Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=2)[N:10]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=2)[C:9]1=[O:30].[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[NH:31]([C:13]1[N:12]=[C:11]2[N:10]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=3)[C:9](=[O:30])[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])[CH2:17][C:16]2=[CH:15][N:14]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Nc1ccccc1
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1ccc(CO)cc1)C(=O)N(c1ccccc1Br)C2
Product: O=C1N(c2ccccc2Br)Cc2cnc(Nc3ccccc3)nc2N1c1ccc(CO)cc1
Temperature: 120 °C
Yield: 35 %

Procedure:
A mixture of 180 mg (0.37 mmol) of 3-(2-bromophenyl)-3,4-dihydro-1-[4-(hydroxymethyl)phenyl]-7-methanesulfonyl-pyrimido[4,5-d]pyrimidin-2(1H)-one and 0.34 ml (3.7 mmol) of aniline was heated at 120° C. for 3 hours. The reaction mixture was cooled to room temperature then triturated with 5 ml of 2M hydrochloric acid. The fawn solid was collected by filtration, washed with water then diethyl ether. The crude material was purified by flash chromatography on silica gel, using 3% methanol in dichloromethane for the elution. Product containing fractions were combined and evaporated to give 65 mg (35%) of 7-anilino-3-(2-bromophenyl)-3,4-dihydro-1-[4-(hydroxymethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as an off-white solid of melting point 129-132° C. [Mass spectrum (ESI) MH+ =502].
Reaction SMILES: O/[CH:2]=[CH:3]/[C:4]([C:6]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[O:5].[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>C1(C)C=CC=CC=1>[CH2:26]([N:28]([CH2:29][CH3:30])/[CH:2]=[CH:3]/[C:4]([C:6]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[O:5])[CH3:27]
Reactant: CCNCC
Reactant: COC(=O)c1ccccc1COc1cc(OC)ccc1C(=O)/C=C/O
Solvent: Cc1ccccc1
Product: CCN(/C=C/C(=O)c1ccc(OC)cc1OCc1ccccc1C(=O)OC)CC
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a 2 L round bottomed flask was added (E)-methyl 2-[[2-(3-hydroxy-1-oxo-2-propenyl)-5-methoxyphenoxy]methyl]benzoate (104 g, 0.304 mol) and 1 L of toluene. After complete dissolution, diethylamine (28.3g, 40 mL, 0.39 mol) was rapidly added under nitrogen via an addition funnel into the stirred solution. The reaction mixture was stirred under nitrogen for 1 h and it was then concentrated under reduced pressure to give approximately 120 g (100% yield) of the title compound as an orange solid: 1H NMR (300 MHz, CDCl3) δ 8.02 (1H, d), 7.84 (1H, d), 7.67 (2H, bd), 7.51 (1H, t) 7.35 (1H, t), 6.54 (2H, m), 5.75 (1H, d), 5.52 (2H, s), 3.80 (3H, s), 3.23 (4h, br), 1.14 (6H, br).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[C:4]([O:12]C)(=O)/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8]>>[OH:12][C:4]1[CH2:5][CH:6]([C:7]([O:9][CH3:10])=[O:8])[N:2]([CH3:1])[N:3]=1
Reactant: COC(=O)/C=C/C(=O)OC
Reactant: CNN
Product: COC(=O)C1CC(O)=NN1C
Temperature: 25 °C

Procedure:
Methyl hydrazine (12 ml, 228 mmol) was added dropwise to dimethyl fumarate (32.8 g, 228 mmol) at −5° C. The mixture was stirred under warming to rt for 16 h and then heated to 100° C. for 3 h. The crude reaction product (36 g, quantitative) was used for the next step without purification. [[M+H]+=159.1]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([OH:26])=O)[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[C:36](=[O:40])[NH:35][C:34]2=[O:41].N1C=CC=CC=1.[ClH:48]>O=P(Cl)(Cl)Cl.O>[ClH:48].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:30][C:31]4[CH:32]=[C:33]5[C:37](=[CH:38][CH:39]=4)[C:36](=[O:40])[NH:35][C:34]5=[O:41])=[O:26])[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2cc(N3CCCC(C(=O)O)C3)nn3ccnc23)nc1OC
Reactant: Nc1ccc2c(c1)C(=O)NC2=O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(Nc2cc(N3CCCC(C(=O)Nc4ccc5c(c4)C(=O)NC5=O)C3)nn3ccnc23)nc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 2 %

Procedure:
A mixture of 1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)piperidine-3-carboxylic acid (500 mg, 1.26 mmol), 5-aminoisoindoline-1,3-dione (250 mg, 1.51 mmol) and pyridine (10 mL) was stirred at 0° C. for 2 h. POCl3 (20 drops) was added and stirred for 10 mins, then water (5 mL) was added and the mixture extracted with ethyl acetate (10 mL). The organic layer was washed with brine (10 mL), then dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give the product. HCl (1 mL) was added and then the mixture concentrated in vacuo to give 1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(1,3-dioxoisoindolin-5-yl)piperidine-3-carboxamide hydrochloride (10 mg, 2%). 1H NMR (300 MHz, DMSO): δ 11.23 (s, 1H), 10.65 (s, 1H), 10.21 (s, 1H), 8.15 (s, 2H), 7.98 (s, 1H), 7.86 (d, 1H, J=8.4 Hz), 7.77 (d, 1H, J=7.8 Hz), 7.43 (d, 1H, J=8.1 Hz), 6.93 (d, 1H, J=8.1 Hz), 4.29 (d, 1H, J=11.7 Hz), 4.14 (d, 1H, J=12.3 Hz), 3.91 (s, 3H), 7.56 (s, 3H), 3.23-3.02 (m, 2H), 2.73 (s, 1H), 2.10-2.06 (s, 1H), 1.82-1.75 (m, 3H). LC-MS: [M+H]+, 543, tR=1.406 min, HPLC: 98.08% at 214 nm, 98.69% at 254 nm, tR=5.25 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:32][C@H:33]2[CH2:53][CH2:52][C:35]3([O:39][C@H:38]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C@@H:37]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[O:36]3)[CH2:34]2)[C:13](=O)[CH2:14][CH2:15][C:16]([C:18]2[S:19][C:20]([CH2:23][O:24]C3CCCCO3)=[CH:21][N:22]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C([O-])(=O)C.[NH4+:58].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:13]2[NH:58][C:16]([C:18]3[S:19][C:20]([CH2:23][OH:24])=[CH:21][N:22]=3)=[CH:15][CH:14]=2)[CH2:32][C@H:33]2[CH2:53][CH2:52][C:35]3([O:36][C@H:37]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C@@H:38]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[O:39]3)[CH2:34]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)C(=O)CCC(=O)c2ncc(COC3CCCCO3)s2)cc1Cl
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)c2ccc(-c3ncc(CO)s3)[nH]2)cc1Cl
Temperature: 110 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
To a solution of 5-[3-chloro-4-(methylsulfonyl)phenyl]-6-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]-1-{5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazol-2-yl}hexane-1,4-dione (416 mg) in acetic acid (2.5 mL) was added ammonium acetate (659 mg), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (151 mg, yield 42%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (19:1, volume ratio). MS: 675 (MH+).
Reaction SMILES: [C:1]([O:9][C@@:10]12[O:16][C@@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>[N+](C)([O-])=O>[C:1]([O:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:16])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O[C@]12CCCC[C@H]1O2)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C[N+](=O)[O-]
Product: O=C(O[C@@H]1CCCCC1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.3 %

Procedure:
To a solution of (1R, 2R)-2-benzoyloxy-1,2-epoxycyclohexane (0.030 g, 0.137 mmol, 93% ee) in anhydrous nitromethane (0.4 mL) was added p-TsOH (0.0024 g, 0.0137 mmol). Upon stirring at room temperature for 10 min, the reaction mixture was quenched with saturated NaHCO3 solution, extracted with ether, dried over anhydrous Na2SO4, filtered, concentrated, and purified on buffered silica gel (0.5-1% Et3N) by flash column chromatography [EtOAc—CH2Cl2-hexane (3:7:40)] to afford (R)-2-benzoyloxy cyclohexanone (0.0267 g, 89% yield, 90% ee).
Reaction SMILES: [N+:1]([C:4]1[CH:33]=[CH:32][C:7]([C:8]([NH:10][CH2:11][C:12](=[O:31])[N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:30])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])[CH2:15][CH2:14]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][C:12](=[O:31])[N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:30])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])[CH2:15][CH2:14]2)=[O:9])=[CH:32][CH:33]=1
Reactant: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(C(=O)NCC(=O)N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cc1
Reaction time: 4 h
Yield: 49.9 %

Procedure:
4-Nitro-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide (57 mg, 0.12 mmol) was dissolved in Methanol (1 mL). 10% Pd/C (10 mg) was added and the resulting mixture stirred for 4 hrs. The mixture was filtered over celite bed, and the filtrate was concentrated to afford 26 mg (49.1% yield) of 4-amino-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LCMS Purity: 97.4%, 1H NMR (CDCl3): δ 7.8-7.5 (m, 5H), 7.4-7.3 (d, 1H), 7.1-7.0 (s, 1H), 6.7-6.6 (d, 2H), 4.3-4.1 (m, 2H), 4.0 (bs, 3H), 3.8-3.5 (m, 5H), 3.4 (t, 1H), 3.2 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9](/[N:11]=[C:12]1/[N:13](C(OCC2C=CC=CC=2)=O)[C:14]([CH2:18][C:19](N(OC)C)=[O:20])=[CH:15][CH:16]=[CH:17]/1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:35]([Mg]Br)=[CH2:36]>C1COCC1>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][C:19](=[O:20])[CH:35]=[CH2:36])[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)Cc1ccc/c(=N\C(=O)OCc2ccccc2)n1C(=O)OCc1ccccc1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(=O)Cc1cccc(NC(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
To a solution of benzyl (2E)-2-([(benzyloxy)carbonyl]imino)-6-(2-[methoxy(methyl)amino]-2-oxoethyl)pyridine-1(2H)-carboxylate (150 mg, 0.33 mmol) in 4 ml anhydrous THF cooled to −40° C. via dry ice/acetone bath under nitrogen atmosphere was added via syringe 1.0M vinylmagnesium bromide (1.5 mL, 1.5 mmol) and the resulting solution stirred for 2 hours allowing to warm to room temperature. The reaction was quenched with water and extracted with ethyl acetate (3×10 mL). The organics were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via preparative TLC plate (1000 μM) eluting with 2.5% methanol in dichloromethane to afford the title compound (64 mg, 67%). LC-MS: C17H16N2O3 calculated 296.32 found m/z (ES) 297.3 (MH)+. 1HNMR (500 MHz, DMSO) δ: 10.12 (s, 1H) 8.05 (d, J=8.5 Hz, 1H), 7.99 (d, J=2.1, 1H), 7.62 (dd, J=2.2, 8.7 Hz, 1H), 7.60-7.34 (m, 5H), 6.40 (dd, J=10.3, 17.7 Hz, 1H), 6.26 (dd, J=10.3, 18.1 Hz, 1H), 5.94 (d, J=10.3 Hz, 1H), 5.22 (s, 2H), 3.60 (s, 2H).
Reaction SMILES: CI.[I-].[CH3:4][N+:5]([CH3:12])([CH2:9][CH2:10][CH3:11])[CH2:6][CH2:7][CH3:8].C([OH:15])C>C(NCCC)CC>[OH-:15].[CH3:4][N+:5]([CH3:12])([CH2:9][CH2:10][CH3:11])[CH2:6][CH2:7][CH3:8]
Reactant: CCO
Agent: CCC[N+](C)(C)CCC
Agent: [I-]
Solvent: CCCNCCC
Solvent: CI
Product: [OH-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
15 ml of dipropylamine in 50 ml of ethanol as a solvent and with KHCO3 as a buffer are reacted with 20 ml of methyl iodide at a temperature of from 40 to 50° C. in a water bath with stirring. After 2 hours, cooling to room temperature was effected, the product dimethyldipropylammonium iodide crystallizing out. The solid filtrate was washed in ethanol. An aqueous solution of the iodide was converted over an Amberlyst anion exchanger into dimethyldipropylammonium hydroxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][C:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)([CH2:11][CH2:12]OS(C)(=O)=O)[C:7]1=[O:26].[CH2:31]([O:33][CH2:34][CH2:35][N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=[C:37]1[N:45]1[CH2:51][CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)[CH3:32]>>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][C:8]([CH2:11][CH2:12][N:48]2[CH2:49][CH2:50][CH2:51][N:45]([C:37]3[N:36]([CH2:35][CH2:34][O:33][CH2:31][CH3:32])[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=4[N:38]=3)[CH2:46][CH2:47]2)([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:7]1=[O:26]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1ccccc1CN1CCC(CCOS(C)(=O)=O)(Cc2ccc(F)cc2)C1=O
Product: CCOCCn1c(N2CCCN(CCC3(Cc4ccc(F)cc4)CCN(Cc4ccccc4OC)C3=O)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(2-methoxybenzyl)-3-(4-fluorophenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give the title compound.
Reaction SMILES: [CH2:1]1[CH2:6]CCC[CH2:2]1.[SH:7][CH:8]([CH3:12])[CH:9]([OH:11])[CH3:10].CCC[CH:16]=[S:17]>O>[CH3:12][CH:8]1[CH:9]([CH3:10])[O:11][CH:2]([CH2:1][CH2:6][S:17][CH3:16])[S:7]1
Reactant: CCCC=S
Reactant: C1CCCCC1
Reactant: CC(O)C(C)S
Solvent: O
Product: CSCCC1OC(C)C(C)S1
Reaction time: 0.5 h

Procedure:
Into a 100 ml reaction flask equipped with spin bar, reflux condenser, heating mantle, hot plate apparatus (with magnetic stirring apparatus) is placed 5 ml cyclohexane, 0.2 grams paratoluenesulfonic acid and 5.3 grams (0.05 moles) of 3-mercapto-2-butanol. Over a period of 30 minutes, 5.2 grams (0.05 moles) of 3-methylthiopropionaldehyde are added to the reaction mass. The reaction mass is then heated to reflux and water of reaction is continuously removed during the refluxing of the reaction mass. The reaction takes place over a period of 7 hours. At the end of the 7 hours the reaction mass is transferred to a separatory funnel and the reaction mass is washed with one 50 ml portion of saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The product is then filtered and distilled on a Microvigreux column yielding the following fractions:
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[O:6][C:5]1=[O:24])[CH:2]=[CH2:3].Cl.[NH2:27][C@@H:28]([CH2:32][CH3:33])[C@@H:29]([OH:31])[CH3:30].C(N(CC)CC)C>C(OCC)(=O)C>[Cl:16][C:12]1[CH:11]=[C:10]([C@H:8]([C@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[OH:6])[CH2:9][C@:4]([CH3:25])([CH2:1][CH:2]=[CH2:3])[C:5]([NH:27][C@@H:28]([CH2:32][CH3:33])[C@@H:29]([OH:31])[CH3:30])=[O:24])[CH:15]=[CH:14][CH:13]=1
Reactant: CC[C@H](N)[C@H](C)O
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@H](c2ccc(Cl)cc2)OC1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CC[C@@](C)(C[C@H](c1cccc(Cl)c1)[C@@H](O)c1ccc(Cl)cc1)C(=O)N[C@@H](CC)[C@H](C)O
Temperature: 90 °C

Procedure:
To a 10 mL round-bottom reaction flask was added (3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one (750 mg, 1.998 mmol), (2S,3S)-3-aminopentan-2-ol hydrochloride (837 mg, 6.00 mmol, reference: J. Org. Chem., 2003, 68 (26), 9948), and triethylamine (1966 μl, 13.99 mmol). The vessel was fitted with a reflux condensor and heated to 85 to 95° C. for 2 d. The reaction was cooled to RT and diluted with ethyl acetate and washed with 1N HCl (2×20 mL) and brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography using 40 to 50% ethyl acetate in hexanes afforded (S)-2-((2R,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-3-hydroxypropyl)-N-((2S,3S)-2-hydroxypentan-3-yl)-2-methylpent-4-enamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2(O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:25](N(CC)CC)[CH3:26].S(Cl)(Cl)=O.C([Mg]Br)C>C1COCC1.C(Cl)Cl>[CH2:25]([C:5]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[NH:8][C:7](=[O:12])[N:6]1[CH2:13][C:14]([F:17])([F:16])[F:15])[CH3:26]
Reactant: CCN(CC)CC
Reactant: O=C1Nc2ccc(F)cc2C(O)(c2ccccc2)N1CC(F)(F)F
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCC1(c2ccccc2)c2cc(F)ccc2NC(=O)N1CC(F)(F)F
Reaction time: 0.42 h

Procedure:
To a −15° C. solution of 6-fluoro-4-hydroxy-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (3.00 g, 8.82 mmol) in THF (40 mL) was added triethylamine (6.14 mL, 44.08 mmol). The reaction was stirred for a couple of minutes and then thionyl chloride (0.68 mL, 9.26 mmol) was added dropwise. After 25 min, 1M ethylmagnesium bromide in THF (27.33 mL, 27.33 mmol) was added over 10 min. After an additional 30 min at −15° C., the reaction was quenched with saturated ammonium chloride solution (60 mL) and extracted with CH2Cl2 (120 mL×2). The combined organics were washed with brine (60 mL), dried over dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase chromatography (0-70% EtOAc/hexanes) followed by chiral reverse phase chromatography (ChiralPak AD packing, 10-60% iPrOH/hexanes with DEA modifier) yielded a yellow residue that was taken up in a minimal amount of CH2Cl2, diluted with hexanes, and then concentrated in vacuo to give (−)-4-ethyl-6-fluoro-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one. 1H NMR (CDCl3, 400 MHz) 8.26 (s, NH); 7.38 (m, 5H, ArH); 6.85 (m, 1H, ArH); 6.70 (m, 1H, ArH); 6.25 (m, 1H, ArH); 3.92 (m, 1H, CH2); 3.48 (m, 1H, CH2); 2.35 (m, 2H, CH2); 0.91 (t, J=6.87 Hz, 3H, CH3); MS (Electrospray): m/z 353.1292 (M+H); [α]D=−41.8° (c0.11, MeOH). For the (+)-enantiomer, [α]D=+41.1° (c0.12, MeOH).
Reaction SMILES: [CH:1]([NH:4][CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Br:20][C:21]1[CH:22]=[C:23]([C:27]2[C:28](=[O:41])[N:29]([CH3:40])[C:30](Cl)=[N:31][C:32]=2[C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[CH:24]=[CH:25][CH:26]=1>ClCCl>[Br:20][C:21]1[CH:22]=[C:23]([C:27]2[C:28](=[O:41])[N:29]([CH3:40])[C:30]([N:7]3[CH2:8][CH2:9][CH2:10][CH:6]3[CH2:5][NH:4][CH:1]([CH3:3])[CH3:2])=[N:31][C:32]=2[C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2)c(-c2cccc(Br)c2)c1=O
Reactant: CC(C)NC[C@H]1CCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)NCC1CCCN1c1nc(-c2ccncc2)c(-c2cccc(Br)c2)c(=O)n1C
Reaction time: 0.17 h

Procedure:
To a 100 mL RBF, was added (R)-isopropyl-pyrrolidin-2-ylmethyl-amine (0.78 g, 3.6 mmol), and 50 mL dichloromethane at 0° C. under nitrogen. 2.1 mL diisopropylethylamine (12 mmol) was added drop wise, and stirred for 10 min. 5-(3-Bromo-phenyl)-2-chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (1.13 g, 3 mmol) was added in one portion. The mixture was stirred at 0° C. to rt for 12 h. The mixture was diluted with 100 mL dichloromethane, washed with sat. NaHCO3 and brine. After purified by flash chromatography, the title compound was yielded in 1.3 g as pale yellow solid. MS (ES+): 482 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.CS([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:19])=[C:16]([F:18])[F:17])(=O)=O.[NH:20]1[C:24]2[CH:25]=[CH:26][C:27]([C:29]([OH:31])=[O:30])=[CH:28][C:23]=2[N:22]=C1.C(=O)([O-])O.[Na+]>O>[F:17][C:16]([F:18])=[C:15]([CH3:19])[CH2:14][CH2:13][CH2:12][CH2:1][N:2]1[C:5]2[CH:25]=[CH:26][C:27]([C:29]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:19])=[C:16]([F:18])[F:17])=[O:31])=[CH:28][C:23]=2[N:22]=[CH:3]1.[F:17][C:16]([F:18])=[C:15]([CH3:19])[CH2:14][CH2:13][CH2:12][CH2:1][N:2]1[C:5]2[CH:28]=[C:27]([C:29]([O:31][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:19])=[C:16]([F:18])[F:17])=[O:30])[CH:26]=[CH:25][C:24]=2[N:20]=[CH:3]1
Reactant: CC(CCCCOS(C)(=O)=O)=C(F)F
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(CCCCOC(=O)c1ccc2c(c1)ncn2CCCCC(C)=C(F)F)=C(F)F
Product: CC(CCCCOC(=O)c1ccc2ncn(CCCCC(C)=C(F)F)c2c1)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 33 %
Yield: 35 %

Procedure:
To 5 ml of N,N-dimethylformamide were dissolved 0.68 g (3.0 mmol) of 6,6-difluoro-5-methyl-5-hexenyl methanesulfonate and 0.24 g (1.5 mmol) of 1H-benzoimidazole-5-carboxylic acid, followed by the addition of 0.42 g (5.0 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane 1:2) to obtain 0.22 g (yield: 35%) of 6,6-difluoro-5-methyl-5-hexenyl 1-(6,6-difluoro-5-methyl-5-hexenyl)-1H-benzoimidazole-5-carboxylate as the first elution component and 0.21 g (yield: 33%) of 6,6-difluoro-5-methyl-5-hexenyl 3-(6,6-difluoro-5-methyl-5-hexenyl)-3H-benzoimidazole-5-carboxylate as the second elution component.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([S:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:38]=[CH:37][C:17]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29][C:27]3=[O:28])[CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)[CH3:8]>O.CO>[CH2:7]([S:9]([CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:38]=[CH:37][C:17]([C:18]([N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29][C:27]3=[O:28])[CH2:24][CH2:25]2)=[O:19])=[CH:16][CH:15]=1)=[O:2])[CH3:8]
Reactant: CCSCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCS(=O)CCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
Sodium metaperiodate (0.28 g) is dissolved in water (4 ml) and thereto is added a solution of 1-{1-[4-(3-ethylthiopropoxy)benzoyl]-4-piperidinyl)-3,4-dihydrocarbostyril (0.4 g) in methanol (15 ml) and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated and the residue is extracted with chloroform. The extract is dried with magnesium sulfate and the solvent is distilled off. The resulting residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:2→ethyl acetate:methanol=20:1) to give 1-{1-[4-(3-ethylsulfinylpropoxy)benzoyl]-4-piperidinyl]-3,4-dihydrocarbostyril (0.12 g).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22]O)[CH2:17][CH2:16]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1>ClCCl>[Cl:3][CH2:22][CH2:21][CH:18]1[CH2:19][CH2:20][N:15]([C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][N:6]=2)[CH2:16][CH2:17]1
Reactant: OCCC1CCN(c2nccc3ccccc23)CC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCCC1CCN(c2nccc3ccccc23)CC1

Procedure:
2.20 ml (30.10 mmol) of thionyl chloride are added dropwise to a solution of 3.09 g (12.10 mmol) of 2-[1-(1-isoquinolyl)-4-piperidyl]ethanol, prepared in step 2.1, in 30 ml of dichloromethane. The reaction mixture is then refluxed for 5 hours.