Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]2[C:10]3([CH2:20][O:21][C:6]=2[CH:5]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11]3=[O:19].Br[C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2C=1C1(C3=CC4OCOC=4C=C3OC1)[C:28](=O)[NH:29]2.Br.BrCC1C=NC=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[N:29]1[CH:30]=[CH:31][CH:32]=[C:33]([CH2:25][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]3([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:5][C:6]=4[O:21][CH2:20]3)[C:11]2=[O:19])[CH:28]=1
Reactant: O=C1Nc2ccccc2C12COc1cc(OC(F)(F)F)ccc12
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Agent: Br
Agent: BrCc1cccnc1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2cccnc2)c2ccccc2C12COc1cc(OC(F)(F)F)ccc12

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using 6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 3-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1′-(pyridin-3-ylmethyl)-6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained, which was treated with 4.0 M HCl in dioxane to give the title compound (70%) as a white solid: mp 151-153° C.; 1H NMR (300 MHz, CD3OD) δ 9.07-8.61 (m, 3H), 8.19-8.04 (m, 1H), 7.42-6.71 (m, 7H), 5.28 (s, 2H), 5.05 (d, 1H), 4.86 (d, 1H); 13C NMR (75 MHz, CD3OD) δ 179.43, 163.5, 151.8, 147.0, 142.9, 142.4, 142.2, 133.0, 130.6, 129.3, 128.9, 125.5, 125.4, 125.3, 114.9, 110.5, 104.9, 82.0, 58.9, 42.0; MS (ES+) m/z 413 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.[CH:23]1([CH2:26][O:27][C:28]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:29]=2[CH:30]=O)[CH2:25][CH2:24]1.[O-]CC.[Na+]>C(O)C>[CH:23]1([CH2:26][O:27][C:28]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:29]=2/[CH:30]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:22][CH:21]=[CH:20][N:5]3[C:6](=[O:19])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:17])([F:18])[F:16])=[CH:10][CH:9]=2)[CH2:24][CH2:25]1
Reactant: O=Cc1cccc(F)c1OCC1CC1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1c(-c2ccc(OC(F)(F)F)cc2)c(/C=C/c2cccc(F)c2OCC2CC2)nc2sccn12
Yield: 44.8 %

Procedure:
The title compound was synthesized by condensation of Intermediate 15 (350 mg, 1.071 mmol) with 2-cyclopropylmethoxy-3-fluorobenzaldehyde (291 mg, 1.501 mmol) in presence of sodium ethoxide (146 mg, 2.147 mmol) in ethanol (15 ml) according to the procedure outlined in Example 24 to give 241 mg of the desired product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 0.23 (d, J=4.8 Hz, 2H), 0.48 (d, J=6.6 Hz, 2H), 0.95-1.05 (m, 1H), 3.77 (d, J=6.9 Hz, 2H), 7.00-7.09 (m, 2H), 7.15-7.23 (m, 2H), 7.42-7.50 (m, 4H), 7.53 (d, J=4.8 Hz, 1H), 7.98-8.08 (m, 2H); ESI-MS (m/z) 503.55 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)(=[O:3])[NH2:2].[ClH:21].O>C(OCC)(=O)C>[ClH:21].[ClH:21].[N:8]1([CH2:7][CH2:6][O:5][CH2:4][C:1]([NH2:2])=[O:3])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOCC(N)=O)CC1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=O)COCCN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
1.4 g (0.005 mol) of tert-butyl 4-(2-carbamoylmethoxyethyl)piperazine-1-carboxylate prepared in Example I.4.1. and 14 ml of a 3M solution of hydrochloric acid in ethyl acetate are introduced into a 50 ml three-necked round-bottomed flask fitted with a water-cooled condenser and a mechanical stirrer. The mixture is stirred at room temperature for 2 hours. The precipitate is filtered off and is washed with ethyl acetate. 1.3 g (100%) of 2-(1-piperazinyl)ethoxyacetamide dihydrochloride are obtained.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([OH:13])[CH:3]=1.[I:14]Cl.O.S([O-])([O-])=O.[Na+].[Na+]>CCCCCCC>[F:1][C:2]1[C:12]([I:14])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([OH:13])[CH:3]=1
Reactant: CCOC(=O)c1ccc(F)cc1O
Reactant: ClI
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCCC
Product: CCOC(=O)c1cc(I)c(F)cc1O
Reaction time: 1 h

Procedure:
Ethyl 4-fluoro-2-hydroxybenzoate (10.2 g, 55 mmol)) was dissolved in n-heptane. Iodo monochloride (12 g, 74 mmol) was added dropwise at ambient temperature with stirring. After 1 h, water was added and then solid sodium sulfite in small portions until the suspension was decolourized. More n-heptane was added to clear solution and the phases separated. The organic phase was dried and concentrated. The product crystallized on cooling. It was collected by filtration and washed with cold n-heptane. The crude yield was 10 g. The product was a mixture of ethyl 4-fluoro-2-hydroxy-5-iodobenzoate (about 80%) and the 5 chloro analogue (about 20%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].[NH:24]1[C:32]2[C:27](=[CH:28][C:29]([C:33](O)=[O:34])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][O:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:33]([C:29]3[CH:28]=[C:27]4[C:32](=[CH:31][CH:30]=3)[NH:24][CH:25]=[CH:26]4)=[O:34])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1ccc2[nH]ccc2c1

Procedure:
According to the general method of Example 50, 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine and indole-5-carboxylic acid were combined to provide N5-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-5-indolecarboxamide as an off white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.34 (t, J=5.5 Hz, 1H), 8.06 (m, 2H), 7.63-7.58 (m, 2H), 7.42-7.38 (m, 3H), 7.22 (t, J=7.1 Hz, 1H), 6.67 (broad s, 2H), 6.50 (s, 1H), 4.58 (m, 2H), 3.81 (t, J=6.6 Hz, 2H), 3.34 (m, 2H), 3.25 (s, 3H), 3.21 (t, J=6.6 Hz, 2H), 1.89 (m, 2H), 1.72 (m,2H); MS (EI) m/e 456.2264 (456.2274 calcd for C26H28N6O2).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[C:8]([CH3:21])([CH3:20])[CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:28][NH:29][CH3:30]>O1CCCC1.O>[CH3:20][C:8]1([CH3:21])[C:9]2[C:14](=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([O:18][CH3:19])[CH:10]=2)[N:5]([C:3](=[O:4])[CH2:2][N:29]([CH3:30])[CH3:28])[CH2:6][CH2:7]1
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CBr)CCC2(C)C
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CN(C)C)CCC2(C)C

Procedure:
A solution of 1-(bromoacetyl)-4,4-dimethyl-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroquinoline (1.0 g, 2.8 mmol) in tetrahydrofuran (35 mL) was treated with potassium carbonate (1.3 g, 9.4 mmol) and dimethyl amine (10 mL, 20 mmol, 2 M in THF, Aldrich). The mixture was heated in sealed tube at 55° C. for 1h, cooled, diluted with water, and extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated to give {2-[4,4-dimethyl-6-(methyloxy)-7-nitro-3,4-dihydro-1(2H)-quinolinyl]-2-oxoethyl}dimethylamine which was taken directly to the next step. ESIMS (M+H)+=322.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C:5]([CH3:8])([CH3:7])[C@@H:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[O:3]1>CCOC(C)=O.CC(O)C.[Pd]>[CH3:1][C:2]1([CH3:18])[O:3][C@H:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[C:5]([CH3:8])([CH3:7])[O:6]1
Reactant: CC1(C)O[C@H](c2ccc([N+](=O)[O-])cc2)C(C)(C)O1
Agent: [Pd]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC1(C)O[C@H](c2ccc(N)cc2)C(C)(C)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.1 %

Procedure:
A mixture of (R)-2,2,4,4-tetramethyl-5-(4-nitrophenyl)-1,3-dioxolane (200 mg, 0.797 mmol) and Pd/C (10%, 60 mg) in EtOAc/IPA (10 mL/10 mL) was stirred under 1 atm H2 atmosphere (balloon) at RT for 16 h. The mixture was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford the desired product (180 mg, 100%), which was directly used into the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][C@H:9]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[C:10]2=O)=[CH:6][CH:5]=1)[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]1[CH:12]=[C:11]2[C:7](=[CH:6][CH:5]=1)[CH2:8][C@H:9]([NH:14][C:15](=[O:20])[C:16]([F:18])([F:17])[F:19])[CH2:10]2)[CH3:2]
Reactant: CCOc1ccc2c(c1)C(=O)[C@@H](NC(=O)C(F)(F)F)C2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc2c(c1)C[C@@H](NC(=O)C(F)(F)F)C2

Procedure:
N-t(2S)-6-Ethoxy-2,3-dihydro-1-oxo-1H-inden-2-yl]-2,2,2-trifluoroacetamide (V, EXAMPLE 4, 5.75 g, 20 mmol) is dissolved in 28.8 ml of trifluoroacetic acid and triethylsilane (9.6 ml, 60 mmol, 3 equiv.) is added. The reaction mixture is heated at reflux for 3 hr and then concentrated under reduced pressure. The product is partitioned between saturated sodium carbonate (30 ml) and ethyl acetate (60 ml). The organic layer is collected and concentrated to a solid. The solid is purified by flash chromatography eluting with ethyl acetate/hexane (3/7) to give the title compound; TLC Rf=0.64 (ethyl acetate/hexane; 30/70)) NMR δ7.12, 6.75, 6.48, 4.76, 4.01, 3.32, 2.81 and 1.40; CMR δ58.7, 156.8, 141.2, 131.4, 125.4, 116.4, 113.8, 110.9, 63.6, 51.6, 39.9, 38.8 and 14.8; FMR (DMSO-d6) δ74.5. MS (CI, NH3) m/z (relative intensity) 291 (100), 273 (10), 243 (20), 160 (30), 132 (20). HRMS (FAB) calculated for C13H12F3NO2 [M+1]=272.0898, found=272.0896.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[N:37]([C:38]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:36]=[N:35][N:34]=2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:7]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:37]([C:38]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:36]=[N:35][N:34]=3)=[CH:25][CH:26]=2)[C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCn1c(=O)[nH]c(Cl)c(-c2ccccc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1c(=O)c(-c2ccccc2)c(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 47.9 %

Procedure:
A mixture of 6-chloro-5-phenyl-3-propyl-pyrimidine-2,4(1H,3H)-dione (0.5 g), 4-bromomethyl-2'-(N-trityltetrazol-5yl)biphenyl (1.11 g) and potassium carbonate (0.32 g) in DMF (20 ml) was stirred at room temperature for 22 hours. The reaction mixture was concentrated to dryness in vacuo and then the residue was dissolved in methylene chloride. The insoluble material was removed from the reaction mixture by filtration and the filtrate was concentrated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless amorphous powders (0.67 g, 48%).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[NH:11][C:10]3[CH:13]=[N:14][C:15]([C:17]([OH:19])=[O:18])=[N:16][C:9]=3[C:8]=2[CH:7]=[C:6]([N+:20]([O-:22])=[O:21])[CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH2:28](O)[CH3:29]>>[CH2:28]([O:18][C:17]([C:15]1[N:14]=[CH:13][C:10]2[NH:11][C:12]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([N+:20]([O-:22])=[O:21])=[CH:7][C:8]=3[C:9]=2[N:16]=1)=[O:19])[CH3:29]
Reactant: CCO
Reactant: O=C(O)c1ncc2[nH]c3c([N+](=O)[O-])cc([N+](=O)[O-])cc3c2n1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ncc2[nH]c3c([N+](=O)[O-])cc([N+](=O)[O-])cc3c2n1

Procedure:
Under argon, 0.2 g of 6,8-dinitro-5H-pyrimido[5,4-b]indole-2-carboxylic acid (Example 8) is refluxed in 20 ml of ethanol with the addition of 1 ml of concentrated sulfuric acid for 8 hours. Subsequently the solution is concentrated to half the quantity and dissolved in methylene chloride. The solution is washed first with water, then with sodium bicarbonate solution, and finally again with water, dried, and concentrated, yielding 0.18 g of 6,8-dinitro-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester, mp 295°-299° C.
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][CH2:8][N:9]([C:16]1[C:21]([N+:22]([O-])=O)=[CH:20][N:19]=[C:18]([Cl:25])[N:17]=1)[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)(C)(C)C.C(O)C.Cl>C(OCC)(=O)C.O>[Cl:25][C:18]1[N:19]=[CH:20][C:21]2[NH:22][C:6](=[O:5])[CH2:7][CH2:8][N:9]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:16]=2[N:17]=1
Reactant: CC(C)(C)OC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCCC1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CCN(C2CCCCC2)c2nc(Cl)ncc2N1
Reaction time: 8 h
Yield: 41.9 %

Procedure:
A solution of 1.53 g (0.004 mole) of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclohexyl-amino]-propionic acid tert-butyl ester (IV-20) in 20 mL of ethyl acetate was added in portions over 10 minutes to a mixture of 2.69 g (0.012 mole) of stannous chloride dihydrate, 12 mL of ethanol and 0.5 mL of hydrochloric acid. The mixture was stirred overnight and then diluted with 30 mL of water and extracted with ethyl acetate. The ethyl acetate extract was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (100:0-92:8) to give 0.47 g of 2-chloro-9-cyclohexyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-20).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[C:10]([CH3:12])[CH:11]=2)[N:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:21][O:22][CH2:23][CH:24]([NH2:28])[CH2:25][O:26][CH3:27].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:9]1[N:4]2[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([NH:28][CH:24]([CH2:25][O:26][CH3:27])[CH2:23][O:22][CH3:21])[C:3]2=[CH:11][C:10]=1[CH3:12]
Reactant: Cc1cc(Br)c2cc(C)c(-c3ccc(Cl)cc3Cl)n2n1
Reactant: COCC(N)COC
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: COCC(COC)Nc1cc(C)nn2c(-c3ccc(Cl)cc3Cl)c(C)cc12
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-7-(2,4-dichlorophenyl)-2,6-dimethylpyrrolo[1,2-b]pyridazine (0.143 g, 0.387 mmol), 1,3-dimethoxypropan-2-amine (0.092 g, 0.774 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-1,1′-biphenyl-2-amine (0.011 g, 0.029 mmol), Cs2CO3 (0.176 g, 0.542 mmol) and Pd2(dba)3 (0.018 g, 0.02 mmol) in DME (5.0 mL) is refluxed for 24 h. After cooling to room temperature, to the mixture is added 1,3-dimethoxypropan-2-amine (0.092 g, 0.774 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-1,1′-biphenyl-2-amine (0.011 g, 0.029 mmol) and Pd2(dba)3 (0.018 g, 0.02 mmol). The mixture is refluxed for another 24 h. After cooling to room temperature, the mixture is filtered and washed with EtOAc. The filtrate is concentrated in vacuo to dryness, the residue is subjected to preparative TLC (silica gel, 1/5 EtOAc/heptane) to give 0.07 g (44%) of light yellow solid as the title compound: mp 154–155° C. (CH2Cl2/heptane); 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J=2.0 Hz, 1H), 7.41 (d, J=8.3 Hz, 1H), 7.36 (d, J=8.3, 2.0 Hz, 1H), 6.35 (s, 1H), 5.65 (s, 1H), 4.88 (d, J=8.4 Hz, 1H), 3.91–3.82 (m, 1H), 3.69–3.66 (m, 2H), 3.61–3.55 (m, 2H), 3.45 (s, 3H), 3.44 (s, 3H), 2.33 (s, 3H), 2.21 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 150.4, 142.4, 136.4, 134.3, 134.1, 129.6, 129.3, 126.8, 123.3, 120.6, 119.3, 95.1, 88.0, 70.9, 59.3, 51.3, 22.4, 12.3; IR (diffuse reflectance) 3336, 2924, 1560, 1490, 1372, 1330, 1192, 1113, 1098, 1078, 1051, 961, 821, 811, 778 cm−1; MS (EI) m/z 407 (M+), 409 (M+); HRMS (FAB) calcd for C20H23Cl2N3O2+H 408.1245, found 408.1244; Anal. Calcd for C20H23Cl2N3O2: C, 58.83; H, 5.68; N, 10.29. Found: C, 58.90; H, 5.78; N, 10.13.
Reaction SMILES: C(=[N:14][C:15]1[CH:16]=[CH:17][C:18](=[O:27])[N:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:20]=1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:28]>O1CCCC1>[ClH:28].[NH2:14][C:15]1[CH:16]=[CH:17][C:18](=[O:27])[N:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:20]=1
Reactant: O=c1ccc(N=C(c2ccccc2)c2ccccc2)cn1-c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: Nc1ccc(=O)n(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-(Benzhydrylideneamino)-1-phenyl-1H-pyridin-2-one (72.0 mg) was dissolved in tetrahydrofuran (3 ml), and aqueous HCl (2 M, 1.0 ml) was added while stirring at rt. The yellow color was faded. After 30 min, the reaction mixture was partitioned between aqueous HCl (1 M, 8 ml) and 40% EtOAc/hexane (15 ml). The aqueous layer was extracted with 40% EtOAc/hexane (15 ml), and the aqueous phase was then concentrated in vacuo to the title compound as beige foam. 1H NMR (DMSO-d6, 400 MHz): δ=6.62 (d, 1H, J=10.0 Hz), 7.42-7.59 (m, 6H), 7.90 (d, 1H, J=2.8 Hz), 10.34 (brs, 2H). MS(ES+): m/z 187.22 (100) [MH+]. HPLC: tR=0.52 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([OH:11])C>>[C:1]([O:11][CH3:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CCO
Product: COC(=O)c1ccccc1

Procedure:
Substantially the same procedure as in Example 7 was repeated, except that the activated catalyst prepared in Example 4 was used, that benzaldehyde was used instead of the methacrolein, and that ethanol was used instead of the methanol, to thereby effect a reaction for producing methyl benzoate. Analysis was made with respect to the reaction mixture which was withdrawn from the outlet of the reactor 10 hours after the start of the reaction. As a result, it was found that the conversion of benzaldehyde was 76.2%, and the selectivity for methyl benzoate was 93.2%.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15](C1NN=CC=1)[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[N:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[N:35][CH:34]=1>>[C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([C:37]1[CH:38]=[N:33][CH:34]=[N:35][CH:36]=1)[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc2nc(-c3ccn[nH]3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: OB(O)c1cncnc1
Product: Cc1cc2nc(-c3cncnc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyrimidin-5-yl)quinolin-6-yl)acetic acid (87) was prepared following the procedure used for (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(1H-pyrazol-5-yl)quinolin-6-yl)acetic acid of Example 70 except that pyrimidin-5-ylboronic acid was used instead of 1H-pyrazol-5-ylboronic acid. 1H-NMR: 400 MHz, (CD3CN) δ: 9.52 (br s, 2 H), 9.26 (s, 1 H), 8.00 (s, 1H), 7.90 (d, J=8.8 Hz, 1 H), 7.83 (d, J=9.2 Hz, 1 H), 7.60 (m, 3 H), 7.37 (d, J=7.6 Hz, 1 H), 5.27 (s, 1 H), 2.65 9s, 3 H), 0.99 (s, 9 H). LCMS-ESI+ (m/z): [M+H]+ calcd for C26H25ClN3O3: 462.15. found: 462.45.
Reaction SMILES: C(N(CC)CC)C.C1COCC1.[NH2:13][C:14]1[C:15]([S:23][CH3:24])=[N:16][C:17]([CH3:22])=[CH:18][C:19]=1[S:20][CH3:21].[Br:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30]>O>[Br:25][CH2:26][CH2:27][CH2:28][C:29]([NH:13][C:14]1[C:15]([S:23][CH3:24])=[N:16][C:17]([CH3:22])=[CH:18][C:19]=1[S:20][CH3:21])=[O:30]
Reactant: O=C(Cl)CCCBr
Reactant: CSc1cc(C)nc(SC)c1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CSc1cc(C)nc(SC)c1NC(=O)CCCBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
Triethylamine (206 mg, 2.04 mmol) was added to a THF (6 ml) solution of 3-amino-2,4-bis(methylthio)-6-methylpyridine (341 mg, 1.70 mmol), and 4-bromobutanoyl chloride (379 mg, 2.04 mmol) was then slowly added thereto dropwise while being cooled with ice. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 75 g, eluent—hexane:acetone=5:1→3:1) to obtain 390 mg (yield 66%) of 4-bromo-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]butanamide as a colorless crystal (melting point: 139 to 140° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])/[C:5](/[O:16][CH2:17][CH3:18])=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)[CH3:2].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])[O:25][C:26]=1[CH3:27]>>[CH2:1]([O:3][C:4](=[O:19])/[C:5](/[O:16][CH2:17][CH3:18])=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[O:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccc2[nH]ccc2c1)OCC
Reactant: COc1ccccc1-c1nc(CCl)c(C)o1
Product: CCOC(=O)/C(=C/c1ccc2c(ccn2Cc2nc(-c3ccccc3OC)oc2C)c1)OCC

Procedure:
In analogy to the procedures described in examples 36a) and 36b), (Z)-2-ethoxy-3-(1H-indol-5-yl)-acrylic acid ethyl ester [preparation 1a)] was reacted with 4-chloromethyl-2-(2-methoxy-phenyl)-5-methyl-oxazole to give (Z)-2-ethoxy-3-{1-[2-(2-methoxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-5-yl}-acrylic acid ethyl ester, which was subsequently saponified to yield (Z)-2-ethoxy-3-{1-[2-(2-methoxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-5-yl}-acrylic acid as colorless solid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]([CH2:14][CH:15]([O:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:16])[CH2:12][OH:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C.Cl>ClCCl>[C:1]([O:9][CH2:10][CH:11]([CH2:14][CH:15]([O:17][C:18](=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:16])[CH2:12][O:13][S:27]([CH3:26])(=[O:29])=[O:28])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(CC(CO)COC(=O)c1ccccc1)OC(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CC(COC(=O)c1ccccc1)COS(C)(=O)=O)OC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice cooled solution of 1.85 g (5.60 mM) of 2-(2-benzoyloxypropan-1-yl)-3-hydroxy-propyl benzoate m5 in 40 ml of dichloromethane are added 0.607 ml (7.84 mM) of methanesulfonyl chloride and 1.34 ml (9.52 mM) of triethylamine. After stirring at 0° C. for 30 minutes, the mixture is poured into an ice cooled 2N aqueous hydrochloric acid and the product is isolated by dichloromethane extraction. The dichloromethane layer is washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate. Evaporation of the solvent gives the crude product of the titled compound m11'.