Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][N:22]([CH2:44][CH2:45][C:46]([OH:48])=O)[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].F[P-](F)(F)(F)(F)F.[N:56]1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CO.N>C(Cl)(Cl)Cl>[CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][N:22]([CH2:44][CH2:45][C:46]([NH2:56])=[O:48])[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(CCC(=O)O)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(CCC(N)=O)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
The resulting 3-((3R,4R)-3,4-bis((9Z,12Z)-octadec-9,12-dienyloxy)pyrrolidin-1-yl)propanoic acid (64 mg, 0.095 mmol) was dissolved in chloroform (2 mL), and stirred overnight at room temperature after adding O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU; Aldrich; 72 mg, 0.190 mmol), diisopropylethylamine (0.083 mL, 0.476 mmol), and a 2 mol/L ammonia methanol solution (0.238 mL, 0.476 mmol). The aqueous layer was extracted with ethyl acetate after adding a saturated sodium bicarbonate aqueous solution to the reaction mixture. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure after filtration. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 90/10) to give compound 57 (46.1 mg, 72.1%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@H:11]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[C:20]=2[O:31][CH3:32])(=[O:18])=[O:17])[C:12](O)=[O:13])=[O:8])=[CH:4][CH:3]=1.[CH:33]1([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:35][CH2:34]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[ClH:1].[CH:33]1([N:36]2[CH2:41][CH2:40][N:39]([C:12](=[O:13])[C@@H:11]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[C:20]=3[O:31][CH3:32])(=[O:17])=[O:18])[CH2:10][NH:9][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:8])[CH2:38][CH2:37]2)[CH2:35][CH2:34]1
Reactant: COc1c(-c2ccncc2)cccc1S(=O)(=O)N[C@@H](CNC(=O)c1ccc(Cl)s1)C(=O)O
Reactant: C1CN(C2CC2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1c(-c2ccncc2)cccc1S(=O)(=O)N[C@@H](CNC(=O)c1ccc(Cl)s1)C(=O)N1CCN(C2CC2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Intermediate 82 (170 mg, 0.34 mmol) was dissolved in 10 ml DCM and N-cyclopropyl piperazine (134 mg, 0.38 mmol) was added followed by DIPEA (0.27 ml, 1.54 mmol) and TBTU (121 mg, 0.38 mmol). After 16 h stirring at RT, the solution was evaporated to dryness and purified by silica gel chromatography (Elution with DCM/methanol from 0 to 10% of methanol). The solid obtained after evaporation of the solvents was dissolved in DCM, HCl 2M in Et2O (5 ml) was added and the solvents were evaporated yielding a white powder. Yield: 112 mg, 50% MS (ES+): m/e=604.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(Cl)[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(C2C=CC=CC=2)(Cl)C(Cl)=O)C=CC=CC=1.N1CCOCC1.[NH:46]1[CH:50]=[CH:49][N:48]=[CH:47]1>C(#N)C>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:47]2[NH:46][CH:50]=[CH:49][N:48]=2)[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(N1CCOCC1)C(Cl)(c1ccccc1)c1ccccc1
Reactant: c1c[nH]cn1
Agent: O=C(Cl)C(Cl)(c1ccccc1)c1ccccc1
Solvent: C1COCCN1
Solvent: CC#N
Product: O=C(N1CCOCC1)C(c1ccccc1)(c1ccccc1)c1ncc[nH]1

Procedure:
A mixture of 15.5 g of diphenylchloroacetic acid morpholide, m.p. 113° C (prepared from diphenylchloroacetyl chloride and morpholine in accordance with the procedure described in Ber. 41, 3593) and 11g of imidazole in 100 ml of acetonitrile is heated at reflux for 18 hours. The solvent is removed by distillation in vacuo and, after addition of 70 ml of water, the residue is extracted with methylene chloride. The extracts are dried and the solvent is removed by distillation to yield diphenyl-imidazolylacetic acid morpholide which is further purified by recrystallization from methanol. The hydrochloride salt, m.p. 118° C, is obtained by treating an ethyl acetate solution of the free base with an ethereal solution of hydrogen chloride.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([O:19][CH3:20])[C:13]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[C:12]3[Cl:32])([OH:8])[C:6]#[CH:7])[CH2:2]1.CCN(CC)CC.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl>[Cl:32][C:12]1[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([C:5]([CH:3]3[CH2:4][N:1]([C:40](=[O:42])[CH3:41])[CH2:2]3)([OH:8])[C:6]#[CH:7])[CH:10]=2)[N:15]=[C:14]([O:19][CH3:20])[C:13]=1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1
Reactant: C#CC(O)(c1ccc2nc(OC)c(Cc3ccc(C(F)(F)F)cc3)c(Cl)c2c1)C1CNC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CC(O)(c1ccc2nc(OC)c(Cc3ccc(C(F)(F)F)cc3)c(Cl)c2c1)C1CN(C(C)=O)C1
Temperature: 40 °C

Procedure:
To a flask containing crude 1-(azetidin-3-yl)-1-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)-benzyl)quinolin-6-yl)prop-2-yn-1-ol (130 mg, 0.28 mmol, Example 16) was added DCM (10 mL) followed by Et3N (0.2 mL, 1.44 mmol) and acetic anhydride (0.1 mL, 1.06 mmol) at room temperature. The mixture was heated to 40° C. for 2 hours and then quenched with a solution of saturated aqueous NaHCO3. The aqueous portion was extracted with DCM (3×35 mL) and the combined organics were dried over MgSO4, filtered and concentrated to dryness. Chromatography on silica gel using (5% MeOH-DCM) provided the title compound as an off white amorphous solid. 1H NMR (500 MHz, CD3OD) δ 8.44 (d, J=1.9 Hz, 1H), 7.94 (d, J=8.7 Hz, 1H), 7.91-7.82 (m, 1H), 7.55 (d, J=8.2 Hz, 2H), 7.42 (d, J=8.1 Hz, 2H), 4.40 (s, 2H), 4.36-4.18 (m, 1H), 4.16-4.01 (m, 4H containing a singlet at 4.07), 4.05-3.98 (m, 1H), 3.93-3.80 (m, 1H), 3.28 (s, 1H), 3.24-3.09 (m, 1H), 1.85 (d, J=3.3 Hz, 3H); MS (ESI): mass calcd. for C26H22ClF3N2O3, 502.1, m/z found 503.2 [M+H]+. 1-(3-(1-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-hydroxyprop-2-yn-1-yl)azetidin-1-yl)ethanone was purified by chiral SFC: (Stationary phase: CHIRALPAK AD-H, 5 μm, 250×20 mm), Mobile phase: 70% CO2, 30% MeOH), to give 2 enantiomers. The first eluting enantiomer was Example 7b and the second eluting enantiomer was Example 7c.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[C:17]([CH3:26])=[C:18]([CH:22]=[CH:23][C:24]=1[F:25])[C:19](Cl)=[O:20]>ClCCl>[Cl:15][C:16]1[C:17]([CH3:26])=[C:18]([C:19]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[O:20])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: Cc1c(C(=O)Cl)ccc(F)c1Cl
Reactant: O=C1CNCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)N2CCNC(=O)C2)ccc(F)c1Cl
Reaction time: 0.5 h

Procedure:
2-piperazinone (0.350 g, 3.5 mmol, commercially available from e.g. Sigma-Aldrich) was dissolved in dichloromethane (DCM) (15 mL), and to this was added triethylamine (0.585 mL, 4.20 mmol). The solution was then cooled to 0° C. before 3-chloro-4-fluoro-2-methylbenzoyl chloride (I58) (0.797 g, 3.85 mmol) in Dichloromethane (DCM) (5 mL) was added dropwise. The solution was stirred, under argon, for 30 minutes before the solvent was evaporated in vacuo. The remaining residue was then re-dissolved in DCM (50 mL) and washed with water (20 mL), a saturated solution of sodium bicarbonate (20 mL) and brine (20 mL). The organic phase was then dried over anhydrous sodium sulphate, which was then filtered off and the solvent was evaporated in vacuo. The remaining solid was then stirred in hexane (30 mL) at 55° C. for 30 minutes, before being filtered to yield the product in 0.843 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:19]=[N+:20]=[N-:21].[Na+].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:19]=[N+:20]=[N-:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester and sodium azide in DMF was stirred at 60° C. overnight. The mixture was poured into water and the resulting mixture was extracted with EtOAc. The organic phase was separated and washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to give the desired product as a pale yellow oil, which was used without further purification. 1H NMR (CDCl3): δ 7.9 (2H, d), 7.12 (2H, d), 4.79 (2H, d), 3.05 (3H, s), 2.58 9 (1H, t).
Reaction SMILES: C([Li])CCC.N12CCN(CC1)CC2.[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=1.CN(C)[CH:24]=[O:25]>C(OCC)C.O>[Cl:14][C:15]1[C:16]([CH:24]=[O:25])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=1
Reactant: Clc1cncc(Cl)c1
Reactant: CN(C)C=O
Agent: C1CN2CCN1CC2
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: O=Cc1ncc(Cl)cc1Cl
Temperature: -70 °C
Reaction time: 0.75 h
Yield: 24.1 %

Procedure:
Add a solution of n-butyl lithium (37.5 mL, 0.06 mol, 1.6 M in hexanes) to a mixture of 1,4-diazabicyclo-[2.2.2]octane (6.16 g, 0.055 mol) in diethyl ether (250 mL) at −10 to −20° C. under a nitrogen atmosphere. Stir for 45 min. and then cool to −70° C. Add 3,5-dichloropyridine (7.40 g, 0.05 mol) in small portions and stir for 1.5 h at this temperature. Add N,N-dimethylformamide (7.75 mL, 0.10 mol) dropwise via syringe and stir for 2 h and allow to slowly warm to ˜−20° C. Add water (200 mL) is added and extract with ethyl acetate. Dry over sodium sulfate and concentrate in vacuo. Elute over silica gel with hexanes/ethyl acetate to give the desired aldehyde (2.12 g, 49%) as a light yellowish solid. MS(ES): (M+1)+ 174.8, 175.8 m/z.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21].O1CCCC1.O>CO>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][OH:21]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(CO)c1
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
Sodium borohydride (1.18 g) was added to a solution of 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (18.3 g) in methanol (50 ml)-tetrahydrofuran (100 ml) in portions at 0° C. After stirring for 30 minutes, water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylalcohol (15.5 g, yield 84%) as colorless crystals. m.p. 101-102° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:8]=1.C(N(CC)CC)C.[C:38]1([CH3:50])[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[C:39]=1[S:46](Cl)(=[O:48])=[O:47].[N-]=C=O.C(O)C(N)(CO)CO>C(Cl)Cl>[CH3:50][C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[C:39]=1[S:46]([N:6]([CH2:5][C:4]1[CH:21]=[CH:22][C:23]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[C:2]([CH3:1])[CH:3]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:8]=1)(=[O:47])=[O:48]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: Cc1cc(CNc2ccc(OCCN3CCCC3)cc2)ccc1OC1CCCCO1
Agent: NC(CO)(CO)CO
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2ccc(OC3CCCCO3)c(C)c2)c2ccc(OCCN3CCCC3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.1 %

Procedure:
To a solution of [3-methyl-4-(tetrahydro-pyran-2-yloxy)-benzyl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (0.062 g, 0.15 mmol) in 0.4 mL methylene chloride was added triethylamine (0.06 mL, 0.45 mmol) and 2-mesitylene sulfonyl chloride (0.066 g, 0.3 mmol). The reaction mixture was stirred at room temperature for 24 hr. PS-isocyanate resin (0.050 g) and PS-trisamine resin (0.050 g) were added and the reaction mixture was stirred for 2 hr. at room temperature. The resin was filtered off with the aid of methylene chloride. The filtrate was concentrated to give the title compound of Step A (0.089 g). MS 593.3 (M+1)+
Reaction SMILES: CS[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][CH:12]=[C:11]([CH:14]=[O:15])[CH:10]=1.Cl[C:17]1C=CC=C(C(OO)=O)C=1.[S:27]([O-:31])([O-])(=[O:29])=S.[Na+].[Na+]>C(OCC)(=O)C>[CH3:17][S:27]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][CH:12]=[C:11]([CH:14]=[O:15])[CH:10]=1)(=[O:31])=[O:29]
Reactant: CSc1ccccc1-c1cc(C=O)c[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccccc1-c1cc(C=O)c[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a solution of 5-[2-(methylthio)phenyl]-1H-pyrrole-3-carbaldehyde (100 mg) in ethyl acetate (5 mL) was added 3-chloroperbenzoic acid (318 mg) under ice-cooling. After stirring at room temperature for 3 hr, a saturated sodium thiosulfate aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→1:3) to give the title compound as pale-yellow crystals (yield 88.9 mg, 78%).
Reaction SMILES: [Mg].C(Br)C.[CH:5]([N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)=[CH2:6].[Cl:12][C:13]1[CH:27]=[CH:26][C:16]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[O:18])=[CH:15][CH:14]=1.[Cl-].[NH4+]>O.O1CCCC1>[Cl:12][C:13]1[CH:27]=[CH:26][C:16]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)([C:8]2[N:7]([CH:5]=[CH2:6])[CH:11]=[CH:10][N:9]=2)[OH:18])=[CH:15][CH:14]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: C=Cn1ccnc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCBr
Product: C=Cn1ccnc1C(O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 24 h

Procedure:
2.19 g (0.09 gr.at.) of magnesium and 10.9 g (0.1 mol) of ethyl bromide were converted into a Grignard compound in 50 ml. of refluxing anhydrous tetrahydrofuran. In the course of 5 minutes a solution of 8.46 g (0.09 mol) of 1-vinylimidazole in 20 ml. of anhydrous tetrahydrofuran was added with stirring to the refluxing mixture, after which the reaction mixture was refluxed for another two hours. A suspension of 22.6 g (0.09 mol) of 4,4'-dichlorobenzophenone in 50 ml. of anhydrous tetrahydrofuran was then added and refluxing was continued for 24 hours. The whole procedure was carried out under a nitrogen atmosphere. After cooling, the reaction mixture was poured into a mixture of ice, water and ammonium chloride. The mixture was then extracted with diethyl ether and the extract was washed with water, dried over sodium sulphate and concentrated. The solid residue was twice crystallized from a mixture of isopropyl alcohol and dimethyl formamide. α,α-Bis(p-chlorophenyl)-1-vinylimidazole-2-methanol was obtained. Melting point 173.5°- 174° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN([CH:10]=[O:11])C>>[NH2:1][C@@H:6]([CH:5]1[CH2:6][C:5]2[C:3](=[CH:2][CH:2]=[CH:3][CH:4]=2)[CH2:4]1)[CH2:10][OH:11]
Reactant: CN(C)C=O
Reactant: C1CCNCC1
Product: N[C@H](CO)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
20% Piperidine in DMF (15 mL) was added to a solution of 9 H-fluoren-9-ylmethyl-(1S)-1-(2,3-dihydro-1H-inden-2-yl)-2-hydroxyethylcarbamate (1.05 g, 2.63 mmol) in DMF (5 mL). The reaction was stirred at 25° C. for 19 h. After solvent evaporation, the crude product was dissolved in ethyl acetate (50 mL) and dried over MgSO4, filtered and concentrated to obtain a crude yellow oil (1.05 g). Mass Spectrum (+ESI): 179 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:3]=1.[Cl:20][CH2:21][CH2:22][CH2:23][N:24]1[C:29](=[O:30])[C:28]([CH3:31])=[CH:27][NH:26][C:25]1=[O:32]>>[ClH:20].[OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:21][CH2:22][CH2:23][N:24]3[C:29](=[O:30])[C:28]([CH3:31])=[CH:27][NH:26][C:25]3=[O:32])[CH2:10][CH2:9]2)=[C:4]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])[CH:3]=1
Reactant: Oc1ccc(N2CCNCC2)c(OCC(F)(F)F)c1
Reactant: Cc1c[nH]c(=O)n(CCCCl)c1=O
Product: Cc1c[nH]c(=O)n(CCCN2CCN(c3ccc(O)cc3OCC(F)(F)F)CC2)c1=O
Product: Cl

Procedure:
substituting 1-[4-hydroxy-2-(2,2,2-trifluoroethoxy)phenyl]piperazine and 3-(3-chloropropyl)-5-methyl-2,4(1H,3H)-pyrimidinedione gave 3-(3-{4-[4-hydroxy-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-5-methyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 232°-242° C.; Anal.: Calcd. for C20H25F3N4O4.HCl: C, 49.63; H, 5.59; N, 11.02%; Found: C, 49.62; H, 5.65; N, 10.66%;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.C([Sn](CCCC)(CCCC)[C:34]1[O:35][CH:36]=[CH:37][N:38]=1)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]([F:19])([F:18])[F:20])=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:34]1[O:35][CH:36]=[CH:37][N:38]=1
Reactant: O=S(=O)(Oc1cc(-c2cnc3nc(C(F)(F)F)cnn23)ccc1F)C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)cnn23)cc1-c1ncco1
Yield: 35.8 %

Procedure:
A solution of trifluoromethanesulfonic acid 2-fluoro-5-(3-trifluoromethylimidazo[1,2-b][1,2,4]triazin-7-yl)phenyl ester (45 mg, 0.104 mmol), 2-(tributylstannyl)oxazole (70 mg, 0.196 mmol), tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.026 mmol) and copper(I) iodide (15 mg, 0.079 mmol) in 1,4-dioxane (4 ml) was heated at 170° C. for 30 min using a Smith Synthesizer microwave apparatus. The mixture was evaporated in vacuo and the residue was purified by chromatography (silica gel, 8% Et2O/CH2Cl2), followed by trituration with diethyl ether, to give 13 mg (35%) of the title compound: 1H NMR (360 MHz, CDCl3) δ 7.37 (1H, s), 7.42 (1H, dd, J 8.7, 10.2 Hz), 7.85 (1H, s), 8.19 (1H, ddd, J 8.8, 4.6, 2.4 Hz), 8.66 (1H, s), 8.82 (1H, dd, J 9.1, 2.4 Hz), 8.86 (1H, s); MS (ES+) m/z 350.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]#[N:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>C1C=CC=CC=1>[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][C:6]1([C:16]#[N:17])[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH2:9][CH2:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: N#CC1c2ccccc2CCc2ccccc21
Reactant: CN(C)CCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: c1ccccc1
Product: CN(C)CCC1(C#N)c2ccccc2CCc2ccccc21

Procedure:
To a solution of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-carbonitrile (100) (Med. Chem. Res. 1, 401 (1991)) (1.0 g, 4.56 mmol) and N-(2-chloroethyl)-N,N-dimethylamine hydrochloride (0.72 g, 5 mmol) in benzene (20 mL) was added 8.8 mL of a 1.3M solution of lithium hexamethyldisilazide (11.4 mmol). The mixture was heated at reflux under nitrogen for 18 hr and the solvent then removed under vacuum. The residue was treated with water (20 mL) and extracted twice with methylene chloride (20 mL). The organic layers were combined, dried over sodium sulfate, and chromatographed directly on silica gel eluted with methylene chloride followed by 95:5:0.5, then 90:10:1 methylene chloride:methanol:ammonium hydroxide. The product fractions were evaporated to dryness in vacuo to give the title compound as a yellow oil.
Reaction SMILES: [OH-:1].[K+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)C(C=NO)[CH2:8][CH2:7]2.[CH2:22]([OH:25])[CH2:23]O>>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)[CH:23]([C:22]([OH:25])=[O:1])[CH2:8][CH2:7]2
Reactant: ON=CC1CCc2cc(Cl)c(C3CCCCC3)cc21
Reactant: [OH-]
Reactant: OCCO
Agent: [K+]
Product: O=C(O)C1CCc2cc(Cl)c(C3CCCCC3)cc21
Temperature: 190 °C
Reaction time: 3 h

Procedure:
600 mg of finely powdered potassium hydroxide are added to a suspension of 500 mg of crude 5-chloro-6-cyclohexyl-indane-1-aldoxime in 20 ml of ethylene glycol and the mixture is stirred for 3 hours at 190°C under nitrogen. It is then cooled to room temperature and the reaction mixture is partitioned between 50 ml of ether and 50 ml of water. The aqueous layer is twice washed with 50 ml of ether at a time. The organic phases are extracted with 50 ml of water and the aqueous phases are adjusted to pH 2 with concentrated hydrochloric acid and extracted twice, with 50 ml of methylene chloride at a time. The methylene chloride phases are washed until neutral, dried over sodium sulphate and evaporated to dryness in vacuo. Chromatography of the evaporation residue on 20 g of silica gel, with benzene/ethyl acetate/glacial acetic acid (80:20;1) as the eluting agent, yields pure 5-chloro-6-cyclohexyl-1-indanecarboxylic acid of melting point 140°-143°C (from petroleum ether).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N+](C1C=C(S(O[CH2:36][C@@H:37]2[CH2:39][O:38]2)(=O)=O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[CH:4][C:5]([O:12][CH2:36][C@@H:37]2[CH2:39][O:38]2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: COC(=O)c1cc(Cl)c(OCc2ccc(OC)cc2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(OCc2ccc(OC)cc2)cc1OC[C@@H]1CO1
Yield: 74 %

Procedure:
A solution of methyl 5-chloro-2-hydroxy-4-[(4-methoxybenzyl)oxy]benzoate (0.37 g, 1.16 mmol), (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (0.30 g, 1.16 mmol) and caesium carbonate (0.45 g, 1.4 mmol) in dimethylformamide (15 mL) was stirred at room temperature overnight. The mixture was partitioned between water and ethyl acetate, and the organic phase was washed twice with water and once with brine, and finally concentrated. The crude material was purified by flash chromatoghrphy on silica gel (eluent:ethyl acetate/n-heptane), yielding the titled compound (0.33, 74%).