Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][NH:14]3)=[CH:6][C:3]=1[C:4]#[N:5].C([OH:21])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][C:13](=[O:21])[NH:14]3)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(-c2cccc3[nH]ccc23)ccc1F
Reactant: CCO
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: N#Cc1cc(-c2cccc3c2CC(=O)N3)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To the suspension of 2-fluoro-5-(1H-indol-4-yl)-benzonitrile (2.68 g, 11.34 mmol) in t-BuOH:ethanol:acetic acid (72 mL:43 mL:23 mL) was added pyridinium tribromide (10.91 g, 34.1 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added acetic acid (55 mL). Zinc dust (4 g, 61.2 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (3×), sat. NaHCO3, brine, dried over Na2SO4, concentrated and triturated with ether to give 1.93 g (68%) of 2-fluoro-5-(2-oxo-2,3-dihydro-1H-indol-4-yl)-benzonitrile.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3[N:17]4[N:18]=[C:19]([CH3:27])[CH:20]=[C:21]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:16]4=[N:15][C:14]=3[CH3:28])=[C:10]([CH3:29])[CH:9]=2)[CH:5]=[CH:4][CH:3]=1.C1C[O:33][CH2:32][CH2:31]1.C([Li])CCC.CON(C)C(=O)C>CCOC(C)=O>[CH2:23]([CH:22]([C:21]1[C:16]2[N:17]([C:13]([C:11]3[S:12][C:8]([C:6]4[N:7]=[C:2]([C:32](=[O:33])[CH3:31])[CH:3]=[CH:4][CH:5]=4)=[CH:9][C:10]=3[CH3:29])=[C:14]([CH3:28])[N:15]=2)[N:18]=[C:19]([CH3:27])[CH:20]=1)[CH2:25][CH3:26])[CH3:24]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(-c4cccc(Br)n4)cc3C)c(C)nc12
Reactant: C1CCOC1
Agent: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4cccc(C(C)=O)n4)cc3C)c(C)nc12
Temperature: 25 °C
Yield: 13 %

Procedure:
To a −78° C. solution of 3-[5-(6-bromo-pyridin-2-yl)-3-methyl-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine) (0.26 g, 0.55 mmol), and THF (5 mL), is added 1.34 M n-Bu-Li (0.43 mL, 0.58 mmol). After 30 minutes N-methoxy-N-methyl-acetamide (0.065 mL, 0.61 mmol) is added and the solution warmed to ambient temperature. The solution is diluted with EtOAc (30 mL), washed with sat. NH4Cl (25 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (15-20% EtOAc/hexane gradient) furnish the title compound (0.030 g, 0.069 mmol, 13%). 1H NMR (CDCl3), δ 0.89 (t, J=7.5 Hz, 6H), 1.75-1.93 (m, 4H), 2.19 (s, 3H), 2.52 (s, 3H), 2.53 (s, 3H), 2.77 (s, 3H), 3.30-3.40 (m, 1H), 6.69 (s, 1H), 7.59 (s, 1H), 7.77-7.85 (m, 2H), 7.87 (dd, J=6.8, 2.2 Hz, 1H). LC/MS (m/z): calcd. for C25H28N4OS (M+H)+: 433.3; found: 433.2.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[C:10]#[CH:11].C([Li])CCC.Br[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:22]=[CH:21]2.Cl>O1CCCC1.CCCCCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1[C:10]#[C:11][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:22]=[CH:21]2
Reactant: CCOC(=O)c1ccc2cc(Br)ccc2c1
Reactant: C#CC1=C(C)CCCC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2cc(C#CC3=C(C)CCCC3(C)C)ccc2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 0.503 g (3.3916 mmol) 1,3,3-trimethyl-2-ethynylcyclohexene (G. Kobrich et al. Chem Ber., 1966, 99,689.) in 4 ml of dry tetrahydrofuran at 0 degrees C. under argon was added dropwise 2.1 ml of 1.6M (3.36 mmol) of n-butyllithium in hexane. This mixture was stirred at 0 degrees C. for 10 minutes, at room temperature for 10 minutes and cooled again to 0 degrees C. To this was added, via cannula, a solution of 0.480 g (3.52 mmol) fused zinc chloride in 4 ml of tetrahydrofuran with stirring at 0 degrees C. for 40 minutes and at room temperature for 5 minutes. A solution of 0.9186 g (3.29 mmol) of ethyl 6-bromo-2-naphthoate (Anderson, L. C. J. Am. Chem. Soc., 1943, 65,242.) in 5 ml of dry tetrahydrofuran was transferred by cannula into a suspension of 0.410 g (0.3584 mmol) tetrakis(triphenylphosphine)palladium in 5 ml of dry tetrahydrofuran and stirred for 5 minutes at room temperature. This mixture was then treated via cannula with the solution of alkynyl zinc and the resultant mixture stirred at room temperature for 18 hours. Ice and 30 ml of 3N HCl was added and the products extracted with 4×50 ml ether. The combined ether extracts were washed with saturated NaHCO3 and NaCl solution, dried (MgSO4) and concentrated to give a brown oil. This oil was purified by HPLC (Waters 6000; Partisil M-9 10/50; 2% ethyl acetate in hexanes) to give the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][N:6]=[CH:7][N:8]([CH3:10])[CH3:9])[CH3:2].CO[C:14](OC)([N:16]([CH3:18])[CH3:17])[CH3:15].CC([O-])(C)C.[K+]>>[CH2:1]([O:3][C:4](=[O:11])/[C:5](/[N:6]=[CH:7][N:8]([CH3:10])[CH3:9])=[C:14](\[N:16]([CH3:18])[CH3:17])/[CH3:15])[CH3:2]
Reactant: COC(C)(OC)N(C)C
Reactant: CCOC(=O)CN=CN(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)/C(N=CN(C)C)=C(/C)N(C)C

Procedure:
A mixture of 4.7 g of N-(dimethylaminomethylene)-glycine-ethyl ester (W. Kantlehner et al., Liebigs Ann Chem. 1980, 344), 8 g of dimethylacetamide-dimethylacetal and 0.4 g of potassium tert-butylate, analogously to 1b), is heated for 8 hours with distilling off of the resulting alcohols. The residue is then fractionated.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:3]=1[CH:4]=[N:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=1[CH3:14].[CH3:20][N:21]=[C:22]=[O:23]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.C(OCC)(=O)C>[CH3:20][NH:21][C:22](=[O:23])[O:13][C:9]1[CH:10]=[C:11]([CH3:12])[C:6]([N:5]=[CH:4][C:3]2[CH:15]=[CH:16][C:17]([O:19][C:22](=[O:23])[NH:21][CH3:20])=[CH:18][C:2]=2[OH:1])=[C:7]([CH3:14])[CH:8]=1
Reactant: CN=C=O
Reactant: Cc1cc(O)cc(C)c1N=Cc1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCOC(C)=O
Product: CNC(=O)Oc1cc(C)c(N=Cc2ccc(OC(=O)NC)cc2O)c(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.5 %

Procedure:
To a 350 milliliter glass pressure bottle equipped with a magnetic stirrer was added 5.15 grams (0.020 moles) of 4-(2,4-dihydroxybenzylideneamino)-3,5-dimethylphenol prepared in Part A, 2.40 grams (0.042 moles) of methyl isocyanate, 100 milliliters of ethyl acetate and 5 drops of dibutyltin diacetate. The resulting reaction mixture was stirred for 18 hours at room temperature, diluted with an additional 100 milliliters of ethyl acetate and washed twice with a 1% aqueous sodium bicarbonate solution followed by a single wash with saturated brine solution. After drying the reaction mixture over magnesium sulfate, it was concentrated under reduced pressure to give 7.25 grams (0.0195 moles) of 4-[2-hydroxy-4-(methylcarbamoyloxy)benzylideneamino]-3,5-dimethylphenyl methylcarbamate in the form of a yellow solid having a melting point of 70°-65° C. and the following structural formula: ##STR19##
Reaction SMILES: [CH2:1]=[C:2]1[C:7](=[CH2:8])[CH:6]2[O:9][CH:3]1[C:4](=[CH2:11])[C:5]2=[CH2:10].[C:12]1(=[O:19])[CH:17]=[CH:16][C:15](=[O:18])[CH:14]=[CH:13]1>C(Cl)(Cl)Cl>[CH2:11]=[C:4]1[C:5](=[CH2:10])[CH:6]2[O:9][CH:3]1[C:2]1[CH2:1][CH:17]3[CH:16]([CH2:8][C:7]=12)[C:15](=[O:18])[CH:14]=[CH:13][C:12]3=[O:19]
Reactant: O=C1C=CC(=O)C=C1
Reactant: C=C1C(=C)C2OC1C(=C)C2=C
Solvent: ClC(Cl)Cl
Product: C=C1C(=C)C2OC1C1=C2CC2C(=O)C=CC(=O)C2C1
Temperature: 80 °C
Yield: 95 %

Procedure:
A mixture of 2 g (13.7 mmol) of 2,3,5,6-tetramethylene-7-oxabicyclo[2.2.1]heptane, 1.47 g (13.7 mmol) of freshly sublimed p-benzoquinone and 20 ml of chloroform was heated at 80° C. for 5 hours under nitrogen. After cooling, the mixture was concentrated to dryness and recrystallised from acetone/methanol (4:1). There were obtained 3.28 g (95%) of 1,2,3,4,8a,9,10,10a-octahydro-2,3-dimethylene-1,4-epoxyanthracene-5,8-dione of melting point 147° C. (decomposition) in the form of yellow crystals.
Reaction SMILES: [CH2:1]([P:6](=S)([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:2][CH:3]([CH3:5])[CH3:4].ClC1C=CC(S(O)(=O)=[O:26])=CC=1>ClC1C=CC=CC=1>[CH2:1]([P:6](=[O:26])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCP(=S)(CCC(C)C)CCC(C)C
Reactant: O=S(=O)(O)c1ccc(Cl)cc1
Solvent: Clc1ccccc1
Product: CC(C)CCP(=O)(CCC(C)C)CCC(C)C
Temperature: 25 °C

Procedure:
4.1 g (15 mmol) of triisoamylphosphine sulfide in 70 ml of chlorobenzene (b.p.=132° C.) are combined with 34.7 g (0.18 mol) of p-chlorobenzenesulfonic acid and then heated for 8 hours at reflux. After cooling to room temperature, the reaction mixture is extracted several times with 80 ml portions of ice water and then the chlorobenzene solution is washed with sodium bicarbonate solution. The solution is dried over sodium sulfate and the chlorobenzene is removed in vacuum. Yield: 3 g of solid identified by mass spectroscopy as triisoamylphosphine oxide.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)(=O)=O.C(#N)C>>[Cl:42][C:37]1[CH:36]=[C:35]([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][CH:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])[CH2:21]2)[CH:40]=[CH:39][C:38]=1[Cl:41]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COc1ccccc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(Cl)c(Cl)c2)C1
Solvent: CC#N
Product: COc1ccccc1C(=O)N1CC[C@@](CCN2CCC(N3CCCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-(2-methoxybenzoyl)pyrrolidine (3.17 g), prepared essentially as described, supra, is mixed with an equimolar amount of 4-(piperidin-1-yl)piperidine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum and the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[NH:8][CH2:9][CH2:10][S:11][C:12]([O:14]C2C=CC([N+]([O-])=O)=CC=2)=O)C=CC=CC=1.[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37].C(N(CC)CC)C.CC1C(=O)C2N3[C@@](OC)([C@H](COC(N)=O)C=2C(=O)C=1OC)[C@H]1N[C@H]1C3>CO>[CH2:36]([N:38]([CH2:39][CH3:40])[C:12]([S:11][CH2:10][CH2:9][NH2:8])=[O:14])[CH3:37]
Reactant: CCNCC
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Solvent: CCN(CC)CC
Solvent: CO
Product: CCN(CC)C(=O)SCCN
Yield: 60 %

Procedure:
2-diethylaminocarbonylthioethylamine (formate: 184 mg) was prepared by subjecting N-triphenylmethyl-2-paranitrophenoxycarbonylthioethylamine (500 mg) and diethylamine (316 μl) to the similar reactions to those described in References 2 and 4. The product was dissolved in anhydrous methanol (4 ml). To the solution were added triethylamine (174 μl) and mitomycin A (273 mg: 0.75 molar equivalent). The reaction solution was treated in a similar manner to that described in Example 1 to obtain Compound 4 (130 mg) in the form of grayish blue powders with a yield of 60%.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:33]([OH:35])[CH3:34])[C@@H:3]1[O:5][C@H:4]1[CH2:6][C@@H:7]1[C@@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:19])[O:9][CH2:8]1.[O-2:36].[Ca+2:37]>O>[CH3:1][C@H:2]([C@H:3]1[C@H:4]([CH2:6][C@H:7]2[CH2:8][O:9][C@@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30])=[O:19])[C@H:11]([OH:14])[C@@H:12]2[OH:13])[O:5]1)[C@H:33]([CH3:34])[OH:35].[CH3:1][C@H:2]([C@H:3]1[C@H:4]([CH2:6][C@H:7]2[CH2:8][O:9][C@@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30])=[O:19])[C@H:11]([OH:14])[C@@H:12]2[OH:13])[O:5]1)[C@H:33]([CH3:34])[OH:35].[OH2:36].[OH2:5].[Ca+2:37]
Reactant: C/C(=C\C(=O)OCCCCCCCCC(=O)O)C[C@@H]1OC[C@H](C[C@@H]2O[C@H]2[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Reactant: [O-2]
Agent: [Ca+2]
Solvent: O
Product: C/C(=C\C(=O)OCCCCCCCCC(=O)[O-])C[C@@H]1OC[C@H](C[C@@H]2O[C@H]2[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Temperature: 5 °C
Reaction time: 1 h
Yield: 131.3 %

Procedure:
Pseudomonic acid (10 g) was suspended in water (26 ml). Calcium oxide (0.58 g) was added to the suspension. The mixture was stirred for one hour, and filtered. The mixture was cooled to 5° C. After standing for 15 h, the crystalline product was filtered and washed with cooled water (10 ml) and dried in an air circulated oven at room temperature. Mupirocin calcium dihydrate (9.4 g, 87%) was obtained.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)(=[O:4])=[O:3].CC1C=CC(S(O[CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:28][CH:27]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])=[CH:30][CH:31]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Reactant: CS(=O)(=O)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1
Temperature: 80 °C

Procedure:
A solution of 4-hydroxyphenyl methanesulfonate (7.04 g @ 82% strength, 30.6 mmol, (prepared by methanesulfonylation of quinol)) dissolved in acetonitrile (72 mL) was added to a mixture of 2-[4-(tert-Butoxycarbonylamino)phenyl]ethyl 4-methylbenzenesulfonate (prepared as described in WO 99/62871) (12.0 g, 30.6 mmol) and potassium carbonate (6.42 g of −325 mesh, 46.0 mmol) under nitrogen and the resulting mixture gently stirred. Acetonitrile (36 mL) and water (12 mL) were added, the stirring rate increased and the reaction mixture was boiled under reflux (80° C.) for 11 to 24 hours. After cooling back to 60° C., the solvent volume was reduced by 6 volumes (˜72 mL) by distillation at reduced pressure. Toluene (108 mL) and water (24 mL) were added and the mixture stirred for 5 minutes at 60° C. The solution was filtered through Celite™ (and/or 5% w/w charcoal) and returned to the reaction vessel at 60° C. The phases were allowed to separate and the lower aqueous phase run off and discarded. Dilute aqueous sodium hydroxide solution (10.2 mL of 2.5%, 0.625 M) was added and the mixture stirred at 60° C. for 5 minutes. The phases were allowed to separate and the lower aqueous phase was run off and discarded. Water (24 mL) was added and stirred at 60° C. for 5 minutes, before the phases were allowed to separate and the lower aqueous phase was run off and discarded. The solvent volume was reduced by distillation at atmospheric pressure until a still-head temperature of ˜110° C. was achieved. Fresh toluene was added to make the total volume up to 8 volumes (96 mL). The solution was cooled to 60° C., filtered and then cooled to 45° C. Iso-hexane (143 mL) was added dropwise over 1 hour, maintaining the temperature at 45° C., and then the solution cooled to 20° C. at 1° C./minute. The resulting solid was isolated by filtration, washed by displacement with iso-hexane (29 mL) and dried in a vacuum oven at 50° C. to yield the title compound as a buff solid (9.9 g, 79%). HPLC (Rt 10.9 mins); m.p. 117-118° C.; 1H NMR (400 MHz, d6-DMSO) δ 9.22 (˜1H, s), 7.36 (2H, d, J=8.0 Hz), 7.23 (2H, d, J=8.8 Hz), 7.17 (2H, d, J=8.4 Hz), 6.98 (2H, d, J=9.2 Hz), 4.13 (2H, t, J=6.6 Hz), 3.29 (3H, s), 2.93 (2H, t, J=6.6 Hz), 1.44 (9H, s); 13C NMR (100.6 MHz, d6-DMSO) δ 157.18, 152.77, 142.44, 137.80, 131.62, 129.04, 124.01, 123.28, 118.15, 115.45, 78.83, 68.69, 36.89, 34.14 and 28.10; MS (ES+) 425 (M+NH4+, 5%), 308 (10%), 120 (100%).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([OH:30])[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:18][CH:17]=1.[CH2:31]([O:33][CH2:34]OCC)[CH3:32]>ClCCl.C(OCC)C>[CH2:31]([O:33][CH2:34][O:30][C@H:22]([C:19]1[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=1)[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH3:32]
Reactant: COC(=O)CCC[C@H](O)c1ccc(F)cc1
Reactant: CCOCOCC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOCC
Solvent: ClCCl
Product: CCOCO[C@@H](CCCC(=O)OC)c1ccc(F)cc1
Temperature: 29 °C
Yield: 113.9 %

Procedure:
40.6 g of phosphorus pentoxide are added to a vigorously stirred solution of 10.5 g (42.7 mmol) of methyl 5-(4-fluorophenyl)-5-(S)-hydroxypentanoate with a purity of 92% area % (Example 1) in 220 ml of dichloromethane and 152 ml (1200 mmol) of 99% pure diethoxymethane in a 4-neck flask with mechanical stirrer, the internal temperature rising from initially 23° C. to 30° C. There is initial formation of a white suspension whose particles quickly agglomerate and form a viscous mass which partly adheres to the bottom of the flask and changes color via yellow to brown. HPLC analysis (system as in Example 5) shows complete conversion of the precursor (tret9.8 min.) into the product (tret 13.4 min.) after only 5 min. The reaction mixture is stirred at 29° C. without external heating (i.e. continuing exothermic reaction) for 0.5 h, but the only effect of this was to increase an impurity (tret 13.2 min.). The reaction mixture is cooled to +10° C. in an ice bath, and 100 g of ice are added to the mixture. The viscous solid mass dissolves only slowly even with vigorous stirring. The mixture is transferred into a separating funnel and diluted with 200 ml of diethyl ether. The organic phase is separated off, and the aqueous phase is extracted again with 100 ml of diethyl ether. The combined extracts are washed with 100 ml of saturated aqueous sodium bicarbonate solution and with 100 ml of saturated aqueous sodium chloride solution, and then concentrated in vacuo, and the residue is dried under HV. 13.83 g of brown oil are obtained. The crude product has a GC purity of 84 area %. It is distilled through a silvered 15 cm vacuum-jacketed Vigreux column under HV (0.005 mbar). After a fore-run (1 g, b.p. 33-88° C., colorless mobile oil), the product distills (9.5 g, b.p. 102-103° C., colorless oil) at a bath temperature of 160-170° C., and 3 g of higher-boiling impurity remain as bottom product. Yield: 9.5 g (33.4 mmol), 78% of theory.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14]C2CCCCO2)=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH:6]2.Cl.O.N>O1CCCC1>[OH:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]2[C:7]=1[NH:6][C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:4]2
Reactant: CCOC(=O)c1cc2c(C)ccc(OCCOC3CCCCO3)c2[nH]1
Agent: Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(C)ccc(OCCO)c2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
Ethyl 4-methyl-7-[2-(2-tetrahydro-2H-pyranyl) oxyethoxy]-1H- indole-2-carboxylate (3.20 g, 9.21 mmol) was dissolved in tetrahydrofuran (70 ml), followed by adding thereto 2N hydrochloric acid (30 ml) at room temperature. The mixture was stirred at room temperature for 3 hours, after which water (200 ml) and then 28% aqueous ammonia were added thereto to neutralize (pH=7 to 8) the reaction mixture. Subsequently, the reaction mixture was extracted twice with ethyl acetate and the extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was crystallized from ethyl acetate to obtain ethyl 7-(2-hydroxyethoxy)-4-methyl-1H-indole-2-carboxylate (1.93 g).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][CH:11]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:22][S:23](NC1C=CC=CC=1N1CCN(C(OC(C)(C)C)=O)CC1)(=[O:25])=[O:24].CS(Cl)(=O)=O.N1C=CC=CC=1>>[CH2:1]([CH:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][CH:11]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][S:23]([CH3:22])(=[O:25])=[O:24])[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccccc1C1CC2CC1CC2Cc1cnccn1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccccc1C1CC2CC1CC2Cc1cnccn1

Procedure:
{2-[2,5-Diaza-5-benzylbicyclo[2.2.1]hept-2-yl]phenyl}-(methylsulfonyl)amine was prepared from 2-[2,5-diaza-5-benzylbicyclo[2.2.1]hept-2-yl]phenylamine (Step 2) (690 mg, 2.5 mmol) according to the procedure for Preparation III using methanesulfonyl chloride (190 μl, 2.46 mmol) and pyridine (220 μl, 2.72 mmol). The crude mix was purified by flash chromatography (SiO2, 3% MeOH in CH2Cl2) to afford the desired sulfonamide (533 mg). MS (ESI, pos. ion) m/z: 358 (M+H), (ESI, neg. ion) m/z: 356 (M−H). Calc'd for Cl9H23N3O2S: 357.47.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])C.CCOCC>C(O)C>[C:24]1([CH2:23][N:20]2[CH2:19][CH2:18][N:17]([C:15]([NH:14][C:8]3([C:6]([OH:7])=[O:5])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:16])[CH2:22][CH2:21]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)C1(NC(=O)N2CCN(Cc3ccccc3)CC2)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: O=C(NC1(C(=O)O)CCCCC1)N1CCN(Cc2ccccc2)CC1
Yield: 42 %

Procedure:
600 ml of 1N aqueous sodium hydroxide solution was added to a solution of 7.62 g (20 mmol) of 1-[[(4-phenylmethyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acid ethyl ester in 300 ml of ethanol, and the mixture was heated under reflux for 2 hours. After ether was added to the reaction solution to wash it, the aqueous layer was neutralized by concentrated hydrochloric acid and extracted with ethyl acetate. After the obtained organic layer was washed with saturated brine, it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2.90 g (42%) of the title compound.