Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13]2[CH:17]=[N:16][NH:15][N:14]=2)[O:4]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH3:26]>CC(C)=O>[CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13]2[CH:17]=[N:16][N:15]([CH2:25][CH3:26])[N:14]=2)[O:4]1
Reactant: CO[C@@H]1O[C@H](c2cn[nH]n2)[C@H]2OC(C)(C)O[C@@H]12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCn1ncc([C@H]2O[C@@H](OC)[C@@H]3OC(C)(C)O[C@@H]32)n1
Temperature: 25 °C
Yield: 46.1 %

Procedure:
A solution of 4-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2H-1,2,3-triazole (Preparation 23) (0.35 g, 1.45 mmol), potassium carbonate (0.2 g, 1.45 mmol) and iodoethane (0.12 ml, 1.45 mmol) in acetone (5 ml) was stirred at room temperature for 48 hours. The reaction mixture was allowed to cool to room temperature, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (99.7:0.3 by volume) gradually changing to dichloromethane:methanol (99:1 by volume) to give initially 4-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2-ethyl-2H-1,2,3-triazole (0.18 g) followed by the title compound (TLC data—Rf 0.25 in solvent system dichloromethane:methanol 98:2 by volume) contaminated with 25% of 5-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-1-ethyl-1H-1,2,3-triazole (0.16 g). This material was used in subsequent steps without further purification.
Reaction SMILES: [CH3:1][C:2]1([C:5]([NH:7][NH2:8])=[O:6])[CH2:4][CH2:3]1.[C:9](Cl)(Cl)=[O:10]>C(Cl)Cl>[O:10]=[C:9]1[N:8]=[N:7][CH:5]([C:2]2([CH3:1])[CH2:4][CH2:3]2)[O:6]1
Reactant: CC1(C(=O)NN)CC1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Product: CC1(C2N=NC(=O)O2)CC1

Procedure:
85 gm of 1-methylcyclopropane carboxylic acid hydrazide was added to methylene chloride on a 3-neck 2-liter round bottom flask. The system was first cooled to 0°-5° C. and 590.5 gm of a 12.5% solution of phosgene added dropwise over a period of time. The system was then heated at reflux for 7 hours. The methylene chloride was removed by stripping. The product was washed with petroleum ether and filtered to give 66.6 gm of 2-oxo-5-(1'-methylcyclopropyl)-1,3,4-oxadiazoline as light brown crystals, m.p. 68°-70° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[NH:24]1[CH:28]=[CH:27][N:26]=[C:25]1[CH:29]=O.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:29]([C:25]3[NH:24][CH:28]=[CH:27][N:26]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Reactant: O=Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2oc(-c3ccc4c(c3)nc(-c3ncc[nH]3)n4C3CCOCC3)nc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 12.6 %

Procedure:
5-(Benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (0.10 g, 0.32 mmol) was dissolved in DMF (3 mL) and water (0.1 mL), 2-imidazolecarbaldehyde (0.03 g, 0.31 mmol) was added followed by oxone (0.13 g, 0.21 mmol), and this was stirred at room temperature for 2.5 hours. Aqueous potassium carbonate solution (0.10 g/15 mL) was added to the reaction solution. This was extracted with chloroform, washed with water, and after drying over magnesium sulfate, this was concentrated and purified by silica gel column chromatography. The crystals obtained were washed with hexane and a small amount of ethyl acetate, and dried to yield the title compound (15 mg, 12.1% yield) as light brown crystals.
Reaction SMILES: [Li]C(CC)C.[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7]1.CN(CCN(C)C)C.CN([CH:26]=[O:27])C>C1COCC1>[O:6]1[C:10]2[C:11]([CH:26]=[O:27])=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7]1
Reactant: CN(C)C=O
Reactant: c1ccc2c(c1)CCO2
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: O=Cc1cccc2c1OCC2
Reaction time: 1 h

Procedure:
sec-BuLi (20.00 ml, 1.4 M in cyclohexane, 28.00 mmol) was added to a solution of 2,3-dihydro-benzofuran (2.40 mL, 21.30 mmol) and TMEDA (10.00 mL) in THF at −20° C. The resulting mixture was stirred for 1 hour, then DMF (3.00 mL, 38.75 mmol) was added and stirring was continued for another 30 minutes. The reaction mixture was quenched with water and diluted with ether. The resulting solution was washed with brine, dried over MgSO4 and concentrated to afford the desired title aldehydei. i Tasker, Andrew S.; Sorensen, Bryan K.; Jae, Hwan-Soo; Winn, Martin; Geldern, Thomas W. von; et al. J. Med. Chem. 1997, 40, 322-330.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH3:17])[CH:8]=1)=O.Cl.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH2:30])=[NH:29])=[CH:23][CH:22]=1.[OH-].[Na+]>CCO.CO>[CH2:16]([N:9]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:15]2[C:7]([C:5]2[CH:4]=[CH:3][N:30]=[C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([OH:20])=[CH:22][CH:23]=3)[N:29]=2)=[CH:8]1)[CH3:17]
Reactant: CCn1cc(C(=O)/C=C/N(C)C)c2cccnc21
Reactant: N=C(N)Nc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CCn1cc(-c2ccnc(Nc3ccc(O)cc3)n2)c2cccnc21

Procedure:
A mixture of (E)-3-(dimethylamino)-1-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)prop-2-en-1-one (5 mmol) in 3 mL EtOH/MeOH (1:2, v/v) was treated with 1-(4-hydroxyphenyl)guanidine hydrochloride (5 mmol) and NaOH (10 mmol). The reaction mixture was microwaved at 150° C. for 25 minutes. The residue was purified by chromatography using EtOAc to elute the titled compound. Recrystallisation from EtOAc yielded white solid. 1H-NMR (DMSO-d6) δ: 1.45 (t, 3H, J=7.2 Hz, CH3), 4.37 (q, 2H, J=7.6 Hz, CH2), 6.74 (d, 2H, J=8.8 Hz, Ph-H), 7.15 (d, 1H, J=5.2 Hz, Pyrimidin-H), 7.20 (q, 1H, J=4.8 Hz, Ar—H), 7.51 (d, 2H, J=8.8 Hz, Ph-H), 8.29 (d, 1H, J=5.2 Hz, Pyrimidin-H), 8.35 (m, 1H, Ar—H), 8.54 (s, 1H, Ar—H), 8.88 (d, 1H, J=6.8 Hz, OH), 9.04 (s, 1H, Ar—H), 9.10 (s, 1H, NH). MS (ESI+) m/z 322.1469 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11](Cl)[N:10]=1>CN(C=O)C.CCOC(C)=O.O>[Cl:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[N:10]=1
Reactant: Clc1cncc(Cl)n1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cncc(-n2cncn2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 1,2,4-triazole (276 mg, 4.0 mmol, 2.0 eq) in 1.5 mL of DMF was added carefully sodium hydride (60 wt. %. in mineral oil, 120 mg, 3.0 mmol, 3.0 eq) (caution: intensive gas development). The reaction mixture was stirred at room temperature for 45 min. 2,6-Dichloropyrazine (298 mg, 2.0 mmol, 1.0 eq) in 0.5 mL of DMF was added and the reaction mixture was heated at 95° C. for 60 min. The mixture was allowed to cool to room temperature and diluted with EtOAc (15 mL) and water (15 mL). The separated organic layer was concentrated under reduced pressure to afford crude material containing the title compound. The crude material was suspended in NMP (2 mL) and directly used in coupling reactions with phenols. ES/MS m/z 182.0, (MH+), Rt=1.68 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][C@H:16](OS(C)(=O)=O)[CH2:15][CH2:14][C@@H:13]1[C:23]([O:25][CH3:26])=[O:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:27]=[N+:28]=[N-:29].[Na+].C([O-])(O)=O.[Na+].O>CN(C)C=O>[N:27]([C@H:16]1[CH2:15][CH2:14][C@H:13]([C:23]([O:25][CH3:26])=[O:24])[C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:17]1)=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@H]1CC[C@@H](OS(C)(=O)=O)C[C@H]1NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H]1CC[C@H](N=[N+]=[N-])C[C@H]1NC(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 72.1 %

Procedure:
To a solution of methyl (1S,2R,4R)-2-{[(benzyloxy)carbonyl]amino}-4-[(methylsulfonyl)oxy]cyclohexanecarboxylate (0.30 g, 0.78 mmol) in N,N-dimethylformamide (2.6 mL) was added sodium azide (0.20 g, 3.1 mmol). The reaction was heated to 80° C. and stirred for 2.5 h. After cooling, the reaction mixture was poured into sat. NaHCO3/water and extracted with EtOAc (3 x). The combined extracts were washed with brine, dried (Na2SO4), and concentrated. The crude was purified on silica gel, eluting with 0-40% EtOAc in hexanes to give 187 mg (72%) of the desired product as a clear gum. LCMS calculated for C16H21N2O4 (M+H-28)+: m/z=305.2. Found: 305.1.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6](/[CH:9]=[CH:10]\[S:11][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:7][CH:8]=1)([OH:3])=O.Cl.[C:32]([CH:34]1[CH2:37][NH:36][CH2:35]1)#[N:33]>>[C:32]([CH:34]1[CH2:37][N:36]([C:1]([C:4]2[N:5]=[C:6](/[CH:9]=[CH:10]\[S:11][C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:7][CH:8]=2)=[O:3])[CH2:35]1)#[N:33]
Reactant: N#CC1CNC1
Reactant: O=C(O)c1csc(/C=C\SC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Product: N#CC1CN(C(=O)c2csc(/C=C\SC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C1
Yield: 66.2 %

Procedure:
In the same manner as in step c) in Example 3, 0.271 g of the title compound was prepared from 0.356 g of 4-carboxy-2-((Z)-2-tritylthioethen-1-yl)thiazole and 0.149 g of 3-cyanoazetidine hydrochloride.
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:23]([N:25]([C@@H:27]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:28]([O:55][CH3:56])[CH2:29][C:30]([N:32]3[CH2:36][CH2:35][CH2:34][C@H:33]3[C@H:37]([O:53][CH3:54])[C@@H:38]([CH3:52])[C:39]([NH:41][C@H:42]([CH3:51])[C@@H:43]([OH:50])[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:40])=[O:31])[CH3:26])=[O:24])[CH:20]([CH3:22])[CH3:21])=O)C3C(=CC=CC=3)C=2C=CC=1.C1COCC1.C(NCC)C>>[OH:50][C@@H:43]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C@H:42]([NH:41][C:39](=[O:40])[C@H:38]([CH3:52])[C@H:37]([C@@H:33]1[CH2:34][CH2:35][CH2:36][N:32]1[C:30](=[O:31])[CH2:29][C@@H:28]([O:55][CH3:56])[C@@H:27]([N:25]([CH3:26])[C:23](=[O:24])[C@H:19]([CH:20]([CH3:21])[CH3:22])[NH2:18])[C@@H:57]([CH3:60])[CH2:58][CH3:59])[O:53][CH3:54])[CH3:51]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: C1CCOC1
Solvent: CCNCC
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](N)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.2 %

Procedure:
To a stirring solution of #132 (1.33 g, 1.60 mmol, 1.0 eq) in 10 mL of THF diethylamine (5 mL, 50 mM, 31.3 eq) was added. The reaction was allowed to stir at room temperature for 4 hours. Reaction was concentrated in vacuo and the residue was purified by silica chromatography (Gradient: 0%-30% methanol in ethyl acetate) producing #133 (418 mg, 43%) as a white solid. LC-MS (Protocol Q1): m/z 605.2 [M+H+] retention time=1.48 minutes.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:17]([C:19]1[CH:23]=[CH:22][O:21][CH:20]=1)=[O:18])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[C:2]1([C:1]2[O:18][C:17]([C:19]3[CH:23]=[CH:22][O:21][CH:20]=3)=[C:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccccc1)C(=O)c1ccoc1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccccc2)oc1-c1ccoc1
Yield: 79.5 %

Procedure:
2.0 g of ethyl 3-benzoylamino-3-(3-furylcarbonyl)propionate, 15 ml of chloroform and 4.9 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 1.5 g of ethyl 2-[2-phenyl-5-(3-furyl)-4-oxazolyl]acetate are thereby obtained. Yield: 79.0%
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][NH2:38])[CH2:32][CH2:31]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([NH:38][CH2:37][CH2:36][N:33]5[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: CN1CCN(CCN)CC1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CN1CCN(CCNc2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 47.7 %

Procedure:
A mixture of 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (300 mg, 0.72 mmol), Pd(OAc)2 (20 mg, 0.1 mmol), 2-(4-methylpiperazin-1-yl)ethanamine (121 mg, 0.936 mmol), X-phos (70 mg, 0.144 mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) was bubbled N2 for 10 min and then stirred at 120° C. for 5 min under the irradiation of microwave. The mixture was filtered over ceilite. The filtrate was concentrated to dryness and purified by pre-HPLC to afford 180 mg of 231. (yield=48%). 1H NMR (CDCl3, 400 MHz): δ8.41 (s, 1H), 8.01 (m, 1H), 7.50-7.45 (m, 1H), 7.06-6.99 (m, 3H), 6.88 (s, 1H), 6.24 (d, J=8.8 Hz, 1H), 4.16-4.14 (m, 2H), 3.42-3.40 (m, 2H), 3.02-3.00 (m, 2H), 2.82-2.70 (m, 10H), 2.42 (s, 3H). LC-MS (ESI): m/z=524 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B(O)O)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.[CH3:29][C:30]1[C:34]2[CH:35]=[CH:36][C:37]([OH:39])=[CH:38][C:33]=2[O:32][N:31]=1>>[CH3:23][O:22][C:20](=[O:21])[CH2:19][C@H:16]1[C:15]2[CH:24]=[CH:25][C:12]([O:11][C@H:9]3[C:10]4[C:6](=[C:5]([O:39][C:37]5[CH:36]=[CH:35][C:34]6[C:30]([CH3:29])=[N:31][O:32][C:33]=6[CH:38]=5)[CH:4]=[CH:3][C:2]=4[F:1])[CH2:7][CH2:8]3)=[CH:13][C:14]=2[O:18][CH2:17]1
Reactant: Cc1noc2cc(O)ccc12
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B(O)O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc6c(C)noc6c5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from (R)-7-fluoro-1-[(S)-3-methoxycarbonylmethyl-2,3-dihydrobenzofuran-6-yloxy]-2,3-dihydro-1H-inden-4-ylboronic acid and 3-methyl-benzo[d]isoxazol-6-ol following a procedure analogous to that described for Intermediate 6. LC (method 3): tR=0.66 min; Mass spectrum (ESI+): m/z=490 [M+H]+.
Reaction SMILES: C(N1CCN([NH:14][C:15](=[O:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)CC1)(OC(C)(C)C)=O.[CH2:24]([C:26]1[S:34][C:33]2[N:32]=[C:31]([CH2:35][CH2:36][CH3:37])[N:30]=[C:29]([N:38]3[CH2:43][CH2:42]N(C(OC(C)(C)C)=O)[CH2:40][CH2:39]3)[C:28]=2[CH:27]=1)[CH3:25]>>[CH2:24]([C:26]1[S:34][C:33]2[N:32]=[C:31]([CH2:35][CH2:36][CH3:37])[N:30]=[C:29]([N:38]3[CH2:43][CH2:42][N:14]([C:15](=[O:23])[CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:40][CH2:39]3)[C:28]=2[CH:27]=1)[CH3:25]
Reactant: CCCc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)c2cc(CC)sc2n1
Reactant: CC(C)(C)OC(=O)N1CCN(NC(=O)Cc2ccccc2)CC1
Product: CCCc1nc(N2CCN(C(=O)Cc3ccccc3)CC2)c2cc(CC)sc2n1
Yield: 36 %

Procedure:
Phenylacetamidopiperazine hydrochloride (Example 141) was reacted 2-propyl-4-chloro-6-ethylthienopyrimidine (Example 159) according to Example 87. Yield 36%, ES-MS: (M+H)+ 409.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:20]=[CH:19][CH:18]=[CH:17][C:5]=2[C:6]=1[CH:7]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]([O:10][CH3:11])=[O:9].C(=O)([O-])[O-].[Na+].[Na+].O.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[O:42][CH2:41][CH2:40][CH2:39]3)O1>CN(C)C=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:13]([O:12][CH:7]([C:6]1[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[S:3][C:2]=1[C:36]1[CH:45]=[CH:44][C:43]2[O:42][CH2:41][CH2:40][CH2:39][C:38]=2[CH:37]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)C(OC(C)(C)C)c1c(Br)sc2ccccc12
Reactant: CC1(C)OB(c2ccc3c(c2)CCCO3)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2)CCCO3)sc2ccccc12
Temperature: 100 °C
Yield: 55.5 %

Procedure:
To a solution of methyl 2-(2-bromo-1-benzothiophen-3-yl)-2-(tert-butoxy)acetate (4c) (40 mg, 0.11 mmol) in N,N-dimethylformamide (2 mL) were successively added sodium carbonate (13 mg, 0.12 mmol), water (500 μL), palladium tetrakis(triphenylphosphine) (18.3 mg, 0.016 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman (29 mg, 0.11 mmol). The mixture was heated at 100° C. for 2 hours. After cooling to room temperature, water (10 mL) was added. The aqueous layer was extracted with ethyl acetate (2×10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired product (4d) as a white solid (25 mg, 0.061 mmol, 55%).
Reaction SMILES: [OH-].[Na+].[N+]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])([O-])=O.[C:15]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]=1[OH:29])([CH3:18])([CH3:17])[CH3:16].Cl>CS(C)=O>[C:25]([C:21]1[CH:22]=[C:23]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N+:12]([O-:14])=[O:13])[CH:24]=[C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:20]=1[OH:29])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=[N+]([O-])c1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(-c2ccccc2[N+](=O)[O-])cc(C(C)(C)C)c1O
Temperature: 60 °C
Yield: 106.6 %

Procedure:
A mixture of 30 mg (0.75 mmol) of powdered sodium hydroxide, 100 mg (0.59 mmol) of 1,2-dinitrobenzene, 155 mg (0.75 mmol) of 2,6-di-t-butylphenol, and 1.0 mL of dimethylsulfoxide was heated at 60° C. for 17 hours and poured into 10 mL of 1N HCl, and the resulting aqueous mixture was extracted with three 10 mL portions of diethyl ether. The ether layers were combined, dried over magnesium sulfate, and concentrated. Purification of the residue by preparative thin layer chromatography (tlc) afforded 206 mg of crude 2,6-di-t-butyl-4-(2-nitrophenyl)phenol.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C@H:8]([OH:21])[CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])=[C:4]([O:24][C:25](=[O:27])[CH3:26])[CH:3]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C@H:8]([O:21][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])=[C:4]([O:24][C:25](=[O:27])[CH3:26])[CH:3]=1
Reactant: CC(=O)Oc1cc(Cl)ccc1OC[C@H](O)CN1C(=O)c2ccccc2C1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cc(Cl)ccc1OC[C@@H](CN1C(=O)c2ccccc2C1=O)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.6 %

Procedure:
To a reaction vessel were added crude (R)-1-(4-chloro-2-acetoxyphenoxy)-3-phthalimido-2-propanol 364 mg (0.90 mmol), triethylamine 137 mg (1.36 mmol) and ethyl acetate 2 mL. To this mixture was slowly dropped methanesulfonyl chloride 134 mg (1.18 mmol) in an ice bath and then the mixture was stirred at room temperature for 3 hours. After washing with an aqueous 5% HCl solution and water successively, the organic layer was taken and the solvent was evaporated to give crude (R)-1-(4-chloro-2-acetoxyphenoxy)-2-methanesulfonyloxy-3-phthalimidopropane 213 mg (yield 98%, chemical purity 97%) as a brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:17]([CH3:19])[CH3:18])[CH:13]([OH:16])[C:14]#[N:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:17]([CH3:19])[CH3:18])[CH:13]([O:16][C:26](=[O:28])[CH3:27])[C:14]#[N:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)C(NC(=O)OCc1ccccc1)C(O)C#N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OC(C#N)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Yield: 90.6 %

Procedure:
To a solution containing 3-[(benzyloxycarbonyl)amino]-2-hydroxy-4-methylpentanenitrile (32.0 g, 0.12 mol) and pyridine (59 mL) was added acetic anhydride (73.6 g, 68 mL, 0.72 mol) dropwise at RT. After 3 h the reaction was diluted with ethyl acetate and washed with water. The organic layer was separated, dried (anhydrous magnesium sulfate) and evaporated. The residue was purified by column chromatography (silica get, 1:1 hexane:ethyl acetate) to give 33.08 g (94.0%) of 3-(S)-[(benzyloxycarbonyl)amino]-2-acetoxy-4-methylpentanenitrile as a viscous yellow oil; TLC Rf =0.70 (silica gel, 1:1 hexane:ethyl acetate).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([NH:22][CH2:23][CH2:24][NH2:25])[N:19]2[CH:26]=[CH:27][N:28]=[C:18]2[CH:17]=1.CN1CCCC1.Cl[C:36]1[N:41]=[CH:40][C:39]([C:42](=[O:44])[CH3:43])=[CH:38][CH:37]=1.CCN(C(C)C)C(C)C>>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([NH:22][CH2:23][CH2:24][NH:25][C:36]2[N:41]=[CH:40][C:39]([C:42](=[O:44])[CH3:43])=[CH:38][CH:37]=2)[N:19]2[CH:26]=[CH:27][N:28]=[C:18]2[CH:17]=1
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: NCCNc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Agent: CN1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nccn23)nc1
Temperature: 130 °C

Procedure:
50 mg (0.155 mmol) of the amine (Example 8A) are introduced into 3 ml of dry N-methylpyrrolidine, 48.3 mg (0.31 mmol) of 1-(6-chloropyridin-3-yl)ethanone and 40.1 mg (0.31 mmol) of DIPEA are added, and the mixture is heated in a microwave at 130° C. for 1.5 h. Purification by preparative HPLC results in 11 mg (15% of theory) of the product as a solid.
Reaction SMILES: [CH:1]1([NH:9][C:10]([NH2:12])=[S:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:14]1([C:18](OCC)=[O:19])[CH2:17][CH2:16][CH2:15]1>>[CH:1]1([NH:9][C:10]2[S:11][C:14]3([C:18](=[O:19])[N:12]=2)[CH2:17][CH2:16][CH2:15]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1(Br)CCC1
Reactant: NC(=S)NC1CCCCCCC1
Product: O=C1N=C(NC2CCCCCCC2)SC12CCC2

Procedure:
Synthesis was performed from N-cyclooctylthiourea and ethyl 1-bromocyclobutanecarboxylate according to Method D2.
Reaction SMILES: COC[O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:21][CH:20]=3)[C:17]([OH:31])=[N:16][N:15]=2)=[C:7]([O:32]COC)[CH:6]=1.Cl>C(O)C>[OH:31][C:17]1[N:18]([C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)[C:14]([C:8]2[CH:9]=[C:10]([CH:11]([CH3:13])[CH3:12])[C:5]([OH:4])=[CH:6][C:7]=2[OH:32])=[N:15][N:16]=1
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1-c1nnc(O)n1-c1ccc(N2CCOCC2)cc1
Agent: Cl
Solvent: CCO
Product: CC(C)c1cc(-c2nnc(O)n2-c2ccc(N3CCOCC3)cc2)c(O)cc1O
Yield: 22.3 %

Procedure:
An ethanol solution (2 mL) of 1,3-bis(methoxymethoxy)-4-{5-hydroxy-4-[4-(morpholin-4-yl)-phenyl]-4H-[1,2,4]triazol-3-yl}-6-isopropylbenzene (IM6-O-a01: 16.3 mg, 0.034 mmol) was mixed with 5 N hydrochloric acid (1 mL) and reacted at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the residue was neutralized with 5% sodium hydrogencarbonate and extracted with dichloromethane (30 mL). The extract was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol=30:1-20:1) to obtain the title compound (OH-a01: white solid, 3.0 mg, 22%).