Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([OH:20])=[C:12]2[C:3]=1[C:4](=O)[C:5]1[CH:6]=[C:7]([C:25]([OH:27])=[O:26])[C:8]([C:22]([OH:24])=[O:23])=[CH:9][C:10]=1[C:11]2=[O:21].[CH:29]([C:32]1[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]([CH3:41])[CH3:40])[C:33]=1[NH2:34])([CH3:31])[CH3:30].ClC1C=CC=CC=1Cl>O>[CH:39]([C:35]1[CH:36]=[CH:37][CH:38]=[C:32]([CH:29]([CH3:31])[CH3:30])[C:33]=1[N:34]=[C:4]1[C:3]2[C:12](=[C:13]([OH:20])[C:14]3[C:19]([C:2]=2[OH:1])=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](=[O:21])[C:10]2[CH:9]=[C:8]([C:22]([OH:24])=[O:23])[C:7]([C:25]([OH:27])=[O:26])=[CH:6][C:5]1=2)([CH3:41])[CH3:40]
Reactant: O=C(O)c1cc2c(cc1C(=O)O)C(=O)c1c(c(O)c3ccccc3c1O)C2=O
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: Clc1ccccc1Cl
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1N=C1c2cc(C(=O)O)c(C(=O)O)cc2C(=O)c2c1c(O)c1ccccc1c2O
Reaction time: 18 h
Yield: 49.3 %

Procedure:
0.5 g (1.32 mmoles) of 6,11-Dihydroxy-naphthacene-5,12-dione-2,3-dicarboxylic acid (product of Example 8), 0.28 g (1.58 mmoles) of 2,6-diisopropylaniline, and 25 ml of o-dichlorobenzene are refluxed for 4 h with azeotropic removal of the reaction water. The mixture is filtered while hot, and the filtrate is kept at 25° for 18 h. The precipitate is washed with hot hexane and dried to give 0.35 g (51%) of red crystals, m.p. 328-330°.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C@H:9]([C@@H:16]([OH:67])[C:17]([O:19][C@@H:20]1[C:50]([CH3:51])=[C:49]2[C:52]([CH3:54])([CH3:53])[C@:22]([OH:66])([C@@H:23]([O:57][C:58]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[O:59])[C@@H:24]3[C@:29]4([O:32][C:33]([CH3:35])=[O:34])[CH2:30][O:31][C@@H:28]4[CH2:27][C@H:26]([O:36][C@@H]4OC[C@@H](O)[C@H](O)[C@H]4O)[C@@:25]3([CH3:56])[C:46]([C@@H:48]2[OH:55])=[O:47])[CH2:21]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].I([O-])(=O)(=O)=O.[Na+]>C(O)C.O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C@H:9]([C@@H:16]([OH:67])[C:17]([O:19][C@@H:20]1[C:50]([CH3:51])=[C:49]2[C:52]([CH3:54])([CH3:53])[C@:22]([OH:66])([C@@H:23]([O:57][C:58]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[O:59])[C@@H:24]3[C@:29]4([O:32][C:33]([CH3:35])=[O:34])[CH2:30][O:31][C@@H:28]4[CH2:27][C@H:26]([OH:36])[C@@:25]3([CH3:56])[C:46]([C@@H:48]2[OH:55])=[O:47])[CH2:21]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: CCCCCC(=O)N[C@@H](c1ccccc1)[C@@H](O)C(=O)O[C@H]1C[C@@]2(O)[C@@H](OC(=O)c3ccccc3)[C@@H]3[C@]4(OC(C)=O)CO[C@@H]4C[C@H](O[C@@H]4OC[C@@H](O)[C@H](O)[C@H]4O)[C@@]3(C)C(=O)[C@H](O)C(=C1C)C2(C)C
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCO
Product: CCCCCC(=O)N[C@@H](c1ccccc1)[C@@H](O)C(=O)O[C@H]1C[C@@]2(O)[C@@H](OC(=O)c3ccccc3)[C@@H]3[C@]4(OC(C)=O)CO[C@@H]4C[C@H](O)[C@@]3(C)C(=O)[C@H](O)C(=C1C)C2(C)C
Temperature: 30 °C
Reaction time: 30 h

Procedure:
To a small reaction flask was added the analogue 7-xylosyl-10-deacetyl taxol C (200 mg) in ethanol (300 ml); Sodium periodate (450 mg in 4 ml water) was added to the resulting solution and the reaction mixture was stirred for 20-40 hours at 20-40° C. The reaction mixture was diluted with water and extracted with ethyl acetate (2×50 ml). The ethyl acetate phase was washed with water, dried over anhydrous sodium sulphate and concentrated in vacuo to a residue. The residue was dissolved in a mixture of methanol--acetic acid and was treated with diethyl hydrozine sulphate (500 mg) for 12-18 hours at 0-40° C. with stirring. The reaction mixture was diluted with water and extracted with chloroform (2×50 ml). The chloroform layer was washed with water (2×50 ml), dried over anhydrous sodium sulphate and concentrated in vacuo to give a residue of 10-DAT, C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].S(=O)(=O)(O)O.[C:16](O)(=[O:18])[CH3:17]>C(OC(=O)C)(=O)C>[C:16]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:1]([CH3:3])=[CH2:2])=[CH:5][CH:6]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)O
Reactant: C=C(C)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: C=C(C)c1ccc(OC(C)=O)cc1
Temperature: 200 °C

Procedure:
134 g of dimeric p-isopropenyl phenol are dissolved under nitrogen in 150 g of acetic acid anhydride, followed by the addition of 0.5 g of concentrated sulphuric acid. The reaction begins with a slight heat effect under which the temperature of the reaction mixture rises to around 50° C and then falls again. When the reaction temperature has fallen to around 30° C, the reaction mixture is slowly heated until, finally, acetic acid distils off under normal pressure. The temperature is regulated in such a way that distillation is continuous. When no more acetic acid distils over, the remaining acetic acid and the excess acetic acid anhydride are distilled off in a water jet vacuum, after which the reaction mixture is cooled. Another 5 g of concentrated sulphuric acid are then added, followed by heating in a high vacuum until p-acetoxy-α-methyl styrene distils off. The temperature of the reaction mixture is regulated in such a way that the reaction mixture distils off continuously; it is in the range from 70° to 120° C and is ultimately increased to 200° C. The reaction product which has distilled over is then redistilled; 119 g (68% of the theoretical) of p-acetoxy-α-methyl styrene are obtained in the boiling range from 80° to 82° C/0.1 Torr.
Reaction SMILES: [CH3:1]/[C:2](/[CH:15]=[CH:16]/[CH:17]=[C:18](\[CH3:30])/[CH:19]=[CH:20]/[C:21]1[C:26]([CH3:28])([CH3:27])[CH2:25][CH2:24][CH2:23][C:22]=1[CH3:29])=[CH:3]\[C:4]([N-:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[OH:14])=[O:5].CN1CCOCC1.[C:38](Cl)(=[O:42])[CH2:39][CH2:40][CH3:41].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CO>[C:38]([O:14][C:8]1[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:7]=1[NH:6][C:4](=[O:5])/[CH:3]=[C:2](\[CH3:1])/[CH:15]=[CH:16]/[CH:17]=[C:18](\[CH3:30])/[CH:19]=[CH:20]/[C:21]1[C:26]([CH3:28])([CH3:27])[CH2:25][CH2:24][CH2:23][C:22]=1[CH3:29])(=[O:42])[CH2:39][CH2:40][CH3:41]
Reactant: CCCC(=O)Cl
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)[N-]c2ccc(O)cc2O)C(C)(C)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCC(=O)Oc1cc(O)ccc1NC(=O)/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
(2E,4E,6E,8E)-[3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)-nona-2,4,6,8-tetraenoyl]-(2,4-dihydroxy)phenylamide (KCBG08) (0.10 g, 0.24 mmol) was dissolved in anhydrous CH2Cl2 (15 mL), and NMM (0.049 g, 0.49 mmol) was added. To the resulting mixture was added dropwise butyryl chloride (0.050 mL, 0.49 mmol) at 0° C., and the resulting solution was stirred for 0.5 h. Finely ground K2CO3 (0.30 g) and MeOH (3 mL) was added to the reaction mixture. After stirring for 1 h, the completion of the reaction was confirmed by TLC. The mixture was washed with CH2Cl2 (30 mL) and H2O (20 mL). The organic layer was dried over anhydrous MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography over silica gel (EtOAc:hexane=1:4) to give 2-[(2E,4E,6E,8E]-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)-nona-2,4,6,8-tetraenoylamino)-5-hydroxyphenyl butanoate (KCBG10, 97 mg, 83%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)[CH:17]=1.C(N=C=NCCCN(C)C)C.O[N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=CC=2N=N1.C1(CN)CC1.C(N(CC)CC)C>CN(C=O)C>[CH:44]1([CH2:43][NH:39][C:22](=[O:24])[C:21]2[CH:20]=[CH:19][C:18]([N:16]3[CH:17]=[C:13]([C:3]4[C:4]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=[CH:15]3)=[CH:26][CH:25]=2)[CH2:46][CH2:45]1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NCC1CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)NCC3CC3)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.1 %

Procedure:
To a solution of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) in DMF (2 mL), was added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (85.9 mg, 0.45 mmol) and N-hydroxybenzotriazole (60.7 mg, 0.45 mmol), followed by adding cyclopropylmethylamine (26 mg, 0.36 mmol) and triethylamine (75 mg, 0.75 mmol). The reaction mixture was stirred at room temperature overnight. Purification by preparative HPLC on reversed phase eluting with an acetonitrile/water [0.1% aq NH3 (25%)] gradient afforded the title compound (14 mg, 13%) which was obtained as a white solid. MS m/e=398.9 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.C(O[C:12](=[O:14])[CH3:13])(=O)C.[NH:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([C:28]3[CH:29]=[N:30][N:31]4[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][C:32]=34)[N:23]=2)[CH2:16]1>CN(C)C1C=CN=CC=1.ClCCl>[C:12]([N:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([C:28]3[CH:29]=[N:30][N:31]4[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][C:32]=34)[N:23]=2)[CH2:16]1)(=[O:14])[CH3:13]
Reactant: N#Cc1ccn2ncc(-c3nccc(N[C@@H]4CCCNC4)n3)c2c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC[C@@H](Nc2ccnc(-c3cnn4ccc(C#N)cc34)n2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 46.1 %

Procedure:
Triethylamine (44 μL, 0.32 mmol), acetic anhydride (8.2 μL, 0.09 mmol) and N,N-dimethylpyridin-4-amine (1.2 mg, 0.01 mmol) were added to a stirred solution of 3-{4-[(3R)-piperidin-3-ylamino]pyrimidin-2-yl}pyrazolo[1,5-a]pyridine-5-carbonitrile (Preparation 7b, 40 mg, 0.06 mmol) in dichloromethane (1.5 mL) and the mixture was stirred at ambient temperature for 20 hours before being partitioned between dichloromethane and 4% aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (100:1 to 20:1 chloroform/methanol) to give the title compound (10 mg, 44%) as a solid.
Reaction SMILES: [CH2:1]([C:3]([CH3:8])([CH2:6][OH:7])[CH2:4][OH:5])[CH3:2].[CH3:9][O:10][CH2:11][CH:12]=O.C(Cl)(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O>[CH3:9][O:10][CH2:11][CH:12]1[O:7][CH2:6][C:3]([CH2:1][CH3:2])([CH3:8])[CH2:4][O:5]1
Reactant: COCC=O
Reactant: CCC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC1(C)COC(COC)OC1
Yield: 89 %

Procedure:
A mixture of 590 g (5 moles) of 2-ethyl-2-methyl1,3-propanediol, 479 g (5.5 moles) of 85% strength methoxyacetaldehyde and 500 ml of chloroform was heated with 10 g of pyridinium p-toluenesulfonate under a water separator until water no longer separated off. The remaining solution was deionized using a mixed-bed ion exchanger, the solvent was removed under reduced pressure and the residue was distilled. 774 g (89% yield) of 2-methoxymethyl-5-ethyl-5-methyl-1,3-dioxane of boiling point 58° C./1 mbar were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH:13]=[O:14])=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[C:8]([CH:13]=[O:14])=[CH:9]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Product: CC(=O)n1cc(C=O)c2ccc([N+](=O)[O-])cc21
Yield: 93.3 %

Procedure:
Substantially the same procedure as in Example 3 was repeated using 6-nitroindole-3-carboxaldehyde (2.3 g) and acetic anhydride (2.47 g) to give 1-acetyl-6-nitroindole-3-carboxaldehyde (2.62 g).
Reaction SMILES: COC([N:5]1[C:13]2[C:8](=[C:9]([NH:14][C:15]([NH:17][CH:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=4)[O:21][CH2:20][CH2:19]3)=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1)=O.COC(N1C2C(=C(NC(NC3C4C(=CC(C(C)(C)C)=CC=4)OCC3)=O)C=CC=2)C=N1)=O>O>[F:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][CH2:19][CH:18]2[NH:17][C:15]([NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[CH:7]=[N:6][NH:5]2)=[O:16]
Reactant: COC(=O)n1ncc2c(NC(=O)NC3CCOc4ccc(F)cc43)cccc21
Agent: COC(=O)n1ncc2c(NC(=O)NC3CCOc4cc(C(C)(C)C)ccc43)cccc21
Solvent: O
Product: O=C(Nc1cccc2[nH]ncc12)NC1CCOc2ccc(F)cc21

Procedure:
The title compound was prepared using the procedure as described in Example 1E, substituting the product of Example 10C for the product of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ 13.00 (broad s, 1H), 8.60 (s, 1H), 8.02 (s, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.21 (m, 1H), 7.08-7.00 (m, 3H), 6.92-6.80 (m, 2H), 4.92 (m, 1H), 4.35-4.11 (m, 2H), 2.20-1.93 (m, 2H). MS (DCI) m/e 327 (M+H)+. Calcd. For C17H15N4O2F.0.1; H2O: C, 62.23; H, 4.67; N, 17.07. Found: C, 62.31; H, 4.46; N, 16.74.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([NH:9][C:10](=[O:13])[O:11][CH3:12])=[O:8])=[C:5]([CH3:16])[CH:4]=1)=O.Cl.[NH2:18][OH:19]>CO.O>[OH:19][N:18]=[CH:1][C:3]1[CH:15]=[CH:14][C:6]([C:7]([NH:9][C:10](=[O:13])[O:11][CH3:12])=[O:8])=[C:5]([CH3:16])[CH:4]=1
Reactant: COC(=O)NC(=O)c1ccc(C=O)cc1C
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)NC(=O)c1ccc(C=NO)cc1C
Yield: 102.8 %

Procedure:
In a solution of 41 mg of methyl N-[4-formyl-2-methyl benzoyl]carbamate in 4 mL of methanol and 1 mL of water, 15 mg of hydroxylamine hydrochloride was added at room temperature with stirring, and continued to stir at the same temperature for 1.5 hour. After the completion of the reaction, 10 mL of water was added in the reaction mixture, and extracted with ethyl acetate (10 mL×2). The combined organic phases were dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 45 mg of the aimed product as white crystal.
Reaction SMILES: C(S([NH:7][C@H:8]([C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)[CH2:9][S:10][C:11]([CH3:18])([CH3:17])[C:12](OCC)=[O:13])=O)(C)(C)C.Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>CO>[F:26][C:21]1[CH:20]=[C:19]([C@H:8]2[NH:7][C:12](=[O:13])[C:11]([CH3:18])([CH3:17])[S:10][CH2:9]2)[CH:24]=[C:23]([F:25])[CH:22]=1
Reactant: CCOC(=O)C(C)(C)SC[C@H](NS(=O)C(C)(C)C)c1cc(F)cc(F)c1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1(C)SC[C@@H](c2cc(F)cc(F)c2)NC1=O
Temperature: 115 °C

Procedure:
To a solution of methyl 2-{[(2R)-2-[(tert-butylsulfinyl)amino]-2-(3,5-difluorophenyl)ethyl]thio}-2-methylpropanoate from Step C (428 mg, 1.09 mmol) in MeOH (20 mL), cooled to 0° C., was added anhydrous HCl gas for 1 minute. The reaction was sealed and allowed to sit at 0° C. for fifteen minutes, after which nitrogen was bubbled through the reaction for twenty minutes. The reaction was concentrated in vacuo. Additional MeOH (30 mL) was added and it was again concentrated in vacuo. This was repeated with another addition of MeOH and triethylamine (440. mg, 4.35 mmol). To the resulting residue was added toluene (10 mL) and triethylamine (440. mg, 4.35 mmol). A reflux condenser was attached and the mixture stirred at 115° C. After one week of stirring, the reaction was judged to be 90% complete by LCMS. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was diluted with diethyl ether (50 mL) and washed individually with 20 mL of each of the following aqueous solutions: 1 M HCl (twice), water, and saturated brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue that was purified by silica gel chromatography, eluting with a gradient of MeOH:CH2Cl2—1:99 to 5:95, to give the title compound. MS: m/z=258 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[O:19][C:18](=[O:20])[NH:17][N:16]=3)=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:29]I>CN(C=O)C>[Br:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]([C:21]([CH3:23])([CH3:22])[CH3:24])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[O:19][C:18](=[O:20])[N:17]([CH3:29])[N:16]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CI
Reactant: CC(C)(C)n1c(-c2ccccc2-c2n[nH]c(=O)o2)nc2cc(Br)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)oc1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
To a round bottom flask is added 5-[2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-phenyl]-3H-[1,3,4]oxadiazol-2-one (100 mg, 0.242 mmol) in DMF (4 mL) at 0° C., followed by the addition of NaH (19 mg, 0.475 mmol). The reaction mixture is stirred at 0° C. for 10 minutes, followed by the addition of MeI (103 mg, 0.726 mmol). The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (20 mL). The organic layer is separated, washed with brine, dried under anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel flash chromatography with 0-5% MeOH/CH2Cl2 as the eluent to afford 5-[2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-phenyl]-3-methyl-3H-[1,3,4]oxadiazol-2-one (92 mg, 89%) as a solid. LCMS (ESMS): m/z 427.63, 429.67 (M++1).
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([N:14]([CH3:16])[CH3:15])=[O:13])C1C=CC=CC=1.C1COCC1>CCO.[C].[Pd]>[NH2:10][C@@H:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([N:14]([CH3:16])[CH3:15])=[O:13]
Reactant: CN(C)C(=O)[C@@H](NC(=O)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)C(=O)[C@@H](N)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 101.8 %

Procedure:
A suspension of 1.67 g of the compound obtained in Step 87-1 and 0.17 g of 10% palladium-carbon in EtOH (20 ml) was stirred at room temperature for 14 hours under hydrogen atmosphere. The stirred solution was added with THF (1 ml) and stirred at room temperature for 1 hour under hydrogen atmosphere. The insoluble matter was separated by filtration and the filtrate was concentrated under reduced pressure to obtain 0.97 g of the title compound (pale yellow solid, crude form).
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:14]3[O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:13]3=[N:12][C:4]=1[CH:5]=[N+:6]2[O-].[NH4+:20].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:14]3[O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:13]3=[N:12][C:4]=1[C:5]([NH2:20])=[N:6]2
Reactant: [O-][n+]1cc2nc3n(c2c2ccccc21)OCCCC3
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1nc1n2OCCCC1
Reaction time: 0.67 h

Procedure:
A solution of 8,9,10,11-tetrahydro[1,2]oxazepino[2′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide (0.1384 g, 0.5421 mmol) in 6 mL of dichloromethane was treated with 3 mL of concentrated aqueous NH4OH solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (0.12 g, 0.65 mmol) was carefully added. Rapid stirring was continued for 40 minutes. The reaction mixture was then diluted with more dichloromethane, washed successively with dilute aqueous K2CO3, H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. The solid was triturated with ether and filtered. Crystallization from acetonitrile gave 0.0369 g of 8,9,10,11-tetrahydro[1,2]oxazepino[2′,3′:1,2]imidazo[4,5-c]quinolin-6-amine as a white powder, dec. 247-255° C. MS (APCI) m/z 255 (M+H)+; Anal. calcd for C14H14N4O: C, 66.13; H, 5.55; N, 22.03. Found: C, 65.82; H, 5.27; N, 22.11.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:14][C:15](=O)[C:16]([O:28][C:29]1[CH:51]=[CH:50][C:32]2[C:33]3[N:37]([CH2:38][CH2:39][O:40][C:31]=2[CH:30]=1)[CH:36]=[C:35]([C:41]1[N:42]([CH:47]([CH3:49])[CH3:48])[N:43]=[C:44]([CH3:46])[N:45]=1)[N:34]=3)([CH3:27])[CH2:17][CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)C1C=CC=CC=1.CCOC(C)=O.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[CH2:20]([O:19][CH2:18][CH2:17][C:16]([O:28][C:29]1[CH:51]=[CH:50][C:32]2[C:33]3[N:37]([CH2:38][CH2:39][O:40][C:31]=2[CH:30]=1)[CH:36]=[C:35]([C:41]1[N:42]([CH:47]([CH3:49])[CH3:48])[N:43]=[C:44]([CH3:46])[N:45]=1)[N:34]=3)([CH3:27])[CH2:15][OH:14])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)(CCOCc4ccccc4)C(=O)OCc4ccccc4)cc2OCC3)n(C(C)C)n1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)(CO)CCOCc4ccccc4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.6 %

Procedure:
To a suspension of LiAlH4 (4.4 mg, 0.116 mmol) in THF (1 mL) was added a solution of 4-benzyloxy-2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-2-methylbutyric acid benzyl ester (36 mg, 0.058 mmol) in THF (2 mL) and stirring at RT was continued for 2.5 h. To the reaction mixture was added EtOAc (0.5 mL) and stirring was continued for 10 min. An aqueous solution of Rochelle's salt was then added and the aqueous phase was extracted with EtOAc (×2). The combined organic phases were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 3-12% MeOH in DCM) affording 4-Benzyloxy-2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-2-methylbutan-1-ol (29 mg, 98%). 1H NMR (CDCl3, 400 MHz): δ 8.41 (1H, d, J=8.83 Hz), 7.60 (1H, s), 7.39-7.27 (5H, m), 6.81 (1H, dd, J=8.83, 2.41 Hz), 6.69 (1H, d, J=2.37 Hz), 5.98-5.85 (1H, m), 4.60-4.50 (2H, m), 4.49-4.35 (4H, m), 3.83-3.69 (2H, m), 3.65-3.55 (2H, m), 3.24 (1H, s), 2.42 (3H, s), 2.20-2.12 (1H, m), 2.07-1.97 (1H, m), 1.57 (6H, d, J=6.75 Hz), 1.31 (3H, s)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)[CH:5]=[CH:6][CH:7]=1.O.[NH2:19][NH2:20]>C(O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[NH:20][N:19]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1cccc(O)c1)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Oc1cccc(C2CC(c3ccccc3)=NN2)c1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
To a 250 ml round bottom flask equipped with magnetic stirrer and reflux condenser was charged 3.2 g (0.0143 moles) of 3-hydroxychalcone, 50 mls of ethanol and 0.7 g (0.0143 moles) of hydrazine monohydrate. The reaction was refluxed for a total of 2 hours, after which it was cooled to ambient temperature. The resulting solid was collected by vacuum filtration, washed with hexane, and dried in vacuuo at 40° C. overnight to afford 3.4 g of the title compound, 3-phenyl-5-(3-hydroxyphenyl)-2-pyrazoline as a tan solid in a 99% isolated yield.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([O:18][C:19]([F:22])([F:21])[F:20])[C:6]([O:16][CH3:17])=[C:7]([CH:9]([O:13]CC)OCC)[CH:8]=1.C[Mg]Br.[O:26]1[CH2:30]CCC1.Cl.[O:32]1CCCC1>>[CH:9]([C:7]1[CH:8]=[C:3]([CH:4]=[C:5]([O:18][C:19]([F:20])([F:21])[F:22])[C:6]=1[O:16][CH3:17])[C:30]([OH:26])=[O:32])=[O:13]
Reactant: CCOC(OCC)c1cc(Br)cc(OC(F)(F)F)c1OC
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: Cl
Agent: [Mg]
Product: COc1c(C=O)cc(C(=O)O)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To magnesium (403 mg), tetrahydrofuran (16 mL), 5-bromo-1-diethoxymethyl-2-methoxy-3-trifluoromethoxybenzene (6.19 g) and a 0.97M methylmagnesium bromide-tetrahydrofuran solution (0.42 mL) were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The reaction solution was cooled to 0° C. and stirred for 45 minutes under a carbon dioxide atmosphere. 4N hydrochloric acid (25 mL) was added and then the mixture was stirred at room temperature for 30 minutes. The organic solvent was distilled off under reduced pressure and the mixture was extracted with diisopropylether. The organic layer was extracted with 1N sodium hydroxide (100 mL) added thereto and the aqueous layer was washed twice with diisopropylether. The aqueous layer was acidified with 4N hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (4.22 g) as a brown solid.