Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S-:4])(=[S:3])[CH3:2].[Na+].Cl[CH:7]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:15][CH:14]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(O)C>[C:1]([S:4][CH:7]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:15][CH:14]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[S:3])[CH3:2]
Reactant: CCOC(=O)C(Cl)c1ccc(-c2ccccc2Cl)cc1
Reactant: CC(=S)[S-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(SC(C)=S)c1ccc(-c2ccccc2Cl)cc1

Procedure:
A mixture of 0.2 moles of sodium dithioacetate and 38 g. (0.12 moles) of ethyl α, 2'-dichloro-4-biphenylylacetate in 300 ml. of absolute ethanol is stirred at room temperature for 15 hours. The reaction mixture is filtered, washed with absolute ethanol and evaporated to dryness in vacuo. The residue is treated with ether, filtered and evaporated to dryness to obtain ethyl α-thioacetylthio-2'-chloro-4-biphenylylacetate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[CH:17]1[NH:21][C:20](=[O:22])[C:19]([CH3:24])([CH3:23])[O:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:31][CH:30]=1.O>CN(C=O)C.CCCCCCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[CH:17]1[N:21]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:31][CH:30]=2)[C:20](=[O:22])[C:19]([CH3:24])([CH3:23])[O:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(OCc2ccccc2)c1C1NC(=O)C(C)(C)O1
Reactant: BrCc1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCCC
Product: COc1cccc(OCc2ccccc2)c1C1OC(C)(C)C(=O)N1Cc1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77.6 %

Procedure:
To a cold (0° C.) solution of 2-(2-benzyloxy-6-methoxy-phenyl)-5,5-dimethyl-oxazolidin-4-one (410 mg) in dry DMF (5 mL) is added portionwise NaH 90% (45 mg, 1.5 eq). The reaction mixture is stirred for 15 min at 0° C. and then commercially available 1-(bromomethyl)-4-phenoxybenzene (395 mg, 1.2 eq) is added and the reaction mixture is stirred at RT for 1 h. The reaction mixture is poured into water, extracted with DCM. The combined organic extracts are dried (MgSO4), filtered and concentrated to yield a crude oil. FC (EN n-heptane: 0/1 to 4/6) gives 2-(2-benzyloxy-6-methoxy-phenyl)-5,5-dimethyl-3-(4-phenoxy-benzyl)-oxazolidin-4-one as a colorless oil (0.495 g, 77%); LC-MS: tR=0.88 min; [M+H]+=510.33.
Reaction SMILES: [CH:1]1([NH:7][C:8]([O:16][N:17]2[C:22]([CH3:24])([CH3:23])[CH2:21][CH:20]([O:25][C:26](=[O:28])[CH3:27])[CH2:19][C:18]2([CH3:30])[CH3:29])=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:38](Cl)(=[O:56])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>C1(C)C=CC=CC=1>[CH:10]1([N:9]([C:38](=[O:56])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:8]([O:16][N:17]2[C:18]([CH3:30])([CH3:29])[CH2:19][CH:20]([O:25][C:26](=[O:28])[CH3:27])[CH2:21][C:22]2([CH3:24])[CH3:23])=[N:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CC(=O)OC1CC(C)(C)N(OC(=NC2CCCCC2)NC2CCCCC2)C(C)(C)C1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCC(=O)N(C(=NC1CCCCC1)ON1C(C)(C)CC(OC(C)=O)CC1(C)C)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
To a solution of compound 1 (4.21 g, 10 mmol) [prepared according to Example 1] in toluene (25 ml) is added triethylamine (1.46 ml, 10.5 mmol) and stearoyl chloride (3.2 g, 10.5 mmol). The mixture is stirred at room temperature for 30 minutes and then additional triethylamine (1.46 ml, 10.5 mmol) and stearoyl chloride (3.2 g, 10.5 mmol) is added. The suspension is stirred at room temperature for 18 hours, then evaporated and chromatographed over silica gel with hexane-ethyl acetate (9:1) to afford 4.03 g of the title compound as a colorless oil.
Reaction SMILES: C([N:8]1[C@@H:13]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:19])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH3:19][C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[NH:8]1
Reactant: CC(C)CC[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC[C@H]1CCC[C@H](C)N1

Procedure:
To a stirred solution of trans-N-Boc-2-methyl-6-isopentylpiperidine (1.5 g, 5.56 mmol) in 15% trifloroacetic acid (35 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 90 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-methyl-6-isopentylpiperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occurred. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid. mp 134.1-134.7° C.; 1H NMR (250 MHz) δ 9.36 (s, 2H), 3.53 (s, 1H), 3.25 (s, 1H), 1.96-1.1 (m, 14H), 0.88-0.82 (d, 6H); 13C NMR (62.7 MHz) δ 51.9 (s), 47.8 (s), 34.7 (s), 28.9 (s), 28.4 (s), 27.8 (s), 26.0 (s), 22.7 (s), 22.1 (s), 17.3 (s), 16.9 (s). FT-IR (neat): 3422, 2949, 1636, 1602, 1587, 1500, 1422, 1384, 1230, 1105, 1030, 998, 895. Elemental Analysis for C, H24NCl: C, 64.20%; H, 11.78%; N, 6.80%. Found: C, 64.08%; H, 11.72%; N, 6.78%.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(CO[CH2:24][C:25]2([OH:39])[CH2:31][O:30][CH2:29][CH2:28][N:27]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:26]2)CC1.S([O-])(O)(=O)=O.[Na+]>C1COCC1>[CH2:24]([C:25]1([OH:39])[CH2:31][O:30][CH2:29][CH2:28][N:27]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:26]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCOCC(O)(COCC2CC2)C1
Agent: O=S(=O)([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCOCC(O)(Cc2ccccc2)C1
Temperature: -80 °C
Yield: 54.5 %

Procedure:
1.6M solution of butyl lithium in hexane (150 mL, 0.24 mol, 1.1 eq) was added to a solution of bromobenzene (25.3 mL, 0.24 mol, 1.1 eq) in THF (200 mL) at −60° C. in a stream of argon. The reaction mixture was cooled to −80° C., and a solution of tert-butyl 6-[(cyclopropylmethoxy)methyl]-6-hydroxy-1,4-oxazepane-4-carboxylate (Preparation 80, 50 g, 0.22 mol, 1 eq) in THF was added. Then the mixture was cooled to −100° C., and a solution of etherate (30.4 g, 0.24 mol, 1.1 eq) was added at this temperature for 30 min. The reaction mixture was heated to 0° C. for 5 h, and 5M sodium hydrogen sulfate solution (50 mL) was added. The organic layer was separated, evaporated, and the residue was distributed between water and ether. The organic layer was separated, washed with water and brine, dried, evaporated, and the residue was dissolved in MeOH (200 mL). Ethylenediamine (30 mL) was added to the mixture, which was heated until boiled, cooled, evaporated, and coevaporated with dioxane. The residue was purified by chromatography on silica (1 L; carbon tetrachloride→chloroform, then MeOH 5%), evaporated and dried to give title compound (37.15 g, 0.12 mol, 55%).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH:12]=O)=O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[NH2:14]/[C:15](/[C:20]#[N:21])=[C:16](\[NH2:19])/[C:17]#[N:18].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:20]([C:15]1[C:16]([C:17]#[N:18])=[N:19][C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=2)=[CH:12][N:14]=1)#[N:21]
Reactant: N#C/C(N)=C(/N)C#N
Reactant: CCCc1ccc(C(=O)C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCc1ccc(-c2cnc(C#N)c(C#N)n2)cc1
Temperature: 25 °C
Yield: 71.7 %

Procedure:
This 4-propylphenylglyoxal (8.0 g, 0.05 mol) and diaminomaleonitrile (5.4 g, 0.05 mol) were dissolved in benzene (50 ml), followed by adding p-toluenesulfonic acid (0.05 g) to the solution, reacting them on heating under reflux for 3 hours, while distilling off water formed, allowing the reaction liquid to cool down to room temperature after completion of the reaction, adding water (50 ml), separating the resulting two layers, twice washing the benzene solution with 5% sodium bicarbonate solution (50 ml), further washing it with water, drying it with anhydrous sodium sulfate, distilling off benzene from the solution, and recrystallizing a remaining solid material from ethanol (10 ml) to obtain the objective product (8.9 g).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)C=O.S[C:12]1[N:17]([CH3:18])[C:16](=[O:19])[CH:15]=[C:14]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:13]=1>C(OCC)(=O)C>[Cl:3][C:12]1[N:17]([CH3:18])[C:16](=[O:19])[CH:15]=[C:14]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:13]=1
Reactant: Cn1c(S)nc(-c2ccncc2)cc1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 77.2 %

Procedure:
Phosphorous oxychloride (26.11 g, 170 mmol) was added to dimethylformamide (180 ml) and stirred 20 min. 2-mercapto-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (24.15 g, 110 mmol) was added to the solution and stirred 5 min and then stirred at 70° C. for 2 hours. Ethyl acetate (630 ml) was added to the ice-cooled solution and precipitate was collected by filtration after 20 minutes stirring. After drying, the precipitate was dissolved in water (400 ml) and pH was adjusted to 10 by aqueous sodium hydroxide. The precipitate was washed with water, filtered and dried to give the title compound (18.82 g, 77%).
Reaction SMILES: [N:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[NH:13][C:14]=2[CH3:15])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC([O-])(C)C.[K+].Br[CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1>C(#N)C.C(OC(=O)C)C.O>[N:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:26])[F:24])=[CH:18][CH:17]=3)[N:13]([CH2:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)[C:14]=2[CH3:15])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1[nH]c(-c2ccc(OC(F)(F)F)cc2)nc1C(=O)NN1CCCCC1
Reactant: BrCC1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(OC(F)(F)F)cc2)n1CC1CCCCO1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a suspension of 100 mg of 5-methyl-2-(4-trifluoromethoxy-phenyl)-1H-imidazole-4-carboxylic acid piperidin-1-ylamide in 3 ml of acetonitrile was added 33 mg of potassium tert-butylate and the reaction mixture was stirred at room temperature for 2 minutes. After such time, 0.034 ml of 2-(bromomethyl)-tetrahydro-2H-pyran (as R3—(CH2)m—Br) was added and the reaction mixture was stirred at 100° C. for 26 hours under argon atmosphere. The reaction mixture was then diluted with ethylacetate/water, the aqueous phase removed, and the organic phase was washed with 2×H2O followed by brine, dried (MgSO4), and after filtration concentrated in vacuo and purified by column chromatography (50 g SiO2, CH2Cl2/MeOH: 24/1) to give 44 mg of the title compound as a pale yellow solid, MS (ISP) 467.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:26])[CH:12]2[N:13](S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH:8]([CH2:9][O:10][CH2:11]2)[C:7]2[CH:6]=[N:5]N[C:3]1=2.[Li+].[OH-].SCC(O)=[O:32]>CN(C=O)C>[F:1][C:2]1([F:26])[CH:12]2[NH:13][CH:8]([CH2:9][O:10][CH2:11]2)[C:7]2[CH:6]=[N:5][O:32][C:3]1=2
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N1C2COCC1C(F)(F)c1[nH]ncc12
Reactant: O=C(O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: FC1(F)c2oncc2C2COCC1N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of compound 107e (100 mg, 0.26 mmol, 1.0 eq) and LiOH (33 mg, 0.78 mmol, 3.0 eq) in DMF (5 mL) was added mercaptoacetic acid (36 mg, 0.4 mmol, 1.5 eq) slowly, the mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo to give 7,7-difluoro-5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene 107a as an oil, used in next step without further purification. MS: calc'd (MH+) 202, measured (MH+) 202.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][OH:10].N1C=CC=CC=1>C(Cl)Cl>[OH:10][CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[NH:6][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: Nc1ccccc1CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccccc1CO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound was synthesized according to the method described in WO 2008/073956 A2. A solution of methanesulfonyl chloride (3.4 mL, 44 mmol) in anhydrous methylene chloride (40 mL) was added dropwise to a stirring solution of 2-aminobenzylalcohol (5 g, 40.6 mmol) and anhydrous pyridine (16 mL, 203 mmol) in anhydrous methylene chloride (80 mL). The resulting mixture was stirred at room temperature for 24 hours and concentrated to ⅓ volume and diluted with ethyl acetate. The organic solution was successively washed twice with 1N aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride solutions, dried (anhydrous sodium sulfate), filtered, and concentrated. The crude residue was passed through a pad of silica gel, washing with ethyl acetate/hexanes to give a yellow oil (6.1 g, 75%). 1H NMR (CDCl3, 300 MHz) δ 7.84 (br s, 1H), 7.53 (d, 1H, J=8.1 Hz), 7.36-7.30 (dt, 1H, J=1.5, 7.8 Hz), 7.25-7.21 (dd, 1H, J=1.5, 7.8 Hz), 7.16-7.11 (dt, 1H, J=1.2, 7.5 Hz), 4.77-4.75 (d, 2H, J=5.1 Hz), 3.04 (s, 3H), 2.60 (t, 1H, J=5.2 Hz).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][NH:11]2)=[CH:7][CH:6]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][N:11]2[C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1c[nH]c2cc(OC)ccc12
Reactant: Clc1ccnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(-c2ccnc3ccccc23)c2cc(OC)ccc12
Temperature: 40 °C
Reaction time: 0.3 h
Yield: 100.3 %

Procedure:
0.384 g (12 mmol) of sodium hydride, at 75% by mass in liquid petroleum jelly, is added at a temperature in the region of 20° C. under an argon atmosphere to a solution of 2.4 g (11.7 mmol) of 6-methoxy-3-methoxycarbonyl-1H-indole in 60 cm3 of dimethylformamide. After stirring at a temperature in the region of 40° C. for 0.3 hours, 1.98 g (12 mmol) of 4-chloroquinoline are added. After stirring at a temperature in the region of 120° C. for 5 hours, the reaction mixture is poured into 200 cm3 of water and extracted with 200 cm3 of ethyl acetate. The organic phase is washed with 3 times 100 cm3 of water and is then dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 3.9 g of a brown residue which is purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate (65/35 by volume)]. After concentrating the fractions under reduced pressure, 2.5 g of 6-methoxy-3-methoxycarbonyl-1-(quinol-4-yl)-1H-indole are obtained in the form of a beige-coloured solid melting at 162° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:15][CH:14]([C:16]2[C:21](Cl)=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:13]1)=[O:11].[NH:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1.C(N(CC)CC)C.CS(C)=O>O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:15][CH:14]([C:16]2[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]3)=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:13]1)=[O:11]
Reactant: O=C(c1nc2ccccc2[nH]1)N1CC(c2nccnc2Cl)C1
Reactant: OC1CCNCC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1nc2ccccc2[nH]1)N1CC(c2nccnc2N2CCC(O)CC2)C1
Temperature: 120 °C
Yield: 84 %

Procedure:
To a mixture of (1H-benzoimidazol-2-yl)-[3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-methanone (0.170 g, 0.50 mmol) and piperidin-4-ol (0.101 g, 1.0 mmol) was added triethylamine (0.10 g, 1.0 mmol) and DMSO (4 mL). The solution was heated to 120° C. for 4 h. Then the mixture was diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 50% EtOAc in petroleum ether) to give (1H-benzoimidazol-2-yl)-{3-[3-(4-hydroxy-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone (0.16 g, 0.42 mmol, 85% yield) as a white solid.
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1C(O)=O)([O-])=O.[N+:16]([C:19]1[CH:39]=[C:38]([N+:40]([O-])=O)[CH:37]=[CH:36][C:20]=1[C:21]([O:23][CH:24]1[CH:30]([OH:31])[C:29]([CH3:33])([CH3:32])[CH2:28][C:27](=[O:34])[C:26]([CH3:35])=[CH:25]1)=[O:22])([O-])=O.[N+](C1C=C([N+]([O-])=O)C=CC=1C(OC1C(C)(C)CC(=O)C(C)=CC1O)=O)([O-])=O>CCCCCC.C(OCC)(=O)C>[NH2:16][C:19]1[CH:39]=[C:38]([NH2:40])[CH:37]=[CH:36][C:20]=1[C:21]([O:23][CH:24]1[CH:30]([OH:31])[C:29]([CH3:33])([CH3:32])[CH2:28][C:27](=[O:34])[C:26]([CH3:35])=[CH:25]1)=[O:22]
Reactant: CC1=CC(OC(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])C(O)C(C)(C)CC1=O
Agent: CC1=CC(O)C(OC(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])C(C)(C)CC1=O
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1=CC(OC(=O)c2ccc(N)cc2N)C(O)C(C)(C)CC1=O
Yield: 26 %

Procedure:
Saishin N (3.68 g, 20 mM) was treated with 2,4-dinitrobenzoic acid (6.79 g, 32 mM) according to the procedures described in Example 20, forming a mixture of 4-(2,4-dinitrobenzoyloxy)-5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one and (per acyl transfer reaction) 5-(2,4-dinitrobenzoyloxy)-4-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one, and then the mixture was reduced at the nitro groups according to the procedures described in Example 19 and fractionated by silica gel column chromatography using hexane-ethyl acetate (3:2) as an eluent. The first eluted portion was crystallized from a mixed solution of ethyl acetate and hexane to obtain 1.65 g (26%) of 4-(2,4-diaminobenzoyloxy)-5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one (AU242) as a brown powder. Melting point: 154° to 156° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)=[O:19])[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C[Si]([Cl:38])(C)C.CCOCC>CC(CC)=O>[ClH:38].[CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)=[O:19])[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Agent: O=C(c1ccco1)N1CCC2(CC1)N[C@@H](Cc1ccccc1)C(=O)N2Cc1ccccc1
Solvent: CCOCC
Solvent: CCC(C)=O
Solvent: O
Product: Cl
Reaction time: 8 h

Procedure:
1,3-(S)-dibenzyl-8-(furan-2-carbonyl)-1,4,8-triazaspiro[4,5]decan-2-one (365 mg, 0.9 mmol) was dissolved in ethyl methyl ketone (2.9 mL), water (8 μL), TMSCl (118 μL), and ether (20 mL) were added and the mixture was stirred overnight. The solid matter was isolated by filtration, washed with ether, and dried in vacuo. The product 1,3-(S)-dibenzyl-8-(furan-2-carbonyl)-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 338 mg (85%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][NH:10][CH2:9][CH:8]2[CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[O:56][N:55]=[CH:54][C:53]=2[C:57](O)=[O:58])=[CH:48][CH:47]=1>CN(C=O)C>[CH3:45][C:46]1[CH:47]=[CH:48][C:49]([C:52]2[O:56][N:55]=[CH:54][C:53]=2[C:57]([N:10]2[CH2:11][C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]([CH2:12][OH:13])[CH2:9]2)=[O:58])=[CH:50][CH:51]=1
Reactant: OCC1CNCC1c1ccccc1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2oncc2C(=O)N2CC(CO)[C@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.4 %

Procedure:
A solution of (4-phenylpyrrolidin-3-yl)methanol (7 mg, 0.033 mmol), TBTU (13 mg, 0.039 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (11 μL, 0.066 mmol, 2 equ.) in DMF (0.3 mL) was added to 5-(4-methylphenyl)isoxazole-4-carboxylic acid (7 mg, 0.033 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (4 mg). MS (ESI, pos. ion) m/z calcd for C22H22N2O3: 362.1630, found 362.1629.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:12]=[C:13]3[N:18]=[C:17]([NH:19][C:20]([C:22]4[N:26]([CH3:27])[N:25]=[CH:24][C:23]=4[C:28]([N:30]4[CH2:33][CH2:32][CH2:31]4)=[O:29])=[O:21])[CH:16]=[CH:15][N:14]3[CH:34]=2)[CH:6]=1)(=O)C.CO.C(Cl)Cl.C([O-])(O)=O.[Na+]>O>[OH:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]3[N:18]=[C:17]([NH:19][C:20]([C:22]4[N:26]([CH3:27])[N:25]=[CH:24][C:23]=4[C:28]([N:30]4[CH2:33][CH2:32][CH2:31]4)=[O:29])=[O:21])[CH:16]=[CH:15][N:14]3[CH:34]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)Oc1cccc(-c2cn3ccc(NC(=O)c4c(C(=O)N5CCC5)cnn4C)nc3n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2cc(-c3cccc(O)c3)nc2n1
Temperature: 25 °C
Yield: 57.2 %

Procedure:
3-(7-(4-(Azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxamido)imidazo[1,2-a]pyrimidin-2-yl)phenyl acetate (Example 105; 25 mg, 54.4 μmol) was combined with MeOH (0.7 ml), CH2Cl2 (0.2 ml) and H2O to give a yellow solution. NaHCO3 (4.57 mg, 54.4 μmol) was added and the reaction mixture was stirred at RT over night. The precipitated light yellow solid was filtered and washed with MeOH and H2O. After drying over night under high vacuum, the product (13 mg, 56%) was obtained as light yellow solid. MS (m/z)=418.2 [M+H+].
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([O:16][CH:17]([CH3:21])[C:18]([OH:20])=O)[N:10]=1.[I-].ClC1C=CC=C[N+]=1C.[C:31]1([S:37]([NH2:40])(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(#N)C>[CH3:15][C:13]1[CH:14]=[C:9]([CH3:8])[N:10]=[C:11]([O:16][CH:17]([CH3:21])[C:18]([NH:40][S:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:39])=[O:38])=[O:20])[N:12]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: Cc1cc(C)nc(OC(C)C(=O)O)n1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C)nc(OC(C)C(=O)NS(=O)(=O)c2ccccc2)n1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (2.84 g, 0.028 mol) was added to 2.00 g (0.0102 mol) of the product of (b) in dry acetonitrile (100 ml) and then, at 50° C., 3.00 g, 0.0118 mol, of 2-chloro-N-methyl pyridinium iodide was also added. The mixture was stirred at 50° C. for 30 minutes and then 3.32 g (0.0212 mol) of benzene sulphonamide and 1.42 g (0.014 mol) of triethylamine were added and the stirring continued at 50° C. for a further 30 minutes. The mixture was allowed to cool to ambient temperature (~20° C.) and left overnight, stirring being maintained for the entire period. The acetonitrile was then removed by evaporation, 50 ml of water added, the mixture acidified to a pH of 2, 50 ml of diethyl ether added and the solution vigorously stirred for 1 hour. The desired product, a beige solid, formed and was filtered off and dried.