>ClCCl>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([Cl:19])=[O:10])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CC1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CC1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tetrahydro-2H-pyran-4-ylacetic acid (89 mg), N,N-dimethyl formamide (1 μL), and dichloromethane (1 mL) was added oxalylchloride (54 μL), and the mixture was stirred at room temperature for 2 hours. The reaction liquid was concentrated under reduced pressure, and then toluene (1 mL) was added thereto, followed by further concentration under reduced pressure, to obtain crude tetrahydro-2H-pyran-4-yl acetyl chloride.
Reaction SMILES: [H-].[Na+].N1C2C(=CC=CC=2)C=[CH:4]1.ClC1N=C(Cl)C(C)=CN=1.[OH:21][CH:22]([CH2:47][N:48]([CH3:50])[CH3:49])[CH2:23][O:24][C:25]1[CH:46]=[CH:45][C:28]([NH:29][C:30]2[N:35]=[C:34]([N:36]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH2:38][CH2:37]3)[CH:33]=[CH:32][N:31]=2)=[CH:27][CH:26]=1>CN1C(=O)CCC1>[OH:21][CH:22]([CH2:47][N:48]([CH3:50])[CH3:49])[CH2:23][O:24][C:25]1[CH:46]=[CH:45][C:28]([NH:29][C:30]2[N:35]=[C:34]([N:36]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37]3)[C:33]([CH3:4])=[CH:32][N:31]=2)=[CH:27][CH:26]=1
Reactant: CN(C)CC(O)COc1ccc(Nc2nccc(N3CCc4ccccc43)n2)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: Cc1cnc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cnc(Nc2ccc(OCC(O)CN(C)C)cc2)nc1-n1ccc2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 22.6 %

Procedure:
Sodium hydride (60% dispersion in oil; 116 mg, 2.9 mmol) was added to a solution of indole (340 mg, 2.9 mmol) in NMP (2 ml) at 0° C. The mixture was stirred at 0° C. for 10 minutes and then added dropwise to a cold (0° C.) solution of 2,4-dichloro-5-methylpyrimidine (489 mg, 3.0 mmol) in NMP (3 ml). The mixture was stirred at 0° C. for 3 hours and then 4-[3-(N,N-dimethyl)amino-2-hydroxypropoxy]aniline hydrochloride (Method 1, 500 mg, 1.76 mmol) was added. The mixture was heated at 100° C. overnight and then silica (2 g) was added. Volatile material was removed by evaporation and the residue was purified by column chromatography, eluting with 0-5% 2.0M methanolic ammonia solution in DCM, to give the product as a white solid (166 mg, 13%). NMR: 2.1 (m, 9H), 2.3 (m, 2H), 3.9 (m, 3H), 4.8 (d, 1H), 6.85 (d, 1H), 6.9 (d, 2H), 7.2 (m, 2H), 7.6 (m, 5H), 8.5 (s, 1H), 9.5 (s, 1H); MS (MH+): 418.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=O.[NH2:20][CH:21]([CH:24]([OH:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:22][OH:23]>C(OCC)(=O)C.CCCCCCC>[OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([NH:20][CH:21]([CH:24]([OH:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:22][OH:23])=[O:5]
Reactant: CCCCCCCCCCCCCCCC(O)C(N)CO
Reactant: CCCCCCCCCCCCCCC(O)C(=O)O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCC(O)C(CO)NC(=O)C(O)CCCCCCCCCCCCCC
Yield: 70 %

Procedure:
4.9 g (0.018 mol) of 2-hydroxyhexadecanoic acid and 5.4 g (0.018 mol) of 2-aminooctadecane-1,3-diol were mixed in a glass tube; the mixture was irradiated with microwaves with the aid of a Synthewave 402™ apparatus from Prolabo--frequency 2450±50 MHz--modulable power rating 300 W. After an irradiation of 15 minutes at 155° C.±5° C., the reaction mixture was solubilized at high temperature in a mixture of 80 ml of ethyl acetate and 20 ml of heptane. The precipitate obtained was recrystallized from ethanol and 7 g of expected pure product were obtained with a yield of 70%.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[S:20])[N:14]([CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][O:23]1)[C:13]2=[O:27]>CN(C)C=O>[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([S:20][CH3:1])[N:14]([CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][O:23]1)[C:13]2=[O:27]
Reactant: O=c1c2cc(Br)ccc2[nH]c(=S)n1CC1CCCO1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1nc2ccc(Br)cc2c(=O)n1CC1CCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium carbonate (6.0 g, 44 mmol), iodomethane (2.5 g, 1.1 mL, 17.6 mmol), and the title compound of Step A (3.0 g, 8.8 mmol) were combined in dimethylformamide (90 mL) and stirred for 2 h at room temperature. The reaction mixture was then concentrated to dryness under reduced pressure, and the ensuing residue was partitioned between 200 mL each of ethyl acetate and water. The phases were separated and the organic phase was subsequently washed with saturated aqueous NaCl and dried over Na2SO4 (anhydrous). Following solvent removal under reduced pressure and trituration of the resulting material with cold hexanes, 2.8 g of the title compound of Step B, a compound of the invention, was obtained as a solid melting at 68-72° C. 1H NMR (300 MHz, CDCl3): δ 1.64-1.83 (m,1H), 1.80-2.18 (m,3H), 2.62 (s,3H), 3.78 (dd,1H), 3.96 (dd,1H), 4.17 (dd,1H), 4.21 (dd,1H), 4.38-4.50 (m,1H), 7.41 (d,1H), 7.73 (dd,1H), 8.36 (d,1H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[N:11]=[C:10]([CH:12]([NH:24][CH3:25])[CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[O:9][N:8]=1)=[O:6])[CH3:3].Cl.[CH3:27]C(O)C>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH3:3][CH:2]([O:4][C:5]([C:7]1[N:11]=[C:10]([CH:12]([NH:24][CH3:25])[CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[O:9][N:8]=1)=[O:6])[CH3:27]
Reactant: CCOC(=O)c1noc(C(Cc2ccc3ccccc3c2)NC)n1
Reactant: CC(C)O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Product: CNC(Cc1ccc2ccccc2c1)c1nc(C(=O)OC(C)C)no1

Procedure:
5-(1-methylamino-2-(2-naphthyl)ethyl)-[1,2,4]oxadiazole-3-carboxylic acid ethyl ester hydrochloride (1.64 g, 4.5 mmol) was suspended in 2-propanol (35 ml). After addition of tetraisopropyl titanate (1.3 g, 4.5 mmol) the reaction mixture was refluxed for 18 h. Hydrochloric acid (1N, 30 ml) was added and the reaction mixture was extracted with ethyl acetate (150 ml). The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml) and water (3×50 ml). After drying (magnesium sulfate) the solution was concentrated in vacuo to give 1.3 g of (R) 5-(1-methylamino-2-(2-naphthyl)ethyl)-[1,2,4]oxadiazole-3-carboxylic acid (2-propyl)ester that was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH:7]=O.[Cl:11][C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1.N1CCCC1>CO>[Cl:11][C:12]1[CH:20]=[C:19]2[C:15](/[C:16](=[CH:7]/[C:6]3[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[CH3:10])/[C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(Cl)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNC1
Product: Cc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 92.5 %

Procedure:
5-Chloro-2-methyl-benzaldehyde (4 g, 16 mmol) and 6-chlorooxindole (2.5 g, 16 mmol) were mixed in anhydrous methanol (20 mL). Then pyrrolidine (1.32 mL, 16 mmol) was added slowly at r.t. The mixture was heated to 70° C. for 3 h and cooled to room temperature. The precipitate was collected by filtration to give title compound as yellow solid (Yield: 4.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:26])([F:25])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2(O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].S(Cl)([Cl:39])=O>C(Cl)(Cl)Cl>[Cl:39][C:5]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[N:7]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[O:22][C:23]([F:24])([F:26])[F:25])(=[O:13])=[O:12])[C:6]1=[O:27]
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(O)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)N2C(=O)C(Cl)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Reaction time: 2 h
Yield: 84.8 %

Procedure:
To a solution of 3.00 g of compound obtained in Step 7-2-2 in CHCl3 (30 ml) was added sequentially 654 mg of Py and 984 mg of thionyl chloride under ice cooling, and the reaction mixture was stirred for 2 hours at the same temperature. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (silicagel 60; mobile phase: EtOAc/n-hexane=1/4; v/v) to obtain 2.63 g of the title compound (orange color solid).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:21])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][C:17]([F:20])([F:19])[F:18])[CH:9]=1)[CH:2]([CH3:4])[CH3:3].Br[CH2:23][CH:24]1[CH2:26][CH2:25]1>>[CH:24]1([CH2:23][N:6]2[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:9][N:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][C:17]([F:20])([F:18])[F:19])[C:7]2=[O:21])[CH2:26][CH2:25]1
Reactant: CC(C)Cc1cn(-c2ccccc2OC(F)(F)F)c(=O)[nH]1
Reactant: BrCC1CC1
Product: CC(C)Cc1cn(-c2ccccc2OC(F)(F)F)c(=O)n1CC1CC1

Procedure:
This material was obtained in analogy to the procedure outlined in example 23 from 4-isobutyl-1-(2-trifluoromethoxy-phenyl)-1,3-dihydro-imidazol-2-one (obtained in example 44, 60 mg) by alkylation with bromomethylcyclopropane (35 mg). 3-Cyclopropylmethyl-4-isobutyl-1-(2-trifluoromethoxy-phenyl)-1,3-dihydro-imidazol-2-one was obtained as a light yellow oil (11 mg). MS (ESI): 355.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[NH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH:7]=1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccc2ccccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2ccc3ccccc3c2)c1
Yield: 37 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (1.0 g, 3.83 mmol) in dioxane (10 ml) was added to a mixture of 2-aminonaphthalene (0.55 g, 3.83 mmol) and NaHCO3 (0.48 g, 5.71 mmol) in water (6 ml), and the resultant solution was stirred at room temperature until the completion of the reaction (control by TLC). The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with petroleum ether-ethyl acetate (3:2, v/v) as eluent. The obtained product was crystallised from petroleum ether-ethyl acetate to give the title compound (0.52 g, 34%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 3.73 (3H, s); 6.67 (1H, d, J=16.0 Hz); 7.21-8.07 (11H, m); 8.16 (1H, s); 10.55 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[Br:9]N1C(=O)CCC1=O.C(Cl)Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:9][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([NH2:8])=[N:5][CH:6]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Nc1cc(Cl)c(Br)cn1
Reaction time: 2 h
Yield: 37.5 %

Procedure:
To a solution of 4-chloro-2-pyridylamine (6.0 g, 46.7 mmol) in chloroform (180 mL) was added N-bromosuccinimide (8.3 g, 46.7 mmol). The solution was stirred in the dark for 2 hours, at which time it was added to CH2Cl2 (800 mL) and 1N NaOH (100 mL). Upon mixing, the layers were separated and the organic layer was washed with NaCl(sat.) (100 mL), dried over Na2SO4, filtered and concentrated. The crude material was purified by SiO2 chromatography (25-35% EtOAc/hexanes) yielding 3.63 g (38%) of 5-bromo-4-chloro-2-pyridylamine. LCMS (m/z): 206.9/208.9 (MH+). 1H NMR (CDCl3): δ 8.18 (s, 1H), 6.62 (s, 1H), 4.52 (bs, 2H).
Reaction SMILES: [C:1]([O:5][C@@H:6]1[CH2:11][N:10]([C:12]([O:14][CH3:15])=[O:13])[C@H:9]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[O:17])[C@@H:8]([C:30]([O:32]C)=O)[CH2:7]1)([CH3:4])([CH3:3])[CH3:2].[OH:34][NH2:35].Cl.NO.C[O-].[Na+].Cl>CO>[C:1]([O:5][C@@H:6]1[CH2:11][N:10]([C:12]([O:14][CH3:15])=[O:13])[C@H:9]([C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][CH2:23]2)=[O:17])[C@@H:8]([C:30]([NH:35][OH:34])=[O:32])[CH2:7]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1C[C@H](OC(C)(C)C)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)N1C[C@@H](OC(C)(C)C)C[C@H](C(=O)NO)[C@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of dimethyl(2S,3S,5S)-5-tert-butoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate (0.038 g, 0.000082 mol) in methanol (0.30 mL, 0.0074 mol) was added 1.640 M of N-hydroxyamine in methanol (1.004 mL), freshly made from the corresponding hydroxylamine HCl salt and sodium methoxide. The mixture was stirred at rt for 1 h then acidified with 1N HCl. The resulting mixture was applied directly on RP-HPLC to give the targeted product as a TFA salt (10 mg, 45%). MS (ESI): (M+H)+=463.2.