Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][C@@H:6]1[O:24][CH3:25])=[O:4].[N-:26]=[N+:27]=[N-:28].[Na+].O>CC(N(C)C)=O>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([N:26]=[N+:27]=[N-:28])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][C@@H:6]1[O:24][CH3:25])=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@H]1C[C@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1OC
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)[C@H]1C[C@H](S(=O)(=O)c2ccc(N=[N+]=[N-])cc2C(F)(F)F)C[C@@H]1OC
Temperature: 50 °C
Yield: 77 %

Procedure:
To a solution of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid methyl ester (500 mg, 1.123 mmol, intermediate in the synthesis of example 58) in DMA (5 ml) was added sodium azide (146 mg, 2.246 mmol) and the reaction mixture was heated to 50° C. for 26 h. Then water was added and the mixture was extracted 3 times with EtOAc. The combined organic layers were dried (Na2SO4) and evaporated. The remaining brown oil was purified by silica gel chromatography (DCM/EtOAc 95:5) to obtain the title compound (351 mg, 77%) as light brown oil. MS (EI): 466.2 (M+OAc)−.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C@@H:12]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(N(CC)CC)C>ClCCl>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][C@@H:12]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)(C)OC(=O)C[C@@H](N)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@@H](Nc1ccccc1[N+](=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-fluoronitrobenzene (150 mg, 1.06 mmol) in dichloromethane (4 mL) was added tert-butyl (3R)-3-amino-3-phenylpropanoate (235 mg, 1.06 mmol) and triethylamine (300 μL, 2.12 mmol). The solution was stirred at room temperature for 4 hours, and was then evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane, to afford the title compound, 1H NMR: (CD3OD), 8.76 (br m, 1H), 8.18 (d, J=7.69, 1H), 7.44 (d, J=7.69, 2H), 7.40-7.37 (m, 2H), 7.32-7.28 (m, 1H), 6.84 (d, J=8.79 1H), 6.73-6.69 (m, 1H), 5.12 (dd, J=13.18, 6.59 1H), 2.91 (d, J=6.59 2H), 1.41 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([C:11]#[N:12])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH:29]=[N:30][NH:31]3)O1>>[NH:31]1[C:32]2[C:28](=[C:27]([C:2]3[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:5]4[S:10][C:9]([C:11]#[N:12])=[CH:8][C:6]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[CH:29]=[N:30]1
Reactant: N#Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: N#Cc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbonitrile (35 mg) was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 (6 mg) by Suzuki coupling according to the General Procedure A to give 402. MS (Q1) 363 (M)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])=[C:4]([N+:13]([O-])=O)[CH:3]=1.[H][H]>C(O)C>[NH2:13][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1NCCCO
Solvent: CCO
Product: Nc1cc(Cl)ccc1NCCCO

Procedure:
A mixture of 34.6 parts of 3-[(4-chloro-2-nitrophenyl)amino]-1-propanol and 320 parts of ethanol is hydrogenated at normal pressure and at room temperature with 8 parts of Raneynickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 30 parts of 3-[(2-amino-4-chlorophenyl)amino]-1-propanol as an oily residue.
Reaction SMILES: [CH3:1][S:2]([CH:5]1[CH2:10][O:9][C:7](=[O:8])[C@@H:6]1[OH:11])(=[O:4])=[O:3].S(=O)(=O)(O)[OH:13]>>[OH:9][CH2:10][CH:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C@@H:6]([OH:11])[C:7]([OH:13])=[O:8]
Reactant: CS(=O)(=O)C1COC(=O)[C@@H]1O
Reactant: O=S(=O)(O)O
Product: CS(=O)(=O)C(CO)[C@@H](O)C(=O)O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
(S)-3-methanesulfonyl hydroxybutyrolactone (1.0 g, 5.6 mmol), D2O (10 ml), and the concentrated sulfuric acid (0.0549 g, 0.56 mmol) were placed in a 25 ml reactor and stirred at 50° C. for 3 hours. The reacting solution was cooled to room temperature and extracted with dichloromethane (10 ml) twice to recover the unreacted (S)-3-methanesulfonyl hydroxybutyrolactone. The presence of the target (S)-4-hydroxy-3-methanesulfonyl hydroxybutyric acid in a pure form in the D2O layer was confirmed by nuclear magnetic resonance.
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3]([O:6][C:7]([N:9]1[CH:14]2[C:15]([C:27](=[O:41])[N:28]([CH:38]3[CH2:40][CH2:39]3)[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=3[Cl:37])=[C:16]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH2:24][CH2:25]O)[CH:19]=3)[CH2:17][CH:10]1[CH2:11][N:12]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:13]2)=[O:8])([CH3:5])[CH3:4].[Cl:51][C:52]1[C:57]([CH3:58])=[CH:56][C:55]([OH:59])=[CH:54][C:53]=1[CH3:60]>>[C:45]([O:44][C:42]([N:12]1[CH2:13][CH:14]2[N:9]([C:7]([O:6][C:3]([CH3:5])([CH3:4])[CH3:2])=[O:8])[CH:10]([CH2:17][C:16]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH2:24][CH2:25][O:59][C:55]4[CH:56]=[C:57]([CH3:58])[C:52]([Cl:51])=[C:53]([CH3:60])[CH:54]=4)[CH:19]=3)=[C:15]2[C:27](=[O:41])[N:28]([CH:38]2[CH2:39][CH2:40]2)[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=2[Cl:37])[CH2:11]1)=[O:43])([CH3:46])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)N1CC2CC(c3cc(CCCO)no3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Reactant: Cc1cc(O)cc(C)c1Cl
Product: Cc1cc(OCCCc2cc(C3=C(C(=O)N(Cc4cccc(Cl)c4Cl)C4CC4)C4CN(C(=O)OC(C)(C)C)CC(C3)N4C(=O)OC(C)(C)C)on2)cc(C)c1Cl

Procedure:
This compound is prepared from compound E6 and 4-chloro-3,5-dimethylphenol, according to the above-described procedure A. LC-MS: tR=1.33 min, ES+: 933.35.
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].Cl.[CH:6]1[CH:7]=[CH:8][C:9]2[C:16](=[O:17])[C:15]([OH:18])=[CH:14][C:12](=[O:13])[C:10]=2[CH:11]=1>C(O)(=O)C>[OH:18][C:15]1[C:16](=[O:17])[C:9]2[C:10]([C:12](=[O:13])[C:14]=1[CH:1]=[CH:2][CH3:3])=[CH:11][CH:6]=[CH:7][CH:8]=2
Reactant: CCC=O
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Agent: Cl
Solvent: CC(=O)O
Product: CC=CC1=C(O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Propionaldehyde (RCHO, R=propyl, 5.0 mL, 69.3 mmol) was added to a solution of concentrated HCl (2 mL) and lawsone (2.00 g, 11.5 mmol) in acetic acid (35 mL) at 60° C. After stirring for 1.25 hours, another portion of propionaldehyde was added (5.0 mL, 69.3 mmol). The solution was then stirred for an additional 1 hour. The solution was allowed to cool to room temperature, and then ice water (200 mL) was added to quench the reaction. The solution was extracted with diethyl ether (3×200 mL) and the organic fractions pooled. The combined organic layers were re-extracted with 5% Na2CO3 (8×150 mL). The aqueous extracts were also pooled and acidified with concentrated HCl. A precipitate formed which was collected by filtration to afford (20) as an orange solid. 2-Hydroxy-3-propenyl-1,4-naphthoquinone (20) (983 mg, 40%): mp 133-134° C.; 1H NMR (CDCl3, 300 MHZ) δ 8.13 (d, J=7.7 Hz, 1H), 8.06 (d, J =7.5 Hz, 1H), 7.80-7.62 (m, 3H), 7.15-6.95 (m, 1H), 6.63 (d, J=16.1 Hz, 1H), 1.99 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClC(Cl)C.[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([C:15](Cl)=[O:16])=[CH:11][CH:10]=1.[CH3:19][N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][C:26]#[N:27].Cl>>[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([C:15]([C:24]2[N:20]([CH3:19])[C:21]([CH2:25][C:26]#[N:27])=[CH:22][CH:23]=2)=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cn1cccc1CC#N
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cc1ccc(C(=O)c2ccc(CC#N)n2C)cc1
Temperature: 25 °C

Procedure:
To a cooled suspension of 26.6 g. (0.2 mole) aluminum chloride in 80 ml. dichloroethane is added dropwise 30.8 g. (0.2 mole) p-toluoyl chloride. The resulting solution is added dropwise to a solution of l-methylpyrrole-2-acetonitrile in 80 ml. dichloroethane cooled externally with an ice bath. After the addition, the resulting solution is stirred at room temperature for twenty minutes and then refluxed for three minutes. The solution is poured into ice acidified with dilute hydrochloric acid. The organic and aqueous fractions are separated. The aqueous fraction is extracted once with chloroform. The organic fractions are combined and washed successively with N,N-dimethyl-1,3-propanediamine, dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic fraction is dried over anhydrous magnesium sulfate. The solvent is then evaporated off. Upon trituration of the residue with methanol, a solid crystallizes, 5-(p-toluoyl)-1 -methylpyrrole-2-acetonitrile, which is removed by filtration and purified by recrystallization from benzene. Additional product is isolated from the mother liquors which are combined, concentrated in vacuo, and the resulting oily residue column chromatographed on neutral alumina using hexane, benzene and ether as successive solvents. The product is isolated by concentrating in vacuo the first few major compound-bearing fractions (10% ether in benzene). The solids are combined and recrystallized from methanol and then from benzene-hexane, m.p. 102-105° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@@H:7]([CH3:16])[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[C:3]1=[O:17].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([S:27](Cl)(=[O:29])=[O:28])=[CH:24][C:23]=2[CH:31]=1.[Cl-].[NH4+]>C(#N)C.N1C=CC=CC=1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([S:27]([NH:1][C@H:2]3[CH2:6][CH2:5][N:4]([C@@H:7]([CH3:16])[C:8]([N:10]4[CH2:11][CH2:12][O:13][CH2:14][CH2:15]4)=[O:9])[C:3]3=[O:17])(=[O:29])=[O:28])=[CH:24][C:23]=2[CH:31]=1
Reactant: O=S(=O)(Cl)c1cc2cc(Cl)ccc2o1
Reactant: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](N)C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: c1ccncc1
Product: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](NS(=O)(=O)c2cc3cc(Cl)ccc3o2)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.1 %

Procedure:
To a solution of (3S)-3-amino-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]pyrrolidin-2-one [Intermediate 40] (0.077 g) in anhydrous acetonitrile (2 ml) were added 5-chloro-1-benzofuran-2-sulfonyl chloride [Intermediate 51] (0.043 g) in acetonitrile (2 ml) and pyridine (0.057 ml), and the mixture was stirred at room temperature for 72 h. Saturated ammonium chloride solution (2 ml) was added and the resultant mixture stirred at room temperature for 20 min. The mixture was concentrated under reduced pressure and the residue partitioned between chloroform and hydrochloric acid (2M). The organic layer was washed with saturated sodium bicarbonate and brine. The organic layer was isolated, dried (over magnesium sulphate) and concentrated under reduced pressure to give the title compound (0.043 g) as a white solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7]C=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O.CS(O[CH2:25][CH2:26][NH:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[C:35](=[O:49])[NH:36][C:37]1[CH:46]=[C:45]2[C:40]([CH2:41][CH2:42][C:43](=[O:48])[N:44]2[CH3:47])=[CH:39][CH:38]=1)(=O)=O>O>[ClH:34].[Cl:34][C:32]1[CH:31]=[CH:30][C:29]([C:35]([NH:36][C:37]2[CH:46]=[C:45]3[C:40]([CH2:41][CH2:42][C:43](=[O:48])[N:44]3[CH3:47])=[CH:39][CH:38]=2)=[O:49])=[C:28]([NH:27][CH2:26][CH2:25][N:5]2[CH2:6][CH2:7][CH:3]([F:2])[CH2:4]2)[CH:33]=1
Reactant: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3NCCOS(C)(=O)=O)cc21
Reactant: Fc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3NCCN3CCC(F)C3)cc21
Temperature: 40 °C
Reaction time: 15 h
Yield: 49.2 %

Procedure:
3-Fluoropyridine hydrochloride (240 mg) and sodium carbonate (250 mg) were added to a dimethylformamide solution of 2-({5-chloro-2-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)carbamoyl]phenyl}amino)ethyl methanesulfonate (595 mg), followed by stirring at 40° C. for 15 hours. Water was added to the reaction liquid, followed by extraction with chloroform. The organic layer was dried with magnesium sulfate and then the solution was concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (basic silica gel, chloroform:methanol, 1:0 to 95:5). By treating the resulting free base with 4 M hydrogen chloride/ethyl acetate solution, 4-chloro-2-{[2-(3-fluoropyrrolidin-1-yl)ethyl]amino}-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)benzamide hydrochloride (156 mg) was obtained as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:5]=[C:4]([NH:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:10][C:9]([NH:8][C:6]1[N:5]=[C:4]([NH:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=[C:2]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:7]=1)([CH3:12])[CH3:11]
Reactant: CC(C)(C)CNc1cc(Cl)nc(NC(C)(C)C)n1
Reactant: C1CNCCN1
Product: CC(C)(C)CNc1cc(N2CCNCC2)nc(NC(C)(C)C)n1
Yield: 86 %

Procedure:
The reaction of 6-chloro-2-(1,1-dimethylethylamino)-4-(2,2-dimethylpropylamino)pyrimidine with piperazine as described in Example 5 gives the title compound in a yield of 86.0%, m.p.:120°-124° C.
Reaction SMILES: O=[C:2]1[CH2:8][O:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.CCN(CC)CC.Cl.[NH2:24][OH:25]>C1COCC1>[OH:25][N:24]=[C:2]1[CH2:8][O:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCOCC(=O)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOCC(=NO)C1
Temperature: 25 °C
Yield: 102.2 %

Procedure:
A solution of tert-butyl 6-methylene-1,4-oxazepane-4-carboxylate 38.2 (1.23 g, 5.74 mmol) in 1,4-dioxane (20 mL) and H2O (20 mL) was treated with sodium periodate (2.46 g, 11.49 mmol) and a solution of 2.5% OsO4 in t-BuOH (0.36 mL, 0.028 mmol). The reaction mixture was stirred at room temperature for 18 hrs. The resulting yellow-white suspension was diluted with H2O and extracted with EtOAc (2×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to provide a brown oil (1.30 g) that was used immediately without further purification. The crude tert-Butyl 6-oxo-1,4-oxazepane-4-carboxylate (4.4 g, 20.4 mmol) was dissolved in THF (100 mL) and treated with Et3N (11.4 mL, 81.8 mmol) and hydroxylamine hydrochloride (3.1 g, 45.0 mmol). The mixture was stirred at room temperature over the weekend. The mixture was concentrated in vacuo to dryness and the residue was suspended between EtOAc and water. The aqueous layer was extracted with EtOAc. The organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to yield (4.8 g) of a semisolid product 38.3. LCMS m/z=253.1 [M+Na], 461.3 [2M] with two equal peaks observed (oxyme steroisomers presumably). Used without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[Cl:11][CH2:12][C:13](Cl)=[O:14]>>[Cl:11][CH2:12][C:13]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:14]
Reactant: O=C(Cl)CCl
Reactant: NC(=O)CC[C@H](N)C(=O)O
Product: NC(=O)CC[C@H](NC(=O)CCl)C(=O)O

Procedure:
To illustrate, creatyl-L-glutamine can be synthesized as follows. First, L-glutamine as the starting material is reacted with 2-chloroacetyl chloride to obtain N-chloroacetyl-L-Glutamine. This intermediate is converted to sarcosyl-L-glutamine in aqueous methylamine solution. Sarcosyl-L-glutamine is further treated to obtain creatyl-L-glutamine. In this way, a dipeptide creatyl-L-glutamine is obtained from glutamine.
Reaction SMILES: [CH3:1][C:2]([CH:5]=[O:6])([CH3:4])[CH3:3].[Li][CH2:8][CH2:9][CH2:10][CH3:11]>C1COCC1.CCCCCC>[CH3:1][C:2]([CH3:4])([CH:5]([OH:6])[CH2:8][CH2:9][CH2:10][CH3:11])[CH3:3]
Reactant: [Li]CCCC
Reactant: CC(C)(C)C=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC(O)C(C)(C)C
Temperature: -65 °C
Reaction time: 1 h

Procedure:
20 g (0.232 mol) of pivaldehyde dissolved in 600 mL of THF was added to a 2 L 3-neck round bottom flask equipped with a magnetic stir bar, thermometer and rubber stopper. The vessel was maintained under N2. The reaction mixture was cooled to −65° C. in a dry ice/acetone bath. 112 mL (0.279 mol) of a 2.5 M BuLi solution in hexane was slowly added in 5 mL portions with a 20 mL glass syringe, maintaining the temperature below −55° C. The reaction was stirred at 60° C. for one hour, then allowed to warm to −5° C. over one hour. The reaction was cooled again to 60° C. and slowly quenched with NH4Cl/H2O solution, maintaining the temperature below −50° C. 100 mL of water were added and the reaction was allowed to warm to room temperature. The THF was removed on a rotary evaporator with a bath temperature of 25° C. until an oil was observed. The product was extracted with ethyl ether, and the ether was dried and evaporated carefully to yield 31.0 g of 2,2-dimethyl-heptan-3-ol that was used directly in a subsequent oxidation reaction. 1H NMR (CDCl3, 500 MHz) δ (ppm): 3.2 (m, 1H), 1.2-1.7 (m, 3H), 0.93 (m, 3H), 0.89 (s, 9H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:32][C:33]1([CH3:41])[O:38][CH2:37][CH:36]([CH2:39][OH:40])[CH2:35][O:34]1.[CH3:42][C:43]1[CH:48]=[C:47]([C:49]2[N:53]=[C:52]([C:54]3[S:61][C:60]([CH3:62])=[C:59]4[C:55]=3[CH2:56][C@H:57]3[C:63]([CH3:65])([CH3:64])[C@H:58]34)[O:51][N:50]=2)[CH:46]=[C:45]([CH3:66])[C:44]=1O>C1COCC1>[CH3:32][C:33]1([CH3:41])[O:38][CH2:37][CH:36]([CH2:39][O:40][C:44]2[C:45]([CH3:66])=[CH:46][C:47]([C:49]3[N:53]=[C:52]([C:54]4[S:61][C:60]([CH3:62])=[C:59]5[C:55]=4[CH2:56][C@H:57]4[C:63]([CH3:64])([CH3:65])[C@H:58]45)[O:51][N:50]=3)=[CH:48][C:43]=2[CH3:42])[CH2:35][O:34]1
Reactant: Cc1cc(-c2noc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)n2)cc(C)c1O
Reactant: CC1(C)OCC(CO)CO1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(-c2noc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)n2)cc(C)c1OCC1COC(C)(C)OC1
Reaction time: 24 h
Yield: 66.6 %

Procedure:
To a solution of triphenylphosphine (161 mg, 0.615 mmol) in dry THF is added DEAD (0.097 mL, 0.615 mmol). The solution is stirred at rt for 1 h before (2,2-dimethyl-[1,3]dioxan-5-yl)-methanol (90 mg, 0.615 mmol) and 2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,2,4]oxadiazol-3-yl]-phenol (150 mg, 0.410 mmol) is added. Stirring is continued for 24 h. The reaction mixture is purified by prep. HPLC (Waters XTerra Prep MS C18 19×50 mm 5 μm, water (0.85% NEt2)/acetonitrile) to give 3-[4-(2,2-dimethyl-[1,3]dioxan-5-ylmethoxy)-3,5-dimethyl-phenyl]-5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,2,4]oxadiazole (135 mg) as colourless lyophilisate; LC-MS: tR=1.29 min, [M+1]+=495.30.
Reaction SMILES: C(OC(N1CC[N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[S:31]1(=[O:39])(=[O:38])[CH2:37][CH2:36][CH2:35]NCC1>>[O:38]=[S:31]1(=[O:39])[CH2:37][CH2:36][CH2:35][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1
Reactant: O=S1(=O)CCCNCC1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Product: O=S1(=O)CCCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1

Procedure:
Compound 275 is synthesized from Intermediate C and [1,4]thiazepane 1,1-dioxide according to General Method H. (LC/MS method 16: ES+ m/z 375.4 [M+H]+, Rt=2.51 min)
Reaction SMILES: Cl.[CH3:2][C:3]1[S:7][C:6]([CH:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21](O)[CH2:20]2.N1(O)C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21]([O:10][C:9](=[O:11])[CH:8]([C:6]1[S:7][C:3]([CH3:2])=[CH:4][CH:5]=1)[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:20]2
Reactant: Cc1ccc(C(Nc2ccccc2)C(=O)O)s1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cc1ccc(C(Nc2ccccc2)C(=O)O[C@H]2CN3CCC2CC3)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.8 %

Procedure:
To a solution of (5-methyl-thiophen-2-yl)-phenylamino-acetic acid hydrochloride (I268) (220 mg, 0.77 mmol), (R)-quinuclidin-3-ol (338 mg, 2.66 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (180 mg, 1.33 mmol) in dry THF (15 mL), is added PS-DCC (1.0 g, 1.330 mmol) and the mixture is shaken at RT for 15 hours. Then (R)-quinuclidin-3-01 (49.3 mg, 0.39 mmol) and PS-DCC (291 mg, 0.39 mmol) are added again and the reaction is shaken at RT for other 3 hours. The resin is filtered off and washed several time with EtOAc. The solvent is concentrated and washed with aq. NaHCO3, water and brine. The organic phase is dried over Na2SO4 and evaporated to obtain the title compound as a brown oil (175 mg, 63% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11](Cl)[C:10]=12)=[O:5])[CH3:2].[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[NH:21][NH2:22].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([NH:22][NH:21][C:20]([O:24][CH2:25][CH3:26])=[O:23])[C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)NN
Reactant: CCOC(=O)c1ncn2c1c(Cl)nc1ccccc12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)NNc1nc2ccccc2n2cnc(C(=O)OCC)c12
Yield: 58.4 %

Procedure:
To a solution of 4-chloroimidazo[1,5-a]quinoxaline 3-carboxylic acid ethyl ester (5.5 g) in acetonitrile (120 ml) was added ethyl carbazate (9 g) and triethylamine (20 ml) with stirring. The mixture was refluxed for 18 hours, then evaporated under water aspirator vacuum to dryness. The residue was taken up in chloroform, washed with water, dried by magnesium sulfate, concentrated to a small volume, then put through a silica gel dry column (2% methanol in chloroform as eluant). From column the product was isolated as an off-white solid (4 g, 58% yield). Recrystallized from a mixture of chloroform and hexane, m.p. 126°-128° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[O:8][CH:7]=[CH:6]1)(=[O:3])[CH3:2].[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C)P(N(C)C)(N(C)C)=O>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][N:27]=[N+:28]=[N-:29])[O:8][CH:7]=[CH:6]1)(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)C=CO[C@@H]1COS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)C=CO[C@@H]1CN=[N+]=[N-]
Reaction time: 24 h

Procedure:
3,4-Di-O-acetyl-1,2-dideoxy-6-O-tosyl-D-arabinohex-1-enopyranose (50g.) was dissolved in hexamethylphosphoramide (800 ml.) and sodium azide (34 g.) was added and the solution was stirred at 25° for 24 hours. The hexamethylphosphoramide was distilled off under high vacuum and the residue was taken up in chloroform and washed with water. The chloroform extract was dried (MgSO4), filtered and evaporated to give a crude gum which was chromatographed on a silica gel column (150 × 7.5 cm.) using 7% acetone in hexane as the eluent to give 3,4-di-O-acetyl-6-azido-1,2,6-trideoxy-D-arabinohex-1-enopyranose (25 g.) as a colorless gum, (Found: C, 47.23; H, 5.30; N, 16.37. C10N13N3O5 requires: C, 47.06; H, 5.13; N, 16.46%), [α]D26 × 25.1° (CH3OH), νmax (CHCl3) 2110, 1755, 1660, 1220, 1040 cm. -1, δ(CDCl3) 2.06, 2.09 (6H, s, OAc), 4.91 (1H, ddd, J = 6.5Hz, 3.0Hz, 1Hz, H2), and 6.53 ppm. (1H, dd, J = 6.5Hz, 1.5Hz, H1).