Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[CH2:14]([N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([N:21]1[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][NH:29][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:13])[CH2:25][CH2:26]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NCCN1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Product: O=C(NCCN1CCN(Cc2ccccc2)CC1)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 4-benzylpiperazin-1 ylethylamine. The product was purified by mass directed purification to give the title compound as an orange solid. m/z (ES+)=398 [M+H]+; RT=2.75 min.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23]C(=O)C)[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=O)C.[F:27][C:28]([F:40])([F:39])[O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.[F-].[Cs+]>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.COCCOC.CO>[O:7]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:33]2[CH:32]=[CH:31][C:30]([O:29][C:28]([F:27])([F:39])[F:40])=[CH:35][CH:34]=2)[CH:13]=1)[C@@H:6]1[S:15][CH2:16][C@@H:17]([OH:23])[C@H:18]([OH:19])[C@H:5]1[OH:4]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: O[C@@H]1[C@@H](O)[C@H](Oc2cncc(-c3ccc(OC(F)(F)F)cc3)c2)SC[C@H]1O
Temperature: 110 °C
Yield: 68 %

Procedure:
0.5 g (1.11 mM) of 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside, 0.275 g (1.33 mM) of 4-(trifluoromethoxy)phenylboronic acid, 0.373 g (2.45 mM) of cesium fluoride and 0.24 g of tetrakis(triphenylphosphine)palladium catalyst grafted onto polystyrene resin are mixed in 3.5 ml of DME and 5 ml of methanol. The reaction mixture is heated at 110° C. for 20 minutes by microwaves. It is filtered and then concentrated under reduced pressure. The crude product is purified by chromatography on a silica column (eluent: dichloromethane/methanol 90/10; v/v) to give the expected product in the form of a white solid with a yield of 68%.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[NH:7][CH:6]=1.[CH3:17][O:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:17][O:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[N:25]1[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=3)[NH:7][CH:6]=2)[CH2:29][CH2:30]1
Reactant: O=[N+]([O-])c1ccc2[nH]cc(CCCI)c2c1
Reactant: COc1cnccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cnccc1N1CCN(CCCc2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Reaction time: 12 h
Yield: 36.1 %

Procedure:
A mixture of 3-[3-iodopropyl]-5-nitro-1H-indole (1.4 g, 4.2 mmol), 1-(3-methoxy-4-pyridinyl)-piperazine (0.98 g, 5.09 mmol) and K2CO3 (1.4 g, 10.2 mmol) in 30 mL of acetonitrile was heated to reflux for 4 h. The reaction mixture was cooled and stirred for 12 h. The solvent was removed and the residue dissolved in ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate. The organic extracts were dried (MgSO4) and concentrated, and the gummy residue was purified by flash silica gel chromatography (5% methanol in dichloromethane as eluant) to give 3-[3-[4-(3-methoxy-4-pyridinyl)-1-piperazinyl]propyl]-5-nitro-1H-indole, (0.6 g, 36%) as a yellow solid: IR (KBr) 3600, 2400, 1600, 1520, 1330, 1250, 815 cm-1 ; 1H NMR (DMSO-d6, 300 MHz) δ8.52 (d, J=2.2 Hz, 1H), 8.10 (s, 1H), 8.02 (d, J=5.3 Hz, 1H), 7.96 (dd, J=2.3, 9.0 Hz, 1H), 7.48. (d, J=9.0 Hz, 1H), 7.42 (s, 1H), 6.81 (d, J=5.4 Hz, 1H), 3.84 (s, 3H), 3.21 (br s, 4H), 3.07 (dd, J=6.4, 14.7 Hz, 2H), 2.79 (t, J=14.7 Hz, 2H), 2.66 (br s, 4H), 1.97 (m, 2H); MS (m/e) 395 (M+).
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[CH3:40][O:41][C:42]1[CH:50]=[CH:49][C:45]([C:46](Cl)=[O:47])=[CH:44][CH:43]=1>>[CH3:40][O:41][C:42]1[CH:50]=[CH:49][C:45]([C:46]([O:1][CH:2]2[CH2:20][CH:19]3[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[CH:13][CH:14]4[C:16]([C:22]([NH:24][S:25]([CH:28]5[CH2:29][CH2:30]5)(=[O:26])=[O:27])=[O:23])([NH:17][C:18]3=[O:21])[CH2:15]4)[CH2:3]2)=[O:47])=[CH:44][CH:43]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1CCCOCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: COc1ccc(C(=O)OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCOCCCC(NC(=O)OC(C)(C)C)C(=O)N3C2)cc1
Yield: 35.7 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-10-oxatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 4-methoxybenzoyl chloride (89 mg, 0.53 mmol). The final trituration (diethyl ether) and filtration gave 44 mg (36%) of 18-(4-methoxybenzoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-10-oxatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 98.9% pure (HPLC), MS m/z 703 (M−H)−, HRMS: calcd. 705.2806 and found 705.2801 (M+H)+, mp 145-147° C.
Reaction SMILES: N1CCCC1.C(OC([O:13][C:14]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[C:23]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([CH2:45][C:46]([O:48][CH3:49])=[O:47])=[CH:41][C:40]=3[C:50]#[N:51])=[CH:35][CH:34]=2)[C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=O)(C)(C)C>O1CCOCC1>[C:50]([C:40]1[CH:41]=[C:42]([CH2:45][C:46]([O:48][CH3:49])=[O:47])[CH:43]=[CH:44][C:39]=1[C:36]1[CH:37]=[CH:38][C:33]([O:32][CH2:31][C:23]2[C:15]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[C:14]([OH:13])[C:26]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:24]=2)=[CH:34][CH:35]=1)#[N:51]
Reactant: COC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OC(=O)OC(C)(C)C)c3C(=O)OC(C)(C)C)cc2)c(C#N)c1
Solvent: C1CCNC1
Solvent: C1COCCO1
Product: COC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)c(C#N)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
Pyrrolidine (33 μl, 0.39 mmol) was added to a solution of crude tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-[({2′-cyano-4′-[(methoxycarbonyl)methyl]-1,1′-biphenyl-4-yl}oxy)methyl]-3-(trifluoromethyl)benzoate (125 mg) obtained in the above in 1,4-dioxane (4 ml), and the mixture was stirred at 50° C. for 2 hours. The residue obtained by removing the solvent under reduced pressure was purified by silica gel preparative thin layer chromatography (developing solvent: n-hexane/ethyl acetate=5/1) to give tert-butyl 6-[({2′-cyano-4′-[(methoxycarbonyl)methyl]-1,1′-biphenyl-4-yl}oxy)methyl]-2-hydroxy-3-(trifluoromethyl)benzoate (100 mg, 60%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11](=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C)C1C=CC=CC=1.Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C1(C)C=CC=CC=1>[CH2:33]([O:32][C:30]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11](=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:31])[CH3:34]
Reactant: CCOC(=O)Cl
Reactant: CCCCCCCC(=O)c1ccc(O)c(C(=O)O)c1
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: CCCCCCCC(=O)c1ccc(OC(=O)OCC)c(C(=O)O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
4.89 g (18.50 mmol) of 2-hydroxy-5-octanoylbenzoic acid and 9 ml (70.30 mmol) of N,N-dimethylaniline are dissolved in 30 ml of toluene. The medium is cooled to 0° C., and 1.77 ml (18.50 mmol) of ethyl chloroformate are then added dropwise. After stirring for 2 hours at room temperature, the mixture is washed with aqueous 0.5N hydrochloric acid solution and then with water. The organic phase is dried over magnesium sulfate, filtered and concentrated. 5.59 g of 2-ethoxycarbonyloxy-5-octanoylbenzoic acid are obtained in the form of a white solid in a yield of 89%.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[C:3]([C:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:8]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)=[CH:24][CH:23]=2)[C:7](=[O:33])[C:6]=1O)=O.O.[NH2:38][NH2:39].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[C:2]([C:3]1[C:5]2[CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:8]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:32]=[CH:31][S:30][CH:29]=4)=[CH:24][CH:23]=3)[C:7](=[O:33])[C:6]=2[NH:38][N:39]=1)([CH3:36])([CH3:35])[CH3:1]
Reactant: NN
Reactant: COC(=O)COc1ccccc1C1C(C(=O)C(C)(C)C)=C(O)C(=O)N1c1ccc(-c2ccsc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)COc1ccccc1C1c2c(C(C)(C)C)n[nH]c2C(=O)N1c1ccc(-c2ccsc2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
A mixture of 4-(2,2-dimethylpropionyl)-3-hydroxy-5-(2-methoxycarbonylmethyloxyphenyl)-1-(4-thiophene-3-ylphenyl)-1,5-dihydropyrrole-2-one (0.207 g, 0.41 mmol), hydrazine hydrate (0.022 mL, 0.45 mmol) and acetic acid (3.1 mL) was stirred at 95° C. for 1 hour. After the reaction was completed, saturated sodium bicarbonate solution was poured into the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with brine, dried over anhydrous sodium sulphate, and then concentrated in vacuo. The resulting residue was triturated with ethyl ether and diisopropyl ether to give 3-t-butyl-5-(4-thiophene-3-ylphenyl)-4-(2-methoxycarbonylmethyloxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazole-6-one (0.191 g, yield: 93%) as pale brown solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.Br[C:12]1[S:13][CH:14]=[CH:15][N:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[S:13]1[CH:14]=[CH:15][N:16]=[C:12]1[N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1
Reactant: Brc1nccs1
Reactant: COC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(c2nccs2)CC1
Temperature: 100 °C

Procedure:
A mixture of methyl piperidine-4-carboxylate (2.045 g), 2-bromothiazole (1.64 g), and Cs2CO3 (5.86 g) in dimethylformamide (15 mL) was heated at 100° C. overnight. After it cooled to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][OH:27])=[CH:21][CH:20]=1>CN1C(=O)CCC1.O>[CH:13]1([O:12][C:4]2[N:3]=[C:2]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][OH:27])=[CH:21][CH:20]=3)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Nc1ccc(CCO)cc1
Reactant: FC(F)(F)c1cc(Cl)nc(OC2CCCC2)n1
Solvent: O
Solvent: CN1CCCC1=O
Product: OCCc1ccc(Nc2cc(C(F)(F)F)nc(OC3CCCC3)n2)cc1
Temperature: 120 °C
Yield: 69.7 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-(cyclopentyloxy)-6-(trifluoromethyl)pyrimidine (0.090 g, 0.34 mmol) and (4-aminophenyl)ethyl alcohol (0.069 g, 0.51 mmol) in NMP (3 mL). The resulting mixture was heated at 120° C. under microwave irradiation for 1 h. After this time, the reaction mixture was cooled and diluted with water (50 mL) affording a solid. The solid was isolated by filtration and chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent to afford the title compound (0.087 g, 70%) as a white solid. MW=367.37. M.p. 173-175° C. 1H NMR (DMSO-d6, 500 MHz) δ 10.01 (s, 1H), 7.56 (br d, J=7.0 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H), 6.73 (s, 1H), 5.30 (septet, J=3.0 Hz, 1H), 4.61 (t, J=5.0 Hz, 1H), 3.62-3.57 (m, 2H), 2.70 (t, J=7.0 Hz, 2H), 2.00-1.90 (m, 2H), 1.80-1.66 (m, 4H), 1.65-1.55 (m, 2H); APCI MS m/z 368 [M+H]+.
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.[CH2:8]([N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:28][CH3:29])[C:22]=2[O:26][CH3:27])[NH:17][C:16]1=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[K+]>>[CH2:8]([N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:28][CH3:29])[C:22]=2[O:26][CH3:27])[N:17]([CH3:16])[C:7]1=[O:6])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COS(=O)(=O)OC
Reactant: COc1ccc2[nH]c(=O)n(Cc3ccccc3)c(=O)c2c1OC
Agent: [K+]
Agent: [OH-]
Product: COc1ccc2c(c1OC)c(=O)n(Cc1ccccc1)c(=O)n2C
Temperature: 80 °C

Procedure:
Dimethyl sulfate (1.442 g, 1.08 ml, 11.43 mM) was added to 3-benzyl-5,6-dimethoxyquinazolin-2,4(1H, 3H)-dione (1.20 g, 3.7 mM). The mixture was heated to 80° C. (oil bath temperature) and then heated at 80°-84° C. for five minutes with vigorous stirring. A white solid was present at all times. Aqueous KOH (~15 ml of a 5N aqueous solution) was added dropwise at 80°-90° C. until the pH of the reaction mixture became basic and stayed basic. Addition of the aqueous KOH took ~20 minutes. A white solid was present during the addition. The mixture was cooled in an ice-H2O bath and the white solid filtered, washed well with H2O (20 ml) and dried to give 1.00 g crude product. mp 149°-152° C. Recrystallization from isopropanol (50 ml) afforded the title compound as a white solid; 0.80 g (66.1%); mp 153°-155° C. CDCl3 (TMS) 7.10-7.80 (m, 6H, 7-H, 10-H, 11-H, 12-H, 13-H, 14-H), 6.82 (d, 1H, J8,7 =10 Hz, 8-H), 5.25 (s, 2H, 9-H), 3.95 (s, 3H, 5 or 6-OCH3), 3.88 (s, 3H, 5 or 6-OCH3), 3.53 (s, 3H, 1-CH3), M+ 326.
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:37])[N:13]2[CH:16]([C:33](=C)[CH2:34][Cl:35])[C:17]([O:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:38]=[O+][O-]>C(Cl)Cl.CO>[O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:37])[N:13]2[C:16](=[C:33]([OH:38])[CH2:34][Cl:35])[C:17]([O:19][CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(CCl)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: O=C(OC(c1ccccc1)c1ccccc1)C(=C(O)CCl)N1C(=O)C2N=C(COc3ccccc3)SC21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a dry ice acetone cooled solution of diphenylmethyl α[3-phenoxymethyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-chloro-2-propen-2-yl)acetate (160 mg) in a mixture of methylene chloride (3.2 ml) and methanol (0.3 ml) is introduced ozone until the reaction mixture shows blue color. Then excess ozone is purged with oxygen, mixed with an aqueous solution of 95% sodium hydrogen sulfite (100 mg), warmed to room temperature to decompose the ozonide. After 1.5 hours, the solution is washed with 5% sodium hydrogen carbonate and water, dried, and concentrated to remove methylene chloride. The resultant oil (132 mg) is purified over thin-layer chromatographic plate (Merck 60F-254) using a mixture of benzene and ethyl acetate (1:1) as developing solvent to give diphenylmethyl α-[3-phenoxymethyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]-hept-2en-6-yl]-α-(2-chloro-1-hydroxyethylidene)acetate (44 mg) as glass.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.[C:9]12(O)[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>ClCCl.O>[C:9]12([C:5]3[CH:4]=[C:3]([Br:8])[CH:2]=[CH:1][C:6]=3[OH:7])[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
34.6 g (200 mmol) of p-bromophenol and 30.4 g (200 mmol) of 1 -adamantanol are dissolved in 100 ml of dichloromethane. To the resulting solution there are slowly added 10 ml of concentrated sulfuric acid. The mixture is stirred for 8 hours at ambient temperature poured into water, neutralized with sodium bicarbonate, extracted with methylene chloride, dried and evaporated. After recrystallization in isooctane 52.8 g of the expected product are obtained. Yield--86%. Melting point: 140°-141° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:34])[CH2:18][C:19]3[CH:24]=[CH:23][C:22](B4OC(C)(C)C(C)(C)O4)=[CH:21][CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl[C:36]1[C:41]([F:42])=[CH:40][N:39]=[CH:38][N:37]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:34])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:36]4[C:41]([F:42])=[CH:40][N:39]=[CH:38][N:37]=4)=[CH:21][CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1cncnc1Cl
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ncncc4F)cc3)nc2)CC1
Temperature: 110 °C

Procedure:
A mixture of N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide 196-1 (30 mg, 0.065 mmol), 4-chloro-5-fluoropyrimidine 196-2 (28 mg, 0.21 mmol) Pd(PPh3)4 (12 mg, 0.01 mmol) and K3PO4 (90 mg, 0.424 mmol) in dioaxane (0.6 mL) was flushed with nitrogen and heated to 110° C. for 2 hours. The salt was removed by filtration and the filtrate was taken to dryness by rotary evaporation. The residue was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(5-fluoropyrimidin-4-yl)phenyl)acetamide 196. MS m/z 435.10 (M+1). 1H NMR 400 MHz (DMSO-d6) δ10.54 (s, 1H), 9.06 (d, 1H), 8.90 (d, 1H), 7.98 (m, 3H), 7.86 (d, 1H), 7.49 (d, 2H), 7.37 (m, 1H), 3.73 (s, 2H), 3.50 (m, 4H), 3.09 (t, 2H), 3.02 (t, 2H), 1.97 (s, 3H).
Reaction SMILES: C(O[C:4](=[O:16])[CH2:5][NH:6][CH2:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:15])C.[N+]([O-])(O)=O.C[C:22]1C=C(C)N(C(N)=N)[N:23]=1>C(O)C>[CH3:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:8]=1[CH2:7][N:6]1[CH2:5][C:4](=[O:16])[NH:23][C:22]1=[N:15]2
Reactant: CCOC(=O)CNCc1c(C)cccc1N
Reactant: Cc1cc(C)n(C(=N)N)n1
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: Cc1cccc2c1CN1CC(=O)NC1=N2
Yield: 61.9 %

Procedure:
A mixture of N-(2-amino-6-methylbenzyl)glycine ethyl ester (1.097 g, 0.0049 mole) and 3,5-dimethylpyrazole-1-carboxamidine nitrate (0.993 g, 0.0049 mole) in absolute ethanol (15 ml) was heated at reflux for 64 hours. The mixture then was filtered and the product washed with hot ethanol to yield the title compound (0.610 g, 61%); identical (ir, nmr) with authentic material prepared according to the procedure of J. Med. Chem., 18, 224 (1975)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1.[H-].[Na+].[CH3:24][Si:25]([CH2:28][CH2:29][O:30][CH2:31]Cl)([CH3:27])[CH3:26]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:7]=3[N:8]([CH2:31][O:30][CH2:29][CH2:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[C:9]=2[CH:10]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(Br)ccc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(c3ccc(Br)cc3n2COCC[Si](C)(C)C)C1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (0.66 g, 1.9 mmol) in DMF (8 mL) was added NaH (60% weight dispersion in mineral oil, 113 mg, 2.82 mmol) followed by SEMCl (0.50 mL, 2.8 mmol). The reaction was stirred at room temperature until complete. The reaction was quenched with H2O, and the aqueous mixture was extracted with CH2Cl2. The organic phase was washed with H2O and brine and dried over Na2SO4. After filtration and concentration, the residue was dried under vacuum to give tert-butyl 7-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate, which and used directly in the next step. To a mixture of tert-butyl 7-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (0.75 g, 1.6 mmol), 4-benzyloxypyridone (0.31 g, 1.6 mmol), 8-hydroxyquilinine (34 mg, 0.23 mmol), K2CO3 (0.26 g, 1.9 mmol) and CuI (45 mg, 0.23 mmol) was added DMSO (6 mL). The reaction mixture was degassed and back-filled with N2. The reaction was stirred at 130° C. overnight. The mixture was cooled and filtered through a layer of Celite. The filtrate was diluted with CH2Cl2, washed with H2O and 5% aqueous LiCl and dried over Na2SO4. The organic solution was filtered and concentrated, and the residue was purified by flash column chromatography (silica gel, 5% CH3OH in CH2Cl2) to give the title compound as a yellow oil (0.12 g, 13%): 1H NMR (500 MHz, CDCl3) δ 7.60 (d, J=8.5 Hz, 1H), 7.44-7.37 (m, 6H), 7.31 (d, J=7.5 Hz, 1H), 7.09 (m, 1H), 6.12 (s, 1H), 6.07 (d, J=6.5 Hz, 1H), 5.40 (s, 2H), 5.07 (s, 2H), 4.65 (m, 2H), 3.86 (m, 2H), 3.51 (t, J=8.0 Hz, 2H), 2.73 (m, 2H), 1.53 (s, 9H), 0.89 (t, J=8.0 Hz, 2H), −0.04 (s, 9H); ESI MS m/z 602 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[H-].[Na+].Cl[CH2:16][C:17]1[NH:18][C:19](=[O:27])[C:20]2[CH2:26][O:25][CH2:24][CH2:23][C:21]=2[N:22]=1>O1CCCC1>[C:8]([O:7][C:6](=[O:12])[N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:16][C:17]1[NH:18][C:19](=[O:27])[C:20]2[CH2:26][O:25][CH2:24][CH2:23][C:21]=2[N:22]=1)([CH3:9])([CH3:11])[CH3:10]
Reactant: COCCNC(=O)OC(C)(C)C
Reactant: O=c1[nH]c(CCl)nc2c1COCC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCN(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 49.8 %

Procedure:
To a solution of tert-butyl 2-methoxyethylcarbamate (185 mg, 1.06 mmol) in anhydrous tetrahydrofuran (5 mL) was added sodium hydride (95%, 127 mg, 4.28 mmol) portion-wise slowly, followed by 2-(chloromethyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (212 mg, 1.6 mmol). The reaction mixture was stirred for 48 h. The reaction was quenched with water (approximately 3 mL) and the solvent evaporated. The residue was re-dissolved in acetonitrile and purified by column chromatography (100% dichloromethane for 5 min, then slow gradient up to 15% methanol in dichloromethane). The resulting clear oil was dissolved with 0.5 mL of acetonitrile and heated in vacuo to give the title compound as a white solid (179 mg). 1H NMR (400 MHz, chloroform-d) 8 ppm 4.60 (s, 2H) 4.21-4.34 (m, 2H) 3.91-4.01 (m, 3H) 3.66-3.79 (m, 2H) 3.51-3.66 (m, 6H) 2.71-2.80 (m, 2H) 1.48 (s, 3H) 1.35 (s, 6H). MS (m/z, MH+): 340.4