Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]2[CH3:31])[C:18]([CH3:32])=[C:17]([CH3:33])[N:16]=1>CN(C)C=O>[ClH:14].[CH3:32][C:18]1[C:19]([N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]2[CH3:31])=[N:20][C:15]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:16][C:17]=1[CH3:33]
Reactant: C1CCNCC1
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(N2CCCCC2)nc(N2CCc3ccccc3C2C)c1C
Product: Cl
Yield: 75.5 %

Procedure:
After piperidine(0.26 ml, 2.61 mmol) and triethylamine(0.36 ml, 2.59 mmol) were added to a solution of 2-chloro-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5 g, 1.74 mmol) in dimethylformamide, 490 mg of the titled compound was obtained in accordance with the same procedure as in Example 1.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([CH2:16][CH2:17][CH3:18])[C:6]=2[O:5][C:4]([C:31]([O:33]CC)=[O:32])=[CH:3]1)[N:13]=[C:12]([C:19]([O:21]CC)=[O:20])[CH:11]=[C:10]3[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[Na+:37]>CO>[O:1]=[C:2]1[C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([CH2:16][CH2:17][CH3:18])[C:6]=2[O:5][C:4]([C:31]([O-:33])=[O:32])=[CH:3]1)[N:13]=[C:12]([C:19]([O-:21])=[O:20])[CH:11]=[C:10]3[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Na+:37].[Na+:37]
Reactant: CCCc1c2nc(C(=O)OCC)cc(Oc3ccccc3)c2cc2c(=O)cc(C(=O)OCC)oc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c2nc(C(=O)[O-])cc(Oc3ccccc3)c2cc2c(=O)cc(C(=O)[O-])oc12

Procedure:
The product of step (b) (0.4162 g) was stirred in methanol (50 cm3) under reflux and was treated with 0.1 N sodium hydroxide solution (17.5 cm3), dropwise. The whole was stirred and refluxed for 15 minutes after addition, cooled, filtered and the filtrate evaporated to dryness. Water (30 cm3) was added and the solution was treated with acetone until complete precipitation was attained. The product was collected by filtration and dried to give 0.22 g of the title compound.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][CH2:10][N:2]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:1])[CH3:16]
Reactant: CCOC(=O)CCBr
Reactant: CNC1CCCCC1
Solvent: CCO
Product: CCOC(=O)CCN(C)C1CCCCC1
Yield: 79.8 %

Procedure:
22 g of N-methylcyclohexylamine were added to 40 mL of ethanol, 10 g of ethyl β-bromopropionate were added, and the mixture was heated and refluxed for two hours. The reaction system was concentrated under reduced pressure, the resulting residue was extracted with 200 mL of ethyl acetate, the organic layer was desiccated over anhydrous magnesium sulfate, and the product was then filtered and concentrated. The residue was purified by distillation under reduced pressure, and 9.4 g of N-cyclohexyl-N-methyl β-alanine ethyl ester (yield of 80%) were obtained. 1.75 g of sodium hydroxide were dissolved in 200 mL of water, 9.4 g of N-cyclohexylmethyl-N-methyl-β-alanine ethyl ester were obtained, and THF was added for dissolution. After stirring for one hour, the product was neutralized using Dowex 50WX4-[H+] and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was recrystallized and 6.7 g of the desired product were obtained (yield of 82%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5](Cl)=[CH:4][CH:3]=1>C(O)(=O)C.CO.[Pd]>[NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCc2c(N)ccc(Cl)c2CC1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCc2cccc(N)c2CC1

Procedure:
9-Amino-6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, prepared according to R. M. DeMarinis et al, J. Med. Chem., 1984, 27, 918, (0.190 g, 0.90 mmol) was dissolved in 10% acetic acid in methanol (50 ml) and 10% Pd/C (150 mg) added. The mixture was stirred at room temperature, under hydrogen/atmos pressure for 4h, then filtered through Kieselguhr and evaporated in vacuo. Residual material was taken up into dichloromethane and 5% NaHCO3 solution; the organic layer was washed with brine, dried (Na2SO4) and evaporated in vacuo to afford the title compound as a colourless oil (133 mg).
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[C:6]1(=[O:11])[CH2:10][CH2:9][CH2:8][CH2:7]1>>[CH:1]([C:6]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:3])[CH3:2]
Reactant: CC(C)[Mg]Cl
Reactant: O=C1CCCC1
Product: CC(C)C1(O)CCCC1
Reaction time: 0.08 h

Procedure:
According to Example 2, i-PrMgCl (3.30 mL; 3.30 mmol; 1.10 equiv) was reacted with cyclopentanone (252 mg; 3.00 mmol) in the presence of LaCl3.2LiCl (0.33 M; 9.09 mL, 3.00 mmol, 1.00 equiv), the conversion was complete after 5 min (GC monitoring). After workup and careful evaporation of the solvents under reduced pressure, the desired product was obtained as colorless oil (353 mg, 92%). The analytical data were found to be in accordance with the literature data.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.C([BH3-])#N.[Na+].[CH3:33][C:34]([CH2:36][OH:37])=O.C(O)(=O)C>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:24][N:25]([CH:34]([CH3:33])[CH2:36][OH:37])[CH2:26]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: CC(=O)CO
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C(C)CO)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile (40 mg, 0.10 mmol) in methanol (2 mL) was treated with sodium cyanoborohydride (16 mg, 0.25 mmol) followed by acetol (28 μL, 0.40 mmol) and stirred at room temperature for 1 h. The reaction mixture was quenched with acetic acid (100 μL, 1.8 mmol), diluted with methanol, and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired products as a mixture of diastereoisomers. This mixture of diastereoisomers was separated by chiral HPLC (RT=3.70 min and 6.58 min; Phenomenex Lux Cellulose C-4 column, 21.2×250 mm, 5 micron particle size, eluting with 20% ethanol in hexanes at 18 ml/min, 5 mg/inj) to give the desired peak 1 isomer (compound 272) (19 mg, 41%) and peak 2 isomer (compound 273) (23 mg, 50%) Peak 1: 1H NMR (300 MHz, DMSO-d5) δ 8.11 (s, 1H), 7.47 (s, 1H), 7.34 (br s, 2H), 6.24 (q, J=6.9 Hz, 1H), 4.43 (t, J=5.2 Hz, 1H), 4.07-3.82 (m, 3H), 3.64 (s, 3H), 3.31-3.24 (m, 1H), 3.17-3.06 (m, 2H), 3.06-2.97 (m, 1H), 2.55 (s, 3H), 2.21-2.11 (m, 1H), 1.72 (d, J=7.1 Hz, 3H), 0.81 (d, J=6.3 Hz, 3H). LCMS for C22H27ClN7O2 (M+H)+: m/z=456.2; Found: 456.2. Peak 2: 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.47 (s, 1H), 7.35 (br s, 2H), 6.24 (q, J=7.0 Hz, 1H), 4.43 (t, J=5.5 Hz, 1H), 4.06-3.91 (m, 2H), 3.89-3.79 (m, 1H), 3.64 (s, 3H), 3.30-3.24 (m, 1H), 3.15-3.00 (m, 3H), 2.55 (s, 3H), 2.21-2.10 (m, 1H), 1.72 (d, J=7.1 Hz, 3H), 0.82 (d, J=6.2 Hz, 3H). LCMS for C22H27ClN7O2 (M+H)+: m/z=456.2; Found: 456.2.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=23)=[C:4]([F:20])[CH:3]=1.Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[N:23]=1.Cl.[OH-].[Na+]>O.C(O)C>[NH2:28][C:24]1[N:25]=[C:26]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=34)=[C:4]([F:20])[CH:3]=2)[CH:27]=[CH:22][N:23]=1
Reactant: N#Cc1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Reactant: Nc1nccc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1c[nH]c2nccc(Oc3ccc(Nc4ccnc(N)n4)cc3F)c12

Procedure:
200 mg (0.66 mmol) of 4-(4-amino-2-fluorophenoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile and 104 mg (0.72 mmol) of 4-chloropyrimidine-2-amine are suspended in 9 ml of water and 4.5 ml of ethanol. 0.33 ml (1.31 mmol) of 4N hydrochloric acid is added, and the mixture is heated at reflux for 2 h. The mixture is made alkaline using concentrated aqueous sodium hydroxide solution, diluted with water and extracted with ethyl acetate. The organic phase is separated off and concentrated. The crude product is purified by preparative HPLC. This gives the title compound as crystals.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[CH3:15][O:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][O:22][NH2:23].C(N(CC)C(C)C)(C)C>COCCOCCOC>[Cl:11][C:6]1[C:7]([NH:8][CH:9]=[O:10])=[C:2]([NH:23][O:22][CH2:21][CH2:20][CH2:19][O:18][CH2:17][O:16][CH3:15])[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=1
Reactant: COCOCCCON
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOCCOC
Product: COCOCCCONc1nc(NC=O)nc(Cl)c1NC=O
Temperature: 100 °C

Procedure:
A mixture of 4,6-dichloro-2,5-diformamidopyrimidine (1.75 g, 7.4 mmol), 3-(methoxymethoxy)propoxyamine (1.0 g, 7.4 mmol) and N,N-diisopropylethylamine (2 g, 15.5 mmol) in dry diglyme was heated to 100° C. for 2 hr. The cooled reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica eluting with ethyl acetate:hexane (50:50) then ethyl acetate to give the title compound as a yellow oil which was crystallised from ethyl acetate (1.2 g, 50%) mp 136°-8° C. νmax (KBr) 3240, 2920, 2880, 1705, 1640, 1590, 1565, 1495, 14650, 1410, and 1380 cm-1 ; δH [(CD3)2SO]1.85 (2H, quintet, J=6.3 Hz, CH2CH2CH2), 3.24 (3H, s, OCH3), 3.58 (2H, t, J=6.3 Hz, CH2OCH2OCH3 ), 3.94 (2H, t, J=6.3 Hz, CH2ONH), 4.5 (2H, s, OCH2O), 8.15 (1H, s, NHCHO), 9.26 (1H, d, J=9.6 Hz, collapses to singlet on D2O, NHCHO), 9.4 (1H, s, D2O exchangeable NHOCH2), 10.73 (1H, s, D2O, exchangeable NHCHO), 10.84 (1H, d, J=9.6 Hz, D2O exchangeable, NHCHO).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[C:8]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:9]=3[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:35]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])(=[O:38])[CH:36]=[CH2:37]>CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:8]2[C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2](/[CH:37]=[CH:36]/[C:35]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:3][CH:4]=3)=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[S:10][C:9]=2[CH:20]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(Br)cc2)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/C(=O)OC(C)(C)C)cc2)cc1
Yield: 61.1 %

Procedure:
To a solution of 3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (79 mg, 0.18 mmol) in DMF (1.7 mL) was added triethylamine (0.125 mL, 0.90 mmol) followed by tert-butyl acrylate (0.184 mL, 1.25 mmol) and Pd(PPh3)2Cl2 (18.9 mg, 0.03 mmol). The mixture was then subjected to microwave irradiation for 1 h at 120° C. after which the reaction was diluted with water (15 mL) and extracted with EtOAc (4×10 mL). The combined organic layers were washed with brine (30 mL), passed through a phase separator to remove water and concentrated in vacuo to give the crude product as an orange oil which was purified by column chromatography (SiO2, 0-50% EtOAc/Heptane) to give (E)-tert-butyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate as a pale yellow oil (55 mg, 0.11 mmol, 63% yield). 1H NMR (400 MHz, CDCl3) δ ppm=1.44 (s, 9H), 3.71 (s, 3 H), 3.78 (s, 3 H), 6.13 (d, J=15.66 Hz, 1 H), 6.76-6.83 (m, 3 H), 6.86 (m, J=8.59 Hz, 2 H), 7.14-7.19 (m, 2 H), 7.31 (m, J=8.59 Hz, 2 H), 7.42 (d, J=16.17 Hz, 1 H), 7.54 (d, J=8.59 Hz, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:19]=[C:15]([C:16](Cl)=[O:17])[C:14]([OH:20])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]2[NH:26][N:27]=[N:28][C:24]=2[CH:23]=1.CN(C)C1C=CC=CC=1.O>O1CCCC1>[NH:26]1[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:16](=[O:17])[C:15]3[CH:19]=[C:11]([N:10]=[N:9][C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH:12]=[CH:13][C:14]=3[OH:20])=[CH:23][C:24]=2[N:28]=[N:27]1
Reactant: COc1ccc(N=Nc2ccc(O)c(C(=O)Cl)c2)cc1
Reactant: Nc1ccc2[nH]nnc2c1
Solvent: O
Solvent: CN(C)c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(N=Nc2ccc(O)c(C(=O)Nc3ccc4[nH]nnc4c3)c2)cc1

Procedure:
5-(4-Methoxyphenylazo)salicoyl chloride (1.46 g) in dry tetrahydrofuran (10 ml) was added dropwise with stirring to a solution of 5-aminobenzotriazole (0.67 g) in dry tetrahydrofuran (15 ml) and dimethylaniline (0.61 g). After 2-3 hours the mixture was poured into water and the solid removed by filtration. The product was crystallized in aqueous pyridine as yellow plates of the monohydrate (1.5 g, 81%), m.p. 275°-6°, λmax (methanol) = 352 nm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4([CH:46]([OH:48])[CH3:47])[CH2:24][CH2:23][N:22]([CH2:25][C:26](=[O:45])[N:27]5[CH2:32][CH2:31][N:30]([C:33]6[CH:38]=[CH:37][C:36]([C:39]7[N:44]=[CH:43][CH:42]=[CH:41][N:40]=7)=[CH:35][CH:34]=6)[CH2:29][CH2:28]5)[CH2:21]4)=[O:19])[CH:15]=3)[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)=[CH:4][CH:3]=1.CCOC(C)=O>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4([CH:46]([OH:48])[CH3:47])[CH2:24][CH2:23][N:22]([CH2:25][C:26](=[O:45])[N:27]5[CH2:32][CH2:31][N:30]([C:33]6[CH:38]=[CH:37][C:36]([C:39]7[N:40]=[CH:41][CH:42]=[CH:43][N:44]=7)=[CH:35][CH:34]=6)[CH2:29][CH2:28]5)[CH2:21]4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(O)C1(C(=O)Nc2ccc3c(c2)c(-c2ccc(F)cc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(O)C1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1

Procedure:
Stirred 3-(1-Hydroxy-ethyl)-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1Trityl-indazol-5-yl]-amide (7N) (65 mg, 0.073 mmol) in 85% TFA (2 ml) at room temperature overnight. Evaporated solvent. Added EtOAc (50 ml) H2O (20 ml) 2M NaOH (3 ml). Separated organic layer, dried over MgSO4, filtered and solvent evaporated yielding a residue which purified on silica gel eluting with 5% v/v MeOH:EtOAc yielding two diastereomeric racemates.
Reaction SMILES: [O:1]=[C:2]1[CH:12]=[N:11][CH:10]2[CH:13]3[N:3]1[CH2:4][CH:5]([CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1)[N:6]3[C:7](=[O:14])[CH:8]=[CH:9]2.C(O)(C(F)(F)F)=O>ClCCl>[NH2:22][CH:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH:5]2[N:6]3[CH:13]4[CH:10]([CH:9]=[CH:8][C:7]3=[O:14])[N:11]=[CH:12][C:2](=[O:1])[N:3]4[CH2:4]2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2CN3C(=O)C=NC4C=CC(=O)N2C43)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(CC2CN3C(=O)C=NC4C=CC(=O)N2C43)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1,1-dimethylethyl {1-[(3,8-dioxo-1,2,5a,8b-tetrahydro-3H,8H-2a,5,8a-triazaacenaphthylen-1-yl)methyl]-4-piperidinyl}carbamate (37 mg, 0.092 mmol) in anhydrous dichloromethane (2 ml) was treated with TFA (1 ml) and stirred at room temperature for 1 hour, evaporated to dryness, mixed with anhydrous dichloromethane and evaporated to a dark gum. This gum was dissolved in 1:1 dichloromethane:methanol (10 ml) and treated with MP-carbonate resin (600 mg) and stirred for 1.5 hours. The reaction was filtered and the resin was washed with 1:1 dichloromethane:methanol (30 ml) and the filtrate was evaporated to dryness. Purification on a 5 g SCX column eluting with a methanol to 2N methanolic ammonia gradient gave the product as a gum. Further evaporation from diethyl ether gave the product as a brown solid (22.8 mg, 82%).
Reaction SMILES: CN(C)C=O.FC(F)(F)S(O[C:12]1[C:13]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:14][C:15]([CH2:18][CH2:19][C:20](=[O:24])[CH2:21][O:22][CH3:23])=[CH:16][CH:17]=1)(=O)=O.[C:34]([C:36]1([OH:44])[CH:41]2[CH2:42][CH2:43][N:38]([CH2:39][CH2:40]2)[CH2:37]1)#[CH:35].C(N(CC)CC)C>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.C(OCC)(=O)C>[CH2:25]([C:13]1[C:12]([C:35]#[C:34][C:36]2([OH:44])[CH:41]3[CH2:42][CH2:43][N:38]([CH2:39][CH2:40]3)[CH2:37]2)=[CH:17][CH:16]=[C:15]([CH2:18][CH2:19][C:20](=[O:24])[CH2:21][O:22][CH3:23])[N:14]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COCC(=O)CCc1ccc(OS(=O)(=O)C(F)(F)F)c(Cc2ccccc2)n1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCC(=O)CCc1ccc(C#CC2(O)CN3CCC2CC3)c(Cc2ccccc2)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
10 ml of N,N-dimethylformamide was added to a mixture of 1.9 g of 2-benzyl-6-(4-methoxy-3-oxobutyl)-3-pyridyl trifluoromethanesulfonate, 773 mg of 3-ethynyl-3-quinuclidinol, 525 mg of tetrakis(triphenylphosphine)palladium(0), 267 mg of cuprous iodide and 2.2 ml of triethylamine, followed by stirring for one hour at 50° C. in an oil bath in a nitrogen atmosphere. After cooling as it was, ethyl acetate was added thereto. The mixture was filtered through Celite, followed by washing with water. The organic phase was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using chloroform/methanol/36% aqueous ammonia (46:5:0.5) as an eluent for separation and purification, to give 1.3 g of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[NH:26][C:27]1[S:28][C:29]2[CH:35]=[C:34]([NH2:36])[CH:33]=[CH:32][C:30]=2[N:31]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:36][C:34]1[CH:33]=[CH:32][C:30]2[N:31]=[C:27]([NH:26][C:17]3[C:16]4[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=4)[N:20]=[CH:19][N:18]=3)[S:28][C:29]=2[CH:35]=1)=[O:6]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)c5ccc(Cl)c(Cl)c5)cc4s3)c2cc1OC

Procedure:
3,4-Dichloro-N-[2-(6,7-dimethoxyquinazolin-4-ylamino)benzo-thiazol-6-yl]benzamide was prepared from 3,4-dichlorobenzoyl chloride (24 mg, 0.113 mmol) and N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 2 (yellowish solid, 49 mg, 92 μmol, 82%). LC/ESI-MS: m/z=526 [M(35Cl2)+H]+; m/z=524 [M(35Cl2)−H]−; Rt=3.82 min.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][C@@H:33]([CH:36]([CH3:38])[CH3:37])[C:34]#[N:35].C(O)=O.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:34]([C@@H:33]([NH:32][C:3](=[O:5])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1)[CH:36]([CH3:38])[CH3:37])#[N:35]
Reactant: CC(C)[C@H](N)C#N
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: O=CO
Solvent: CN(C)C=O
Product: CC(C)[C@@H](C#N)NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 7.1 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 45 mg, 0.104 mmol), (S)-2-amino-3-methylbutanenitrile (Int-XIII), formic acid salt (15.04 mg, 0.104 mmol), 4-methylmorpholine (42.2 mg, 0.417 mmol), and HATU (51.6 mg, 0.136 mmol) were dissolved in DMF (1 mL). After stirring 1 h, this was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give single enantiomer N—((S)-1-cyano-2-methylpropyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (3.8 mg, 0.007 mmol, 7.1% yield, and its purity was 100%): LCMS=512.1 [M+H]+; 1H NMR (500 MHz, methanol-d4) δ ppm 8.16 (2 H, d, J=8.32 Hz), 7.48-7.72 (7 H, m), 5.19 (1 H, s), 4.63 (1 H, d, J=7.49 Hz), 2.01-2.15 (1 H, m, J=13.80, 6.83, 6.83, 6.66 Hz), 1.07 (3 H, d, J=6.66 Hz), 0.95 (3 H, d, J=6.94 Hz); HPLC peak RT=3.0 min (Method E).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[H-].[Na+].[H][H].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.O>[CH2:18]([O:13][C:10]1[CH:11]=[CH:12][C:3]([CH2:2][OH:1])=[C:4]2[C:9]=1[N:8]=[CH:7][CH:6]=[CH:5]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: [H][H]
Reactant: OCc1ccc(O)c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCc1ccc(OCc2ccccc2)c2ncccc12
Reaction time: 4 h
Yield: 55.4 %

Procedure:
5-(Hydroxymethyl)-8-hydroxyquinoline (1) (6.44 g, 36.75 mmol) was dissolved in dry dimethylformamide (40 ml) and sodium hydride (1.3 g of 80% suspension in mineral oil, corresponding to 1.04 g, 43.3 mmol) was added. The mixture was stirred until hydrogen evolution ceased (~45 min). Benzyl bromide (4.5 ml, 6.47 g, 37.8 mmol) was added and the mixture was stirred for 4 h. The solution was poured into water (350 ml) and stirred for 20 min, and the precipitate was filtered and washed with water. After crystallization from benzene, 5.4 g of product (2) was obtained; mp 192°-194° C. An analytical sample was recrystallized from toluene; Rf 0.68 (chloroform-methanol, 9:1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[CH3:8][C:9]1([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[O:10]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:9]2([CH3:8])[C:13](=[O:14])[CH:12]=[C:11]([CH:15]=[CH:6][C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[O:10]2)=[CH:17][CH:18]=1
Reactant: CC1=CC(=O)C(C)(c2ccc(F)cc2)O1
Reactant: O=Cc1ccsc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(c2ccc(F)cc2)OC(C=Cc2ccsc2)=CC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.8 %

Procedure:
To a solution of 3-thiophenecarboxaldehyde (1.3 g, 1.2 mM) and 2,5-dimethyl-2-(4-fluorophenyl)-3(2H)-furanone (2.0 g, 9.8 mM) in ethanol (75 mL), was added 1N aqueous sodium hydroxide (2 mL, 2 mM). The reaction solution was stirred at room temperature for one day. After saturated aqueous sodium chloride (400 mL) was added, the aqueous layer was extracted with dichloromethane (3×100 mL). The combined dichloromethane extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a brown oil. The crude product was purified by chromatography (silica gel, pet. ether-ethyl acetate) to afford a yellow solid (1.8 g, 62% yield), m.p. 97°-98° C.