Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1.Cl.[C:12]1([O:20][CH3:21])[C:13](=[CH:16][CH:17]=[CH:18][CH:19]=1)[O:14][CH3:15]>>[CH3:15][O:14][C:13]1[CH:16]=[C:17]([CH:18]=[CH:19][C:12]=1[O:20][CH3:21])[CH2:2][C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1
Reactant: COc1ccccc1OC
Reactant: O=c1[nH]cc(CO)c(=O)[nH]1
Agent: Cl
Product: COc1ccc(Cc2c[nH]c(=O)[nH]c2=O)cc1OC

Procedure:
A solution of 5.0 g of 5-hydroxymethyluracil, 150 ml of veratrole and 0.5 ml of concentrated hydrochloric acid was heated at 140° C. for one hour. The precipitate was filtered, washed with ether and recrystallized from hot methanol, 6.85 g, M+ 263.20.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]1[C:15]2[CH:14]=[CH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1>C(Cl)(Cl)Cl>[C:1]([N:10]1[C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[CH:13]=[CH:14][C:15]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]1=2)(=[O:3])[CH3:2]
Reactant: C1=Cc2ccccc2Nc2ccccc21
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)N1c2ccccc2C=Cc2ccccc21
Yield: 94 %

Procedure:
Acetyl chloride (11.0 ml) was added to a chloroform (250 ml) solution of 5H-dibenzo[b,f]azepine (25.0 g) under ice-cooling. The solution was heated under reflux for 30 minutes, then allowed to cool. The organic phase was washed with a saturated sodium bicarbonate aqueous solution, water, and saturated brine; dried over anhydrous sodium sulfate; and filtered. The filtrate was concentrated, and the resulting residue was recrystallized from ethyl acetate-hexane to obtain N-acetyl-5H-dibenzo[b,f]azepine (28.6 g; yield, 94%) as a white solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1.[CH:35]([S:37]([CH:40]=C)(=[O:39])=[O:38])=[CH2:36].Cl.C(OCC)C>C(Cl)Cl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([CH:29]5[CH2:34][CH2:33][N:32]([CH2:36][CH2:35][S:37]([CH3:40])(=[O:39])=[O:38])[CH2:31][CH2:30]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2cc(C4CCNCC4)ccc2OCC3)c(F)c1
Reactant: C=CS(=O)(=O)C=C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CS(=O)(=O)CCN1CCC(c2ccc3c(c2)-c2nn(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1

Procedure:
Following the procedure for 152, 2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperidin-4-yl-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride was reacted with vinyl sulfone. The crude product was dissolved in DCM and treated with 4N HCl. After stirring for 10 min diethyl ether was added and the solid precipitate collected by filtration to give 175 as a white solid. 1H NMR (400 MHz, DMSO-d): δ 10.63 (s, 1H); 8.45 (s, 1H); 8.30 (s, 1H); 7.85 (td, J=8.75, 5.90 Hz, 1H); 7.72 (t, J=9.62 Hz, 1H); 7.42 (t, J=8.57 Hz, 1H); 7.22 (d, J=2.33 Hz, 1H); 7.11 (dd, J=8.45, 2.37 Hz, 1H); 6.97 (d, J=8.34 Hz, 1H); 4.22 (t, J=5.02 Hz, 2H); 3.82 (t, J=7.50 Hz, 2H); 3.76-3.63 (m, 2H); 3.59 (d, J=9.30 Hz, 2H); 3.16 (s, 3H); 3.14 (m, 2H); 3.06 (t, J=5.04 Hz, 2H); 2.66 (s, 1H); 1.96-1.76 (m, 4H). LCMS: RT=7.54 min, M+H+=555
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:13][CH:12]=[C:11]([CH:23]=[O:24])[C:10]2=[O:25])=[O:5])[CH3:2].S(=O)(=O)([OH:28])N.Cl([O-])=O.[Na+]>ClCCl.O>[CH2:1]([O:3][C:4]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:13][CH:12]=[C:11]([C:23]([OH:28])=[O:24])[C:10]2=[O:25])=[O:5])[CH3:2]
Reactant: NS(=O)(=O)O
Reactant: CCOC(=O)Oc1cc2occ(C=O)c(=O)c2cc1OC(=O)OCC
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Oc1cc2occ(C(=O)O)c(=O)c2cc1OC(=O)OCC

Procedure:
The compound (1.05 g) obtained in (b) of Example 1 was dissolved in 31.5 ml of dichloromethane, and a solution of 1.05 g of sulfamic acid in 18.9 ml of water was added at 10° C. with stirring. Then, a solution of 525.6 mg of sodium chlorite in 1.2 ml of water was added. The solution was stirred at the same temperature for 1 hour, and allowed to separate. The dichloromethane layer was washed with water (once) and then with a saturated aqueous solution of sodium chloride (twice), and dried over magnesium sulfate. The solvent was distilled off, and ethyl ether was added to the residue to solidify it. The solidified product was collected by filtration, and dried to afford 950 mg of the desired product.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[O:10]1[CH:14]=[CH:13][CH2:12][CH2:11]1>O1CCOCC1>[O:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: C1=COCC1
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Yield: 55 %

Procedure:
Into 30 ml of dioxane were suspended 1.3 g of 5-fluorouracil. To this suspension were added 1.4 g of 2,3-dihydrofuran and the mixture was reacted in an autoclave for 5 hours at 170° C. After completion of the reaction, the reaction liquid was treated in the same manner as described in Example 1 whereby 0.40 g of the starting 5-fluorouracil was recovered as a substance insoluble in chloroform and 1.10 g of 1-(2-tetrahydrofuryl)-5-fluorouracil was obtained. The yield of the end product was 79.5% based on the consumed 5-fluorouracil.
Reaction SMILES: O[C:2]1([C:23]([F:26])([F:25])[F:24])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][S:13]([C:10]1[CH:9]=[CH:8][C:7]([N:5]2[CH:6]=[C:2]([C:23]([F:26])([F:25])[F:24])[N:3]=[C:4]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:14])=[O:15]
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccccn2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccccn2)cc1
Yield: 64.9 %

Procedure:
A mixture of 2-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine from step 2 (1.0 g, 2.6 mmol) and p-toluenesulfonic acid monohydrate (0.2 g, 2.7 mmol) in toluene (100 ml) was heated to reflux for 24 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude mixture (1.2 g) was purified by chromatography on silica gel using ethyl acetate/toluene (1/1) to give pure 2-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine (620 mg, 65%) as a white solid: mp (DSC) 184° C. Anal. Calc'd. for C16H12N3SO2F3: C, 52.30, H, 3.29, N, 11.44. Found: C, 52.23, H, 3.23, N, 11.19.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:39])[CH2:41][OH:42])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)cc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f45) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl.Cl.[CH3:16][N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([NH2:26])[C:20]=2[N:19]=[CH:18]1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:26][C:25]2[C:20]3[N:19]=[CH:18][N:17]([CH3:16])[C:21]=3[CH:22]=[CH:23][CH:24]=2)[CH:7]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: Cn1cnc2c(N)cccc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1cccc2c1ncn2C
Yield: 61.5 %

Procedure:
A heavy walled resealable tube, was charged with ethyl 4,6-dichloropyridazine-3-carboxylate (500 mg, 2.26 mmol) and 1-methyl-1H-benzo[d]imidazol-4-amine dihydrochloride (498 mg, 2.26 mmol) in acetonitrile (3.5 mL) with stirring. DIPEA (877 mg, 1.19 mL, 6.79 mmol) was added and the tube was heated with stirring in an oil bath at 80° C. for 24 h. Solvents evaporated and crude purified by flash chromatography (silica 20-45 μM, 80 g, Thomson, 0 to 20% acetone in dichloromethane, 20 min) to give ethyl 6-chloro-4-(1-methyl-1H-benzo[d]imidazol-4-ylamino)pyridazine-3-carboxylate (461 mg, 1.39 mmol, 61%) as a light yellow solid. 1H NMR (CHLOROFORM-d) δ: 10.42 (s, 1H), 7.92 (s, 1H), 7.30-7.45 (m, 2H), 7.23-7.28 (m, 1H), 7.20 (s, 1H), 4.59 (q, J=7.1 Hz, 2H), 3.91 (s, 3H), 1.51 (t, J=7.2 Hz, 3H); LC-MS 332.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([N:28]([C:32]2[CH:42]=[C:41]([CH3:43])[C:35]3[N:36]([CH3:40])[C:37](=[O:39])[O:38][C:34]=3[CH:33]=2)[C:29](=[O:31])[CH3:30])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[CH3:40][N:36]1[C:35]2[C:41]([CH3:43])=[CH:42][C:32]([N:28]([C:24]3[CH:23]=[C:22]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[N:27]=[CH:26][N:25]=3)[C:29](=[O:31])[CH3:30])=[CH:33][C:34]=2[O:38][C:37]1=[O:39]
Reactant: CC(=O)N(c1cc(C)c2c(c1)oc(=O)n2C)c1cc(Cl)ncn1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(N(C(C)=O)c4cc(C)c5c(c4)oc(=O)n5C)ncn3)CC1)C(=O)N2
Temperature: 80 °C

Procedure:
59 mg (0.21 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 65 mg (0.19 mmol) N-(6-chloro-pyrimidin-4-yl)-N-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-yl)-acetamide and 81 mg (0.59 mmol) potassium carbonate in 1.5 mL NMP were combined and stirred at 80° C. The reaction mixture was purified by preparative HPLC. The product-containing fractions were combined and evaporated down. The solid obtained was washed with diethyl ether and dried.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][CH3:20])[N:13]=1.[OH-].[Na+]>CC#N.O>[Cl:11][C:12]1[N:13]=[C:14]([NH:19][CH3:20])[N:15]=[C:16]([NH:1][C@@H:2]2[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]2)[N:17]=1
Reactant: CNc1nc(Cl)nc(Cl)n1
Reactant: N[C@H]1CC[C@@H](C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CNc1nc(Cl)nc(N[C@H]2CC[C@@H](C(=O)O)CC2)n1
Reaction time: 3 h

Procedure:
Commercially available cis-4-aminocyclohexanecarboxylic acid (17.46 mmol) was added to the above crude solution of 4,6-dichloro-N-methyl-1,3,5-triazin-2-amine in CH3CN:H2O (1:1, 28.6 mL). The reaction mixture was stirred at room temperature to 40° C. for 3 hours while the pH was maintained between 9 and 10 with addition of a NaOH solution. LCMS analysis showed the complete consumption of 4,6-dichloro-N-methyl-1,3,5-triazin-2-amine. The crude product was used in the next step. MS (ES+): m/e 286.0 [M+H]+.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([N:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:21][CH2:20]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C(#N)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:20][CH2:21][N:22]([C:25]([N:27]3[CH2:28][CH2:29][N:30]([C:33]4[CH:34]=[CH:35][N:36]=[CH:37][C:38]=4[Cl:1])[CH2:31][CH2:32]3)=[O:26])[CH2:23][CH2:24]2)(=[O:17])=[O:18])=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(N1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Solvent: CC#N
Product: O=C(N1CCN(c2ccncc2Cl)CC1)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Reaction time: 48 h
Yield: 72.4 %

Procedure:
N-Chlorosuccinimide (3.06 g) was added to a stirred suspension of 1-(4-bromophenylsulphonyl)-4-[1-(4-pyridyl)piperazin-4-ylcarbonyl]piperazine (10.1 g) in acetonitrile (350 ml) at 20° C. The mixture was stirred for 48 hours and the acetonitrile evaporated. Water (200 ml) was added to the mixture and the aqueous phase was extracted with dichloromethane (3×200 ml). The organic extracts were combined, dried and evaporated, and the residue purified by column chromatography on silica gel, eluting with dichloromethane:methanol (97:3) to give a foam on evaporation. Trituration with diethyl ether (200 ml) gave 1-(4-bromophenylsulphonyl)-4-[1-(3-chloro-4-pyridyl)piperazin4-ylcarbonyl]piperazine as a cream-coloured solid (7.82 g): mp 194-195° C.: 1HNMR (CDCl3); 3.04 (t, 4H), 3.18 (t, 4H), 3.42 (m, 8H), 6.78 (d, 1H), 7.91 (d, 2H), 7.70 (d, 2H), 8.34 (d, 2H), 8.42 (s, 1H); EI-MS m/z 528 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH2:29][O:30][CH3:31])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>>[CH:32]1([C:35]([N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]3[C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=5[O:27][CH2:28][CH2:29][O:30][CH3:31])[C:13]=4[NH:12][CH:11]=3)=[O:9])[CH2:3][CH2:2]2)=[O:36])[CH2:34][CH2:33]1
Reactant: O=C(Cl)C1CC1
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)NC3CCNCC3)c[nH]c12
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)NC3CCN(C(=O)C4CC4)CC3)c[nH]c12

Procedure:
Starting from 4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A184) and cyclopropanecarbonyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:17](O)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH:13][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=3)[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1N=C(N)N1CCN=C21
Reactant: O=C(O)c1cccnc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Reaction time: 8 h
Yield: 68 %

Procedure:
7-Methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Step 4, 31.2 g, 57.7 mmol), nicotinic acid (10.7 g, 86 mmol) and diisopropylethylamine (30.1 mL, 173 mmol) were suspended in DMF (250 mL), and PyBOP (45 g, 86 mmol) was added portionwise. The reaction soon became much thicker with a new solid. After stirring overnight, the solid was collected by filtration then washed with EtOAc (150 mL). The solid was dissolved in CH2Cl2 (1000 mL), washed with water (600 mL) and the organic layer dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound (12.6 g, 68%): HPLC MS RT=1.18 min, MH+=322.1; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 4.12 (3H, s), 4.28-4.35 (2H, m), 4.60-4.66 (2H, m), 7.63 (1H, t), 7.72-7.86 (3H, m), 8.76 (1H, d), 8.93 (1H, dd), 9.48 (1H, d).
Reaction SMILES: [CH2:1]([C:4]1([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)[CH2:13][C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[O:7][CH2:6][CH2:5]1)[CH:2]=C.[O:19]=[O+][O-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[N:14]1([C:4]2([CH2:1][CH:2]=[O:19])[CH2:13][C:8]3([CH2:12][CH2:11][CH2:10][CH2:9]3)[O:7][CH2:6][CH2:5]2)[CH:18]=[CH:17][CH:16]=[N:15]1
Reactant: C=CCC1(n2cccn2)CCOC2(CCCC2)C1
Reactant: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=CCC1(n2cccn2)CCOC2(CCCC2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 23 %

Procedure:
To a solution of 1-[9-(prop-2-en-1-yl)-6-oxaspiro[4.5]decan-9-yl]-1H-pyrazole (80 mg, 0.32 mmol) in DCM (5 mL) at −78° C. was bubbled with O3 until the solution turned blue. The resulting solution was bubbled with N2 for 5 min. To it was added PPh3 (168 mg, 0.64 mmol). And the solution was stirred for 4 h at rt. After removal of the solvent, the residue was purified by flash column chromatography to give 2-[9-(1H-pyrazol-1-yl)-6-oxaspiro[4.5]decan-9-yl]acetaldehyde (15 mg, 23% yield). LCMS m/z 249 (M+1) observed.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:9]([CH2:20][O:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:8][C@H:7]([O:30][C@H:31]2[C@@H:44]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@H:43]([O:53][CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C@@H:42]([CH2:61][O:62][CH2:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[O:41][C@@H:32]2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:6]1[O:70][C:71](=[O:78])[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)C=C>CO.ClCCCl.Cl[Pd]Cl>[C:71]([O:70][C@H:6]1[C@@H:5]([OH:4])[C@H:10]([O:11][C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@@H:9]([CH2:20][O:21][C:22](=[O:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:8][C@@H:7]1[O:30][C@H:31]1[C@@H:44]([O:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C@H:43]([O:53][CH2:54][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C@@H:42]([CH2:61][O:62][CH2:63][C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=2)[O:41][C@@H:32]1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:78])[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1
Reactant: C=CCO[C@@H]1[C@H](OC(=O)c2ccccc2)[C@@H](O[C@@H]2[C@@H](OCc3ccccc3)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: Cl[Pd]Cl
Solvent: CO
Solvent: ClCCCl
Product: O=C(OC[C@H]1O[C@H](O[C@@H]2[C@@H](OCc3ccccc3)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H](O)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Yield: 97.5 %

Procedure:
PdCl2 (40 mg) was added to a solution of the allyl ether (24) (1.09 g, 0.97 mmol) in MeOH (10 mL) and 1,2-DCE (10 mL) and the combined mixture was heated (70°, 40 min). After the time, the solvents were evaporated and the residue subjected to FC (20-30% EtOAc/hexanes) to yield the alcohol (25) as a colourless oil (0.96 g, 91%). 1H NMR (CDCl3) δ 3.68-3.81, 3.97-4.06, 4.32-4.71 (3 m, 18 H; H-2I,-3I,-4I,-5I,-6aI,-6bI,-3II,-5II,-6aII,-6bII, CH2Ph), 4.84 (d, 1 H, JA,B 12 Hz; A of AB quartet), 5.05 (d, 1 H, J1,2 1.9 Hz; H-1I), 5.26 (d, 1 H; J1,2 1.9 Ha; H-1II), 5.61 (dd, 1 H, J2,3 3.3 Hz; H-2II), 5.67 (dd, 1 H, J3,4 9.8, J4,5 9.9 Hz; H-4II), 7.13-7.40, 7.48-7.59, 7.98-8.06 (3 m, 35 H; Ar). 13C NMR (CDCl3) δ 60.61, 63.32 (2C; C-6I,-6II), 69.06, 69.12, 69.25, 69.44, 70.45, 72.14, 72.65, 72.77, 73.48, 74.79, 75.48, 75.47, 76.23 (13C; C-3I,-4I,-5I,-2II,-3II,-4II,-5II, OCH2, CH2Ph), 79.66(C-2I), 98.34, 99.40 (C-1I,-1II), 127.70-138.47 (42C; Ar), 165.97, 166.36, 166.97 (3C; C═O).
Reaction SMILES: [H-].[Na+].CO.[C:5](/[C:8](=[C:13](\[C:15]1[C:24]([NH:25][C:26]([O:28]CC)=O)=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)/[OH:14])/C(OC)=O)(=[O:7])[CH3:6]>C1C=CC=CC=1>[C:5]([C:8]1[C:26](=[O:28])[NH:25][C:24]2[C:15]([C:13]=1[OH:14])=[CH:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=1[CH:23]=2)(=[O:7])[CH3:6]
Reactant: CCOC(=O)Nc1cc2ccccc2cc1/C(O)=C(\C(C)=O)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: CC(=O)c1c(O)c2cc3ccccc3cc2[nH]c1=O
Temperature: 72 °C
Reaction time: 0.08 h

Procedure:
To a dispersion of sodium hydride (95%) (0.90 g, 37.5 mmol, 2.6 equiv) in benzene (100 ml) at room temperature under nitrogen was added dropwise methanol (3.0 ml, 2.37 g, 74.1 mmol, 5.2 equiv). After stirring for 5 minutes, methyl (2Z)-2-acetyl-3-{3-[(ethoxycarbonyl)amino]-2-naphthyl}-3-hydroxyprop-2-enoate (1-3) (5.06 g, 14.2 mmol, 1.0 equiv) was added and the reaction was heated to 72° C. for 20 hours. The solvent was evaporated under reduced pressure and the solid residue was stirred with water (50 ml) for 30 minutes followed by 1 N HCl (100 ml) for an additional 30 minutes. The solid was filtered, washed with water (100 ml) and hexanes (100 ml) and dried to yield 3-acetyl-4-hydroxybenzo[g]quinolin-2(1H)-one (1-4) as a yellow solid. LRMS m/z (M+H) 254.2 found, 254.1 required.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[NH:4][C:3]1=[O:14]>CO.[Pd]>[NH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:2]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH3:1])[C:3](=[O:14])[NH:4]2
Reactant: CCOC(=O)CC1(C)C(=O)Nc2cccc([N+](=O)[O-])c21
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC1(C)C(=O)Nc2cccc(N)c21
Reaction time: 3 h

Procedure:
A mixture of (±)-ethyl (3-methyl-4-nitro-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate from Step B (2.66 g, 9.56 mmol) and 10% Pd/C (500 mg) was stirred vigorously in MeOH (50 mL) under an atmosphere of hydrogen (ca. 1 atm). After 3 h, the mixture was filtered through a pad of Celite, washing with MeOH, and the filtrate was concentrated in vacuo to give the title compound. MS: m/z=249 (M+1).
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH3:14]>>[CH3:9][C:10]1[NH:7][C:1]2[C:6]([C:11]=1[CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=[CH:3][CH:2]=2
Reactant: NNc1ccccc1
Reactant: CCCCC(C)=O
Product: CCCc1c(C)[nH]c2ccccc12
Reaction time: 3 h
Yield: 27.7 %

Procedure:
Phenylhydrazine (162.2 g) was placed in a reaction flask fitted with a mechanical stirrer, reflux condenser with attached drying tube, internal thermometer, and addition funnel. Acetic acid (900 ml) was added, resulting in an orange solution. To this mixture was then added 2-hexanone (170 g) over 5 min, and the resulting mixture was heated to reflux with stirring for three hours. After cooling, the acetic acid solvent was removed by rotary evaporation, and the residue was poured into water (4.5 liters). This mixture was extracted three times with ethyl ether (1 liter each) and the combined organic extracts were washed twice with 1N HCl (1 liter each), once with water (1.5 liters), once with saturated sodium bicabonate solution (1 liter) and then once with brine (1 liter). The organic layer was then dried (MgSO4) and evaporated to afford an oil which was purified by two successive vacuum distillations. The title compound (72.1 g) was obtained as an oil distilling between 91.5° and 95° at a pressure of 0.0067 Pascals (0.05 mTorr). An additional portion of the title compound was obtained by chromatography of the stillpot residue over flash silica gel (500 g), eluting with dichloromethane. Evaporation of the appropriate fractions afforded more material which was combined with the distillate above to provide a total of 159.1 grams (61% yield) of the title compound, which was used immediately in step (c).