Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][NH:11][CH:12]=1)=[O:7])[CH3:4].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[CH2:13]([N:10]1[CH:9]=[C:8]([C:6]([O:5][CH2:3][CH3:4])=[O:7])[CH:12]=[N:11]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (containing 63%, 652 mg) in dimethylformamide (abbreviated as DMF hereinafter) was added a solution of 4-ethoxycarbonylpyrazole (2.00 g) in DMF (15 ml) at room temperature. After stirred for 30 min at room temperature, to the mixture was added benzylbromide (2.04 ml). After stirred for 30 min, the mixture was quenched by addition of water. The mixture was extracted with ethyl acetate--n-hexane. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give the title compound (2.98 g) having the following physical data.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([OH:14])[CH:8]=2)([O-:3])=[O:2].[H-].[Na+].Cl[CH2:18][C:19]1[N:20]=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:22][C:23]=1[CH3:24].S([O-])([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH2:18][C:19]1[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=1[CH3:24])[CH:8]=2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2cc(O)ccc2c1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2cc([N+](=O)[O-])cnc2c1
Reaction time: 8 h
Yield: 48.3 %

Procedure:
In DMF (9 mL) was dissolved 3-nitro-7-hydroxyquinoline (800 mg, 4.24 mmol.). Sodium hydride (168 mg, 4.24 mmol.) and 4-chloromethyl-5-methyl-2-phenyloxazole (880 mg, 4.24 mmol.) were added to the resulting solution under chilling with ice. The mixture was stirred overnight at 50°-60° C. After the completion of reaction was confirmed, ethyl acetate and aqueous sodium sulfate were added. The ethyl acetate portion was recovered, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1), to give 740 mg of the desired compound as a yellow-white crystalline product (yield 48%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]/[C:8]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=1)=[O:9].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.O>O1CCCC1>[OH:18][C:15]1[CH:16]=[CH:17][C:12](/[CH:11]=[CH:10]/[C:8](=[O:9])/[CH:7]=[CH:6]/[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: CCCCC/C=C/C(=O)CCc1ccc(O)c(OC)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCC/C=C/C(=O)/C=C/c1ccc(O)c(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
[6]-Shogaol (276 mg, 1.0 mmol) was dissolved in tetrahydrofuran (THF) and cooled down to 0° C. To this mixture, a solution of DDQ (181 mg, 0.8 mmol) in THF was added. The mixture was stirred at 0° C. for 30 minutes and then warmed to room temperature (RT) for 3 hours. Then water was added and the resulting mixture was extracted with EtOAc (×3). The organic phase was washed with water (×1) and brine (×1), dried over anhydrous NaSO4, and filtered. The filtration was evaporated and the residue was purified by chromatography column (CC) (hexane/ethyl acetate=8:1 and 6:1) to give the desired compound as a yellow oil (170 mg, yield: 62%); 1H NMR (600 MHz, CDCl3) δ 7.59 (1H, d, J=15.9 Hz, H-1), 6.82 (1H, d, J=15.9 Hz, H-2), 6.44 (1H, d, J=15.6 Hz, H-4), 6.99 (1H, dt, J=15.6, 7.0 Hz, H-5), 2.27 (2H, q, J=7.0 Hz, H-6), 1.51 (2H, m, H-7), 1.34-1.29 (4H, m, H-8 and H-9), 0.90 (3H, t, J=6.8 Hz, H-10), 7.07 (1H, d, J=1.4 Hz, H-2′), 6.93 (1H, d, J=8.2 Hz, H-5′), 7.14 (1H, dd, J=8.2, 1.4 Hz, H-6′), and 3.93 (3H, s, OMe-3′); 13C NMR (150 MHz, CDCl3) δ 143.3 (d, C-1), 123.3 (d, C-2), 189.3 (s, C-3, C═O), 129.1 (d, C-4), 148.0 (d, C-5), 32.7 (t, C-6), 27.9 (t, C-7), 31.4 (t, C-8), 22.4 (t, C-9), 14.0 (q, C-10), 127.4 (s, C-1′), 109.7 (d, C-2′), 148.1 (s, C-3′), 146.8 (s, C-4′), 114.8 (d, C-5′), 122.9 (d, C-6′), and 56.0 (q, OMe-3′); positive ESI-MS, m/z 275 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](/[N:11]=[C:12](/[NH:32][C:33](=[O:42])[CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)\[NH:13][CH2:14][CH2:15][CH2:16][C@H:17]2[C:20](=[O:21])[NH:19][C@@H:18]2[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:43]1([N:49]=[C:50]=[O:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]1([CH2:7][CH2:8][C:9](/[N:11]=[C:12](/[NH:32][C:33](=[O:42])[CH2:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)\[NH:13][CH2:14][CH2:15][CH2:16][C@H:17]2[C:20](=[O:21])[N:19]([C:50](=[O:51])[NH:49][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@@H:18]2[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCc1ccccc1)/N=C(\NCCC[C@H]1C(=O)N[C@@H]1C(=O)OCc1ccccc1)NC(=O)CCc1ccccc1
Reactant: O=C=Nc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCc1ccccc1)/N=C(\NCCC[C@H]1C(=O)N(C(=O)Nc2ccccc2)[C@@H]1C(=O)OCc1ccccc1)NC(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 149 (50 mg, 1.0 eq.) in DCM (2 mL) was added phenylisocyanate (29 μL, 3.0 eq.), triethylamine (12 μL, 1 eq.) and DMAP (1 mg). The reaction was stirred for 18 hours at room temperature and then diluted with dichloromethane and washed with 1N HCl and water. The organic layer was then concentrated in vacuo and purified via silica gel chromatography eluting with 15% EtOAc in hexanes to give 150 (10 mg).
Reaction SMILES: CC([O:5][CH2:6][C:7]1[C:11]([CH2:12][OH:13])=[C:10]([CH:14]([CH3:16])[CH3:15])[O:9][N:8]=1)(C)C.O[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[N:30]=[C:29]([C:34]([O:36][CH3:37])=[O:35])[CH:28]=[CH:27]3)=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[OH:5][CH2:6][C:7]1[C:11]([CH2:12][O:13][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([O:36][CH3:37])=[O:35])[CH:28]=[CH:27]4)=[CH:22][CH:23]=2)=[C:10]([CH:14]([CH3:15])[CH3:16])[O:9][N:8]=1
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Reactant: CC(C)c1onc(COC(C)(C)C)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(CO)noc4C(C)C)cc3)ccc2n1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 70.4 %

Procedure:
To a solution of [3-{[(1,1-dimethylethyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolyl]methanol (407 mg, 1.79 mmol), methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (500 mg, 1.79 mmol) and triphenylphosphine (517 mg, 1.97 mmol) in dichloromethane (4 mL) was added diisopropyl azodicarboxylate (0.354 mL, 1.97 mmol) dropwise. The solution was heated in a microwave reactor at 100° C. for 10 minutes and then adsorbed onto silica gel and purified by chromatography (silica gel, 0-40% ethyl acetate in hexanes gradient elution) to afford a solid which was dissolved in dichloromethane (114 mL). Trifluoroacetic acid (114 mL, 1.48 mol) was added at a rapid pace. The mixture was stirred for approximately 1.5 hours and then concentrated. The residue was taken up with ethyl acetate and poured into water. Then solid sodium carbonate was added until the pH was between 9 and 10. The layers were separated and the ethyl acetate layer was dried over magnesium sulfate and concentrated. The resulting solid was washed with ether to afford methyl 6-[4-({[3-(hydroxymethyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (545 mg, 54%). 1H-NMR (400 MHz, DMSO-d6) δ 8.57 (d, J=9 Hz, 1H), 8.33 (s, 1H), 8.18 (s, 2H), 8.12 (d, J=9 Hz, 1H), 7.83 (d, J=9 Hz, 2H), 7.17 (d, J=9 Hz, 2H), 5.46 (br s, 1H), 5.06 (s, 2H), 4.54 (s, 2H), 3.94 (s, 3H), 3.33 (septet, J=7 Hz, 1H), 1.24 (d, J=7 Hz, 6H). LRMS (ESI) m/z 433 (M+H)+.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:50][CH2:51][C:52](=[O:54])[CH3:53].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:50][CH2:51][C:52](=[O:54])[CH3:53])[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)CCCl
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(OC(F)F)ccc21
Temperature: 65 °C

Procedure:
To a solution of N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (100 mg, 0.156 mmol) in DMF (4 mL) was added 4-chlorobutan-2-one (20 mg, 0.187 mmol) followed by K2CO3 (65 mg, 0.468 mmol). The mixture was heated at 65° C. for 1.5 hours. After cooling to room temperature, the mixture was poured into water, filtered and dried to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-oxobutyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide. The crude product was used in the next step without purification. MS: (M+H)+=713.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[N:6]=1)[CH2:3][NH2:4].[OH:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=O)[CH3:24])=[CH:18][CH:17]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[OH:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[N:6]=2)[CH3:24])=[CH:18][CH:17]=1
Reactant: NCC(O)c1cccc(Cl)n1
Reactant: CC(=O)Cc1ccc(OCCO)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(Cc1ccc(OCCO)cc1)NCC(O)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
21.2 g (0.122 mol) of 2-hydroxy-2-(6-chloro-pyridin-2-yl)-ethanamine and 21 g (0.108 mol) of 1-(4-(2-hydroxyethoxy)-phenyl)-propan-2-one are dissolved in 500 ml of absolute methanol, mixed with 7.3 g (0.122 mol) of acetic acid and 7.2 g (0.114 mol) of sodium cyanoborohydride and stirred overnight at ambient temperature. Then 300 ml of methanol are distilled off in vacuo, diluted with 400 ml of water, acidified with hydrochloric acid and then extracted three times with 250 ml of methylene chloride. The aqueous phase is then made alkaline with ammonia and extracted with methylene chloride. The organic phase obtained is dried over sodium sulphate and concentrated by evaporation, and the oil obtained initially crystallises out after a short time.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:14][C:13](=[O:15])[NH:12][C:11]3[CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH:18]=[CH:19][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][C:28](OC(C)=O)=[O:29]>CC(O)=O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:17]2[CH:18]=[CH:19][C:10]3[N:9]=[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:28](=[O:29])[CH3:27])[CH:7]=[CH:6][CH:5]=4)[CH2:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[CH:25][CH:24]=1
Reactant: Nc1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1

Procedure:
Prepared from 4-(3-amino-phenyl)-8-(4-fluoro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 70) by treatment with Ac2O in HOAc at 80° C. Obtained as a light yellow solid (9 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].Cl.Cl[CH2:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19].O>CN(C)C=O>[CH2:16]([N:17]([CH2:20][CH3:21])[CH2:18][CH2:19][S:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:15]
Reactant: CCN(CC)CCCl
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCSc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C

Procedure:
To a solution of 7.0 g (45 mmol) of 4-nitrothiophenol and 22.5 mL of 4N aqueous potassium hydroxide in 40 mL of dimethylformamide add a solution of 9.53 g (55 mmol) of 2-chloro-N,N-diethylethanamine hydrochloride in 40 mL of dimethylformamide. Heat the reaction mixture for about 3 h at 100° C. After this time, cool the mixture to room temperature and add 150 mL of water. Extract th aqueous mixture with 3×200 mL of methylene chloride. Combine the methylene chloride extracts and extract these with 200 mL of 1N aqueous hydrochloric acid. Make the acid extract basic with saturated aqueous sodium bicarbonate solution
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:3]=1.[I-:17].[Na+].C1(C)C=CC=CC=1.CNCCNC>[Cu]I.O>[I:17][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:3]=1
Reactant: CCOC(=O)c1ccc(Br)cc1S(C)(=O)=O
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(I)cc1S(C)(=O)=O
Yield: 64.5 %

Procedure:
To a mixture of ethyl 4-bromo-2-methanesulfonylbenzoate (13.88 g), sodium iodide (13.54 g) and copper(I) iodide (4.30% g) were added toluene (46 mL) and N,N′-dimethylethylenediamine (4.86 mL), and the mixture was stirred with heating under reflux for 8 hr under a nitrogen stream. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer, the obtained residue was purified by column chromatography (hexane:ethyl acetate) to give ethyl 4-iodo-2-methanesulfonylbenzoate (10.32 g). To a mixture of the obtained ethyl 4-iodo-2-methanesulfonylbenzoate (3.22 g), (R)-3-methylisothiazolidine 1,1-dioxide (1.23 g) described in Preparation Example 2, copper(I) iodide (4.30 g), N,N′-dimethylethylenediamine (0.92 mL) and potassium carbonate (2.52 g) was added toluene (9.2 mL), and the mixture was stirred with heating under reflux for 8 hr under a nitrogen stream. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer, and the obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (1.7 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@H:9]2[CH2:15][N:14]([C:16]3[N:17]([CH3:29])[C:18](=[O:28])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][N:23]=4)[N:21]=3)[CH2:13][CH2:12][CH2:11][O:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[O:30]1CCCC1.C(=O)([O-])[O-].[Na+].[Na+].OO>C(O)C>[CH3:29][N:17]1[C:18](=[O:28])[CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][N:23]=2)[N:21]=[C:16]1[N:14]1[CH2:13][CH2:12][CH2:11][O:10][C@@H:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]([NH2:2])=[O:30])[CH2:15]1
Reactant: C1CCOC1
Reactant: Cn1c(N2CCCO[C@@H](c3cccc(C#N)c3)C2)nc(-c2ccncn2)cc1=O
Agent: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: Cn1c(N2CCCO[C@@H](c3cccc(C(N)=O)c3)C2)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-[2-(3-cyano-phenyl)-[1,4]oxazepan-4-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (A039) (300 mg, 0.772 mmol), tetrahydrofuran (1.90 ml) and 3.0N-sodium carbonate (1.90 ml) in ethanol (1.90 ml) was added 30%-hydrogen peroxide (1.90 ml) at room temperature. The mixture was stirred at room temperature for 2 hours and partitioned between water and chloroform. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was washed with diethyl ether to afford (S)-3-[4-(1-Methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-[1,4]oxazepan-2-yl]-benzamide (A015) as pale yellow solid (293 mg, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[NH:12][NH:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:21]1([CH:27]=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(Cl)(Cl)Cl>[CH:21]1([CH2:27][N:12]2[CH:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[C:10](=[O:20])[NH:11]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1NNC(c2ccncc2)C1c1ccc(Cl)c(Cl)c1
Reactant: O=CC1CCCCC1
Solvent: ClC(Cl)Cl
Product: O=C1NN(CC2CCCCC2)C(c2ccncc2)C1c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(3,4-Dichloro-phenyl)-5-pyridin-4-yl-pyrazolidin-3-one 0.30 g and 0.2 mL cyclohexanecarbaldehyde in chloroform 20 mL was added NaBH3(CN) 0.1 g at 0° C., the reaction was warmed 50° C. and stirred for 1 hour. The reaction was quenched with sat.NaHCO3 25 mL at 0° C. The reaction mixture was extracted with dichloromethane, 3×50 mL. The combined organic phase was washed with brine, dried over anhydrous Na2SO4. After purification by flash chromatography, the title compound was obtained as yellow solid 0.4 g. MS (ES+): 404 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=2)[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].O.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(OCC)(=O)C>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:2][CH:3]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=3)[CH2:4]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)Cc1ccc2c(c1)CC(N)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
A mixture of methyl (2-aminoindan-5-yl)acetate hydrochloride (2.43 g), potassium carbonate (5.52 g), water (60 ml), ethyl acetate (60 ml) and 4-chlorophenylsulfonyl chloride (2.11 g) is stirred at room temperature for one hour. The ethyl acetate layer is separated from the reaction mixture, washed with aqueous saline solution, dried, and distilled under reduced pressure to remove the solvent. The resulting crude product is recrystallized from a mixture of ethyl acetate and n-hexane to give methyl [2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetate (3.02 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][C:17]1([CH3:43])[CH2:22][CH2:21][CH2:20][C:19](=O)[CH:18]1/[CH:24]=[CH:25]/[C:26]#[C:27][C:28]1[CH:42]=[CH:41][C:31]([C:32]([O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])=[O:33])=[CH:30][CH:29]=1.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C>ClCCl.C(OCC)(=O)C>[CH3:16][C:17]1([CH3:43])[C:18](/[CH:24]=[CH:25]/[C:26]#[C:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:40])[CH3:39])=[O:33])=[CH:41][CH:42]=2)=[C:19]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH2:20][CH2:21][CH2:22]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC1(C)CCCC(=O)C1/C=C/C#Cc1ccc(C(=O)OCC[Si](C)(C)C)cc1
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(C)CCCC(OS(=O)(=O)C(F)(F)F)=C1/C=C/C#Cc1ccc(C(=O)OCC[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Trifluoromethanesulfonic anhydride (0.109 mL, 0.65 mmol) was added to a solution of (trimethylsilyl)ethyl (±)-(E)-4-(4-(2,2-dimethyl-6-oxocyclohexyl)but-3-en-1-ynyl)benzoate (Compound G, 150 mg, 0.38 mmol) and 2,6-di-tert-butyl-4-methylpyridine (DBMP, 218 mg, 1.06 mmol) in dichloromethane (4 mL). The flask was sealed with a plastic cap and stirred for 2 days at room temperature. The solution was diluted with ethyl acetate and washed with 10% aqueous H3PO4. The layers were separated and the aqueous layer extracted three times with ethyl acetate. The combined organic layers were washed with 5% aqueous NaHCO3, and brine, and dried (Na2SO4). The solvents were removed under reduced pressure, and the residue was purified by silica gel chromatography (10:1, hexane:ethyl acetate) to give the title compounds as a 1:1 mixture of isomers. The compounds were separated by HPLC using a Whatman Partisil-10 1×50 cm column (95:5, hexane:ethyl acetate) to provide the title compound as a colorless oil:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([OH:15])=[C:10]([C:16]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=1)[CH:9]=[CH:8]2.F[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1.O>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([O:15][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[C:10]([C:16]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=1)[CH:9]=[CH:8]2
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1ccc2c(O)c(-c3ccc(SC)cc3)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc([N+](=O)[O-])cc3)c(-c3ccc(SC)cc3)ccc2c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Place sodium hydride (1.05 eq.) in dry dimethylformamide in a 3 neck flask equipped with a mechanical stirrer, addition funnel with nitrogen purge, and a temperature probe under nitrogen. Charge the addition funnel with 6-methoxy-2-(4-methylthiophenyl)naphthalene-1-ol (1 eq.) dissolved in dry dimethylformamide. Add this solution dropwise to the stirred sodium hydride solution at a rate that holds the temperature below 35° C. Stir the reaction mixture for 30 minutes before adding 4-fluoronitrobenzene with additional dry dimethylformamide. Heat the solution to 60° C. Once the reaction is complete, cool the flask and add water slowly to cause precipitation of the product. Filter the crude product and wash with water and then methyl tert-butyl ether. Dry the filter cake in a vacuum oven to give 6-methoxy-2-(4-methylthiophenyl)-1-(4-nitrophenoxy)naphthalene.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Cl[CH:21]([CH3:24])[C:22]#[CH:23].C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>CO>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH:22]([CH3:23])[C:21]#[CH:24])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: C#CC(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: C#CC(C)N1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 50.1 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (2.5 g) is alkylated using (rac)-3-chloro-but-1-yne (0.86 g; 9.5 mmol) and K2CO3 (3.28 g; 23.7 mmol) at 50° C. for 14 days. After aqueous work-up the crude material (1.51 g) is de-acetylated in MeOH (40 ml) using DBU (0.3 ml) at reflux. After aqueous work-up (rac)-5-amino-3,3-dimethyl-1-(1-methyl-prop-2-ynyl)-6-nitro-1,3-dihydro-indol-2-one (1,3 g) is obtained and used without further purification.