Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[NH:7][C:6](=[O:8])[N:5]([CH:9]([CH3:11])[CH3:10])[C:4](=[O:12])[CH:3]=1.[CH3:13][C@H:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCCCCC>O1CCOCC1>[CH:9]([N:5]1[C:4](=[O:12])[CH:3]=[C:2]([NH:21][C@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:13])[NH:7][C:6]1=[O:8])([CH3:11])[CH3:10]
Reactant: C[C@H](N)c1ccccc1
Reactant: CC(C)n1c(=O)cc(Cl)[nH]c1=O
Solvent: C1COCCO1
Solvent: CCCCCC
Product: CC(C)n1c(=O)cc(N[C@@H](C)c2ccccc2)[nH]c1=O
Temperature: 80 °C
Reaction time: 24 h
Yield: 68.9 %

Procedure:
To a solution of 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (1.3, 1.0 g, 5.31 mmol) in 1,4-dioxane (20 mL) was added (S)-α-methylbenzylamine (Sigma-Aldrich, 1.43 g, 11.7 mmol, 2.2 equiv). The reaction mixture was stirred at 80° C. for 24 h. After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The residual was taken up in EtOAc (70 mL) and washed with aqueous 1N HCl (2×50 mL) and brine (40 mL). The organic layer was dried with anhydrous Na2SO4 and then concentrated under reduced pressure to half the original volume to yield a precipitate. Hexane (20 mL) was added and the mixture was stirred at room temperature. The resulting solid was collected by filtration, washed with hexane (20 mL), and dried to yield 1.0 g (69%) of the title compound as a white solid. LC/MS: m/z (ES+) 274 (M+H)+.1H-NMR (400 MHz, d6-DMSO): δ 9.77 (s, 1H), 7.32 (m, 4H), 7.24 (m, 1H), 6.50 (d, J=6.8 Hz, 1H), 4.87 (m, 1H), 4.52 (m, 1H), 4.31 (d, J=6.8 Hz, 1H), 1.37 (m, 3H), 1.24 (m, 6H). 1H NMR (400 MHz, CD3OD) δ ppm 7.39-7.20 (m, 5H), 5.01 (m, 1H), 4.48 (m, 1H), 1.49 (d, J=6.7 Hz, 3H), 1.36 (m, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:15][C:14]3([CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28](O)=[O:29])[CH:21]=4)[O:16]3)[CH2:13]2)=[CH:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:45][O:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][O:48]1>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:15][C:14]3([CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28]([NH:45][O:46][CH:47]5[CH2:52][CH2:51][CH2:50][CH2:49][O:48]5)=[O:29])[CH:21]=4)[O:16]3)[CH2:13]2)=[CH:3]1
Reactant: Cn1cc(CN2CC3(CC(=O)c4cc(/C=C/C(=O)O)ccc4O3)C2)c2ccccc21
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: Cn1cc(CN2CC3(CC(=O)c4cc(/C=C/C(=O)NOC5CCCCO5)ccc4O3)C2)c2ccccc21
Yield: 45.5 %

Procedure:
A suspension of (E)-3-[1′-(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (180 mg, 0.447 mmol) in DCM (5 ml) was treated with TEA (0.09 ml, 0.67 mmol) and then with EDC (128 mg, 0.67 mmol), HOBt (90 mg, 0.67 mmol) and NH2OTHP (67 mg, 0.57 mmol) following the procedure described in Example 30, Step B, giving (E)-3-[1′(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (102 mg) as a white solid.
Reaction SMILES: C([O:4][C@@:5]1([CH2:38][CH3:39])[C:35]2[CH:34]=[C:33]3[N:11]([CH2:12][C:13]4[C:14]3=[N:15][C:16]3[C:17]5[C:18]=4[N:19]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:20]([N:26]([CH3:28])[CH3:27])=[N:21][C:22]=5[CH:23]=[CH:24][CH:25]=3)[C:10](=[O:36])[C:9]=2[CH2:8][O:7][C:6]1=[O:37])(=O)C.NN.[ClH:42]>CO.O1CCOCC1>[ClH:42].[CH3:28][N:26]([CH3:27])[C:20]1[N:19]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:18]2=[C:13]3[CH2:12][N:11]4[C:33](=[CH:34][C:35]5[C@:5]([CH2:38][CH3:39])([OH:4])[C:6](=[O:37])[O:7][CH2:8][C:9]=5[C:10]4=[O:36])[C:14]3=[N:15][C:16]3[C:17]2=[C:22]([CH:23]=[CH:24][CH:25]=3)[N:21]=1
Reactant: CC[C@@]1(OC(C)=O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cccc3c1c2N(CC(C)C)C(N(C)C)=N3
Agent: Cl
Agent: NN
Solvent: CO
Solvent: C1COCCO1
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cccc3c1c2N(CC(C)C)C(N(C)C)=N3
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of (9S)-9-acetoxy-2-(dimethylamino)-9-ethyl-1-(2-methylpropyl)-1H,12H-pyrano[3″,4″:6′,7′]indolizino[1′,2′:6,5]pyrido[4,3,2-de]quinazoline-10,13(9H,15H)-dione (8.7 mg, 0.023 mmol) in methanol (2 ml) and 1,4-dioxane(2 ml) cooled in an ice-bath was added anhydrous hydrazine (100 μl). The mixture was warmed to room temperature and stirred for 3 hr. 10% HCl in methanol was added dropwise to acidify the reaction mixture and the mixture was stirred at room temperature for 2 h. After concentrated under reduced pressure, the obtaining residue was purified by reversed phase column chromatography (water/methanol=1/0-1/2) to give the product (7.4 mg, 85%) as a yellow powder.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.[C:17]([CH2:19][N:20]([C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[NH:31][C:32]1[C:37]([Cl:38])=[CH:36][N:35]=[C:34](Cl)[N:33]=1)[S:21]([CH3:24])(=[O:23])=[O:22])#[N:18]>>[Cl:38][C:37]1[C:32]([NH:31][C@@H:26]2[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]2[N:20]([CH2:19][C:17]#[N:18])[S:21]([CH3:24])(=[O:23])=[O:22])=[N:33][C:34]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:35][CH:36]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CS(=O)(=O)N(CC#N)[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4N(CC#N)S(C)(=O)=O)n3)cc2CC1

Procedure:
N-((1R,2R)-2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-N-cyanomethyl-methanesulfonamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and N-cyanomethyl-N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 308c. Product isolated as a pale yellow foam (63 mg, 32%). LCMS (m/e) 562 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.89 (s, 1H), 7.30-7.19 (m, 2H), 7.07 (d, 1H, J=7.9 Hz), 5.39 (d, 1H, J=8.7 Hz), 4.12-3.63 (m, 4H), 3.56 (t, 2H, J=5.6 Hz), 3.38 (s, 3H), 3.01-2.91 (m, 4H), 2.97 (s, 3H), 2.84-2.68 (m, 6H), 2.36-2.26 (m, 1H), 2.18-2.09 (m, 1H), 2.02-184 (m, 2H), 1.72-1.57 (m, 1H), 1.50-1.30 (m, 3H).
Reaction SMILES: [CH2:1]([O:3]/[CH:4]=[CH:5]/[C:6](Cl)=[O:7])[CH3:2].[NH2:9][C:10]1[CH:30]=[CH:29][C:13]([CH2:14][C:15]2[NH:16][C:17](=[O:28])[C:18]3[N:23]([CH3:24])[N:22]=[C:21]([CH2:25][CH2:26][CH3:27])[C:19]=3[N:20]=2)=[CH:12][CH:11]=1>N1C=CC=CC=1>[CH3:24][N:23]1[C:18]2[C:17](=[O:28])[NH:16][C:15]([CH2:14][C:13]3[CH:29]=[CH:30][C:10]([NH:9][C:6](=[O:7])/[CH:5]=[CH:4]/[O:3][CH2:1][CH3:2])=[CH:11][CH:12]=3)=[N:20][C:19]=2[C:21]([CH2:25][CH2:26][CH3:27])=[N:22]1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(N)cc3)nc12
Reactant: CCO/C=C/C(=O)Cl
Solvent: c1ccncc1
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(NC(=O)/C=C/OCC)cc3)nc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(E)-3-ethoxyacryloyl chloride (J. Chem. Soc; 1958,153) (298 mg, 0.0022 mol), was added dropwise to an ice-cooled solution of 5-(4-aminobenzyl)-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one (600 mg, 0.002 mol) in pyridine (15 ml) and the reaction stirred at room temperature for 20 hours. The mixture was partitioned between water (30 ml) and dichloromethane (30 ml), the aqueous layer acidified to pH1 with 2M aqueous hydrochloric acid solution and then extracted with dichloromethane (2×40 ml). The combined organic extracts were dried (MgSO4), filtered and evaporated under reduced pressure, to give, after recrystallisation from ethyl acetate/methanol the title compound (483 mg), m.p.241-243° C.
Reaction SMILES: CN[C@@H:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4]N1CCCCC1.C([Li])CCC.[C:22]1(=[O:29])CCCC[CH:24]=[CH:23]1>CCOCC.[Cu]I>[CH2:16]([C@H:11]1[CH2:3][CH2:4][CH2:24][CH2:23][C:22](=[O:29])[CH2:12]1)[CH2:15][CH2:14][CH3:13]
Reactant: CN[C@H](CN1CCCCC1)c1ccccc1
Reactant: O=C1C=CCCCC1
Agent: [Cu]I
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[C@H]1CCCCC(=O)C1
Temperature: -65 °C
Reaction time: 0.08 h
Yield: 63.1 %

Procedure:
(S)-N-methyl-1-phenyl-2-(1-piperidinyl)ethanamine (348.4 mg, 1.60 mmol) was dissolved in ether (12 mL) and n-butyl lithium (2.5M in hexanes, 0.61 mL, 1.53 mmol) was added to the solution at -65° C. The solution was stirred for 5 min at -65° C., gradually (for 20 min) warmed to 0° C. and stirred for 10 min at 0° C. To a second flask was added CuI (254 mg, 1.33 mmol) and 10 mL of diethyl ether. This solution was cooled to -40° C. and treated with n-butyl lithium (0.51 mL, 1.28 mmol). The solution in the first flask was cooled to -35° C. and added via canula to the solution of n-BuCu in the second flask. The resulting solution was stirred for 15 min at -35° C., for 10 min at -30° C., and cooled to -78° C. After 30 min, 2-cycloheptenone (141 mg, 1.28 mmol) was added slowly at -78° C. The reaction mixture was quenched after 1 hr by adding 4N NH4Cl (15 mL) at -78° C. and extracted with ether (20 mL). The extract was washed with 1N HCl (15 mL), dried (Na2SO4) and concentrated. The oily residue was purified by column chromatography on silica gel (10:1=hexanes/ethyl acetate) to afford (S)-3-n-butylcycloheptanone (136 mg, 63% chemical yield, 96% ee, [α]D =-33.0 (c= 3.2, chloroform)).
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:23]([CH3:43])([CH3:42])[CH2:24][C:25](=[O:41])[C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]2[C:37](=[O:38])[O:36][N:35]=[C:34]([CH3:39])[C:33]=2[CH:40]=1)=[O:27].[SiH4]>CN(C=O)C.C(OCC)(=O)C>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:23]([CH3:43])([CH3:42])[CH2:24][C:25]([OH:41])([C:2]([F:4])([F:3])[F:1])[C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]2[C:37](=[O:38])[O:36][N:35]=[C:34]([CH3:39])[C:33]=2[CH:40]=1)=[O:27]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1noc(=O)c2ccc(NC(=O)C(=O)CC(C)(C)c3cc(F)ccc3Br)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [SiH4]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1noc(=O)c2ccc(NC(=O)C(O)(CC(C)(C)c3cc(F)ccc3Br)C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.7 %

Procedure:
0.23 ml (1.25 mmol) of trifluoromethyl(trimethyl)silane and 256 mg (0.79 mmol) of cesium carbonate are added at 0° C. to a solution of 290 mg (0.63 mmol) of 6-[4-(2-bromo-5-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one in 7 ml of DMF. After 24 hours, the same amount of silane and base are added and stirred for another 24 hours at room temperature. The batch is diluted with 150 ml of ethyl acetate, washed with water and saturated NaCl, dried (Na2SO4) and concentrated by evaporation in a vacuum. Purification by column chromatography of the residue on silica gel yields 230 mg of product.
Reaction SMILES: [C:1]([CH2:3][CH2:4][P:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])[O:6][CH2:7][CH3:8])#[N:2].N.[H][H]>C(O)C.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][P:5]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:9])[O:6][CH2:7][CH3:8]
Reactant: CCOP(=O)(CCC#N)c1ccccc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOP(=O)(CCCN)c1ccccc1

Procedure:
To 22.72 g of ethyl 2-cyanoethyl(phenyl)phosphinate in 400 ml of ethanol are added 34 g of liquid ammonia and 4.5 g of Raney-Nickel. The mixture is heated to 80° and treated with hydrogen at 100 bar. After 30 minutes hydrogen up-take stops. The reaction mixture is filtered and the filtrate distilled to give ethyl 3-aminopropyl(phenyl)phosphinate as a colorless oil, b.p. 110°/13 Pa.
Reaction SMILES: N[N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.O.[ClH:12].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=O>C(O)(C)C>[ClH:12].[CH:8]1[CH:7]=[CH:6][C:5]2[CH2:4][CH2:3][N:2]3[C:10]=2[C:9]=1[C:17]1[CH2:18][NH:13][CH2:14][CH2:15][C:16]=13
Reactant: O=C1CCCCN1
Reactant: NN1CCc2ccccc21
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: c1cc2c3c(c1)c1c(n3CC2)CCNC1
Yield: 72.9 %

Procedure:
A mixture of 1-amino-2,3-dihydroindole (1.0 g, 5.9 mmol), piperidone hydrochloride monohydrate (0.91 g, 5.9 mmol) and isopropanol (29 mL) was brought to reflux for 4 hours. The resulting brown solid was filtered and washed with cold diethylether (20 mL) and dried under Vacuum, affording the title compound (1.01 g, 74%). 1H NMR (CD3OD, 300 MHz) δ7.15 (d, 1H, J=7.7 Hz), 6.85-6.96 (m, 2H), 4.39-4.50 (m, 4H), 3.75 (t, 2H, J=7.3 Hz), 3.57 (t, 2H, J=6.2 Hz), 3.15 (t, 2H, J=6.2 Hz) ppm.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=4)=[N:18][N:17]4[CH2:27][CH2:28][CH2:29][C:16]=34)[CH:11]=2)[N:6]=[CH:5]1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH3:26][C:22]1[N:21]=[C:20]([C:19]2[C:15]([C:10]3[CH:11]=[C:12]4[C:7](=[CH:8][CH:9]=3)[N:6]=[CH:5][N:4]([CH2:3][CH2:2][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:13]4=[O:14])=[C:16]3[CH2:29][CH2:28][CH2:27][N:17]3[N:18]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: C1COCCN1
Reactant: Cc1cccc(-c2nn3c(c2-c2ccc4ncn(CCCl)c(=O)c4c2)CCC3)n1
Product: Cc1cccc(-c2nn3c(c2-c2ccc4ncn(CCN5CCOCC5)c(=O)c4c2)CCC3)n1
Temperature: 140 °C
Yield: 74 %

Procedure:
Combine 3-(2-chloro-ethyl)-6-[2-[6-methyl-(pyridin-2-yl)]-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-3H-quinazolin-4-one (Example 6; 30 mg, 0.07 mmol) and morpholine (1 mL) in a pressure tube. Seal the tube and place in a microwave reactor. Radiate the mixture and heat at 140° C. for 1 h. The crude product is purified with silica gel chromatography, using dichloromethane to 10:1 dichloromethane/methanol as eluting solvents to give 25 mg (74%) of the target compound. MS ES+ m/e 457.5 (M+1). 1H NMR (400 MHz, CD2Cl2) δ 8.3 (d, J=2.0 Hz, 1H), 8.0 (s, 1H), 7.7 (dd, J=8.0, 2 Hz, 1H), 7.6 (m, 2H), 7.5(d, J=7.6 Hz, 1H), 7.0 (d, J=8 Hz, 1H), 4.3 (t, J=7.2 Hz, 2H), 4.1 (t, J=5.6 Hz, 2H), 3.6 (m, 4H), 3.1 (t, J=6.8 Hz, 2H), 2.7 (m, 4H), 2.5 (m, 4H), 2.4 (s, 3H).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][O:27][CH:28]([CH3:33])[CH2:29][C:30](O)=[O:31]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:30](=[O:31])[CH2:29][CH:28]([O:27][CH3:26])[CH3:33])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: COC(C)CC(=O)O
Agent: Cl
Product: COC(C)CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (13.9 mg, 46.1%), MS (ISP) m/z=431.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.070 mmol) and 3-methoxybutanoic acid
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:1][CH2:2][N:10]=[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]1[OH:17]
Reactant: CC(=O)c1ccccn1
Reactant: Nc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: OC1C=CC=CC1=NCCc1ccccn1
Temperature: 140 °C
Reaction time: 72 h
Yield: 33 %

Procedure:
450 μl (3 mmol) of 2-acetylpyridine (reagent 1), 331 mg (3 mmol) of 2-aminophenol (reagent 2) and a few mg of para toluene sulfonic acid were dissolved in 20 mL of dry toluene. The reaction mixture was stirred at a temperature of 140° C. for a period of time of 3 days. The solution was evaporated to dryness. After a chromatography on silica gel (heptane/AcOEt 8:2), 208 mg of ligand L27 were obtained as yellow solid with a yield of 33%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([C@@:20]([O:37][SiH:38]([CH3:40])[CH3:39])([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:21][CH2:22][C:23]4[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=4[C:25]([CH:27]=[O:28])=[O:26])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[OH-:41].[K+]>CCO.O.[N+]([O-])([O-])=O.[Ag+]>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([C@@:20]([O:37][SiH:38]([CH3:40])[CH3:39])([C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:21][CH2:22][C:23]4[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=4[C:25]([C:27]([OH:41])=[O:28])=[O:26])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[SiH](C)O[C@](CCc1ccccc1C(=O)C=O)(c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1)C(C)(C)C
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C[SiH](C)O[C@](CCc1ccccc1C(=O)C(=O)O)(c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
To a solution of the aldehyde from Step 2 (14 g, 24.6 mmol) in EtOH (118 mL) was added a solution of AgNO3 (10 g, 59 mmol) predissolved in H2O (23 mL) followed by a solution of KOH (118 mL, 118 mmol of 1M) dropwise. The mixture was stirred at room temperature overnight. The bulk of the EtOH was removed by evaporation, the aqueous was acidified with 1N HCl (118 mL) and extracted with EtOAc twice (100 mL). The organic extracts were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography first with pure EtOAc then using 95:5 EtOAc: AcOH, to yield 5.0 g of the title compound. 1H NMR (CD3COCD3) d 0.15 (s, 6H), 0.95 (s, 9H), 2.0 (m, 2H), 2.95-3.18 (m, 2H), 4.95 (t, 1H), 7.35-7.65 (m, 8H), 7.75-7.97 (m, 5H), 8.0 (s, 1H), 8.32 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]([OH:17])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C1C=CC=CC=1.C(N(CC)C#CC)C.[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][C:43]=1[O:44][CH3:45])[C:40](=[CH:46][C:47]1[CH:52]=[C:51]([O:53][CH3:54])[C:50]([O:55][CH3:56])=[C:49]([O:57][CH3:58])[CH:48]=1)[NH:39][CH2:38][CH2:37]2>N1C=CC=CC=1>[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][C:43]=1[O:44][CH3:45])/[C:40](=[CH:46]/[C:47]1[CH:52]=[C:51]([O:53][CH3:54])[C:50]([O:55][CH3:56])=[C:49]([O:57][CH3:58])[CH:48]=1)/[N:39]([C:15](=[O:17])/[CH:14]=[CH:13]/[C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:38][CH2:37]2
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1OC
Reactant: COc1cc2c(cc1OC)C(=Cc1cc(OC)c(OC)c(OC)c1)NCC2
Agent: CC#CN(CC)CC
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)/C(=C/c1cc(OC)c(OC)c(OC)c1)N(C(=O)/C=C/c1cc(OC)c(OC)c(OC)c1)CC2

Procedure:
To a solution of 100 parts of 3-(3,4,5-trimethoxyphenyl)-2-propenoic acid in 1125 parts of benzene is added 22 parts of N,N-diethyl-1-propyne-1-amine. The resultant mixture is stirred for 2 hours, whereupon a solution of 75 parts of 3,4-dihydro-6,7-dimethoxy-1-[(3,4,5-trimethoxyphenyl)methylene]isoquinoline [Ber. deut. chem. Ges., 55, 2889 (1922)] in 200 parts of pyridine is introduced. The mixture thus obtained is stirred and heated at 65° for 3 hours, then cooled, consecutively washed with water and aqueous 5% sodium bicarbonate, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residue is crystallized from a mixture of ethyl acetate and ether to give (1Z,2E)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-[(3,4,5-trimethoxyphenyl)methylene]-2-[3-(3,4,5-trimethoxyphenyl)-1-oxo-2-propenyl]isoquinoline melting at 180°-183°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][OH:23])[C:11](=[O:26])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:28][CH:29]1[CH2:31][CH2:30]1.CC(C)([O-])C.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][O:23][CH2:28][CH:29]3[CH2:31][CH2:30]3)[C:11](=[O:26])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: BrCC1CC1
Reactant: CC[C@@H](CO)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](COCC1CC1)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1.48 g (3.77 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-14S)-1-hydroxybutan-2-yl)piperidin-2-one (Example 68, Step A) and bromomethylcyclopropane (0.828 mL, 7.54 mmol) in DMF (20 mL) was added sodium t-butoxide (0.544 g, 5.66 mmol) at 0° C. The mixture was stirred at 0° C. for 2 h and then warmed to rt. Then the reaction was stirred at rt for 14 h. The reaction was quenched with sat. aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with water and sat. aq. NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluent: 20%-40% EtOAc/Hexanes, gradient elution) provided the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[CH:18]=[CH:17][S:16][C:12]3=[CH:13][N+:14]=2[O-])=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH2:36]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH3:37]>CS(C)=O>[CH2:36]([N:38]1[CH2:43][CH2:42][N:41]([C:13]2[N:14]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:10]=[C:11]3[CH:18]=[CH:17][S:16][C:12]=23)[CH2:40][CH2:39]1)[CH3:37]
Reactant: COc1ccc(-c2cc3ccsc3c[n+]2[O-])cc1
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCN1CCN(c2nc(-c3ccc(OC)cc3)cc3ccsc23)CC1
Temperature: 0 °C

Procedure:
5-(4-Methoxyphenyl)thieno[2,3-c]pyridine-6-oxide (3.0 g) was reacted with phosphorus oxychloride (15 ml) at 100° C. for 3 hr. The reaction mixture was poured into ice-water, neutralized with sodium carbonate and extracted with ethyl acetate. The organic layer was washed with water and brine and dried. The extract was filtered through silica gel, and the column was washed with ethyl acetate. The filtrates were combined and concentrated. The resulting 7-chloro-5-(4-methoxyphenyl)thieno[2,3-c]pyridine (2.1 g) was reacted reacted in N-ethylpiperazine (5 ml) and dimethyl sulfoxide (20 ml) with potassium carbonate (5.0 g) at 100° C. for 1 day. The reaction solution was evaporated, and the resulting residue was partitioned between ethyl acetate and water and extracted with ethyl acetate. The organic layer was washed with water and dried. Then, the solvent was removed, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 0.93 g of the title compound of as a pale brown oil.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH:6]1[C:14]2[C:13]3C=C[CH:17]=[CH:18][C:12]=3[S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.C(I)C.Cl>C1COCC1>[CH2:3]([C:2]1[C:1]2[S:11][C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:14]=3[C:13]=2[CH:12]=[CH:18][CH:17]=1)[CH3:4]
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)sc1ccccc12
Agent: Cl
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1cccc2c1sc1ccccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
n-Butyllithium (108 mmols, 46 ml of 2.4M solution in hexane) was added to a stirred solution of dibenzothiophene (10 g, 54 mmole) in dried THF (150 ml) at 0° C. over a period of 1 hr under dry N2 atmosphere. This reaction mixture was stirred 5 hrs at room temperature then the reaction mixture was cooled to −70° C. and a solution of ethyl iodide in dry THF was added dropwise and stirred at room temperature for over night. This reaction mixture was poured slowly into a cold 1N HCl (200 ml). Organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×500 ml). Organic layers mixed together and concentrated to dryness to get crude product. The crude product was purified by silica gel column chromatography.