Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[CH:10]=[C:9](C(C)(C)C)[CH:8]=[CH:7][C:6]=1[CH3:15].ClC1C=CC=CC=1CC1C=CC(C(C)(C)C)=CC=1C.C1(C)C=CC=CC=1>[Fe](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:15]
Reactant: Cc1ccc(C(C)(C)C)cc1Cc1ccccc1Cl
Agent: Cl[Fe](Cl)Cl
Agent: Cc1cc(C(C)(C)C)ccc1Cc1ccccc1Cl
Solvent: Cc1ccccc1
Product: Cc1ccccc1Cc1ccccc1Cl
Temperature: 50 °C
Reaction time: 6 h
Yield: 15.7 %

Procedure:
3.49 g (10.00 mmol) of an isomeric mixture comprising 45% of 2-(2-chlorobenzyl)-4-tert.-butyl-toluene and 55% of 2-(2-chlorobenzyl)-5-tert.-butyltoluene (total content of both isomers in the charge material: 78%), 9.2 g (100.00 mmol) of toluene, dried, and 0.8 g (5.00 mmol) of anhydrous, sublimed iron(III) chloride were placed in a flask, fitted with magnetic stirrer and reflux condenser. The mixture was stirred for 6 h at 50° C. The mixture (13.5 g) was then cooled to room temperature and analyzed by gas chromatography. 15.7% of 2-(2-chlorobenzyl)toluene (corresponding to the theoretical yield) could be detected as the only diphenylmethane derivative.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)=[C:4]([F:24])[CH:3]=1.[Cl:25][C:26]1[N:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:27]=1[C:28](Cl)=[O:29]>>[Cl:25][C:26]1[N:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:27]=1[C:28]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)=[C:4]([F:24])[CH:3]=1)=[O:29]
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)c(F)c1
Reactant: O=C(Cl)c1cc(Cl)cnc1Cl
Product: O=C(Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)c(F)c1)c1cc(Cl)cnc1Cl
Yield: 44.2 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 180 using Compound 182 (50 mg, 0.16 mmol) and 2,5-dichloro-nicotinoyl chloride (36 mg, 0.17 mmol) to provide 183 (35 mg, 45% yield) as a dark solid. LC-MS (M+H=496, obsd.=496).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:8]=2[CH:9]=1)=O.[C:16]([NH2:19])(=[S:18])[CH3:17]>C(O)C>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:7]2[O:6][C:5]([C:3]3[N:19]=[C:16]([CH3:17])[S:18][CH:2]=3)=[CH:9][C:8]=2[CH:10]=1
Reactant: CC(N)=S
Reactant: COc1ccc2oc(C(=O)CBr)cc2c1
Solvent: CCO
Product: COc1ccc2oc(-c3csc(C)n3)cc2c1

Procedure:
A solution of 2-bromo-1-(5-methoxy-benzofuran-2-yl)-ethanone (0.6 g, 2.2 mmol) and thioacetamide (0.4 g, 5.1 mmol) in ethanol (15 mL) were refluxed for 1hour. The reaction mixture was concentrated in vacuo and subjected to flash chromatography on silica gel (14% ethyl acetate:hexanes) to afford the title compound as a solid, (0.47 g; m.p. 136-137° C.).
Reaction SMILES: [NH:1]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([OH:20])=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].N([C:55]([O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56])[C@H](C(N[C@H](C(C(OCC)=O)=O)CC1C=CC=CC=1)=O)CC(C)C.C(OCC1C=CC=CC=1)C1C=CC=CC=1.[Na].C(Cl)(Cl)Cl>C(O)C1C=CC=CC=1.CO>[NH:1]([C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([C:55]([O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56])=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CCOC(=O)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na]
Solvent: c1ccc(COCc2ccccc2)cc1
Solvent: OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)C(=O)OCc1ccccc1
Yield: 17 %

Procedure:
This compound was prepared from Z-Leu-Phe-OH and benzyl oxalyl chloride in 17% yield by the procedure described in the synthesis of Z-Leu-Phe-CO2Et, except that benzyl oxalyl chloride was used in place of ethyl oxalyl chloride and sodium benzyloxide in benzyl alcohol was used for enol ester hydrolysis. Single spot on TLC, Rf =0.63 (CHCl3 :CH3OH=50:1). Pale yellow solid, mp 117°-119° C. MS(FAB) m/e=532 (m+1). H1NMR ok.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:10]([O:12][C:13](=[O:38])[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br)[C:19]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH3:11].C([O-])([O-])=O.[K+].[K+]>CC#N.CN(C=O)C.CCOC(C)=O>[CH2:10]([O:12][C:13](=[O:38])[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:19]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH3:11]
Reactant: Sc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CCCOc1cccc(CCCCCCSc2cc(Cl)cc(Cl)c2)c1CCC(=O)OCC
Temperature: 80 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
To a solution of 3,5-dichlorothiophenol (1.67 g, 9.34 mmol) in MeCN (120 mL) and DMF (80 mL), 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (4.0 g, 8.49 mmol) was added, followed by K2CO3 (3.52 g, 25.48 mmol). The reaction mixture was stirred at 80° C. overnight. At this time, after cooling, the reaction was diluted with EtOAc (300 mL), washed with water (twice with 150 mL) and brine, and dried over Na2SO4. Concentration under reduced pressure provided an oil. A sample (2.73 g) was purified by FCC (10% EtOAc/Hex) provide a pure sample (1.20 g) of 4-[3-[6-(3,5-Dichloro-phenylsulfanyl)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester. 1H NMR (CDCl3): δ 7.26 (s, 1H), 7.12 (s, 2H), 7.09 (dd, 1H), 6.75 (d, 1H), 6.69 (d, 1H), 4.14 (m, 4H), 3.99 (t, 2H), 2.98-2.89 (m, 4H), 2.64-2.46 (m, 6H), 2.13 (m, 2H), 1.67-1.39 (m, 8H), 1.27 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:27])/[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:17])=[C:9]([O:28][CH3:29])[C:8]([CH3:30])=[C:7]2[C:3]=1[C:4](=[O:31])[O:5][CH2:6]2.[C:32]12([C:42](Cl)=[O:43])[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][CH:34]([CH2:35]3)[CH2:33]1)[CH2:39]2.O>N1C=CC=CC=1>[C:32]12([C:42]([O:1][C:2]3[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:27])/[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:17])=[C:9]([O:28][CH3:29])[C:8]([CH3:30])=[C:7]4[C:3]=3[C:4](=[O:31])[O:5][CH2:6]4)=[O:43])[CH2:39][CH:38]3[CH2:37][CH:36]([CH2:35][CH:34]([CH2:40]3)[CH2:33]1)[CH2:41]2
Reactant: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: c1ccncc1
Solvent: O
Product: COc1c(C)c2c(c(OC(=O)C34CC5CC(CC(C5)C3)C4)c1C/C=C(\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Morpholinoethyl E-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate (10.0 g) was dissolved in pyridine (50.0 ml) followed by the addition of 1-adamantanecarbonyl chloride (10.0 ml). The mixture was stirred at room temperature for 90 minutes, then poured into water and extracted with ethyl acetate. The organic solution was dried and evaporated to give morpholinoethyl E-6-[1,3-dihydro-4-(1-adamantoyloxy)-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl]-4-methyl-4-hexenoate.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:17]=1)[CH2:9][CH2:10][CH3:11])(C)(C)C.[ClH:23].O1CCOCC1>ClCCl>[ClH:23].[ClH:23].[CH3:21][S:18]([C:16]1[CH:17]=[C:12]([CH:8]([NH2:7])[CH2:9][CH2:10][CH3:11])[CH:13]=[N:14][CH:15]=1)(=[O:20])=[O:19]
Reactant: CCCC(NC(=O)OC(C)(C)C)c1cncc(S(C)(=O)=O)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCC(N)c1cncc(S(C)(=O)=O)c1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A suspension of [1-(5-methanesulfonyl-pyridin-3-yl)-butyl]-carbamic acid tert-butyl ester (3.2 g, 9.6 mmol) in dichloromethane (12 mL) is treated HCl in dioxane (4.0 N, 24 mL, 96 mmol) and stirred for 30 min. The solvent is then removed in vacuo. The resultant residue is triturated with anhydrous ethyl ether (50 mL) and filtered (note: the collected solids are hygroscopic and turn into a liquid when left exposed to air.) Methanol is added and the solution is concentrated in vacuo to yield 1-(5-methanesulfonyl-pyridin-3-yl)-butylamine dihydrochloride (2.8 g, 100%) as a dark brown solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])/[CH:5]=[CH:6]/[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[Na].[C:16](OCC)(=[O:19])[CH2:17][SH:18]>C(O)C>[CH2:13]([O:12][CH:4]([O:3][CH2:1][CH3:2])[CH:5]1[CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:16](=[O:19])[CH2:17][S:18]1)[CH3:14]
Reactant: CCOC(=O)/C=C/C(OCC)OCC
Reactant: CCOC(=O)CS
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1C(=O)CSC1C(OCC)OCC
Temperature: 25 °C

Procedure:
The starting material is prepared as follows: 8.65 g of ethyl 4,4-diethoxycrotonate are added at once at 0° to the mixture prepared from 1 g of pulverized sodium, 40 ml of ethanol and 4.94 ml of ethyl thioglycolate, evaporating the mixture after stirring it at room temperature and adding 43 ml of dimethylsulfoxide and 20 ml of dimethylformamide. The mixture is stirred at 0° for 1/2 hour and at room temperature for 2 hours, poored into cold water and extracted with diethyl ether. The aqueous layer is acidified with 21.7 ml of cold 2N hydrochloric acid and extracted with diethyl ether. The extract is dried and evaporated, to yield the ethyl 2-diethoxymethyl-4-oxo-tetrahydrothiophene-3-carboxylate showing in the Ir spectrum-bands at 1750, 1725, 1660, 1615 cm-1.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].[NH2:8][C:9]1[O:10][CH:11]=[C:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]=1[C:14]#[N:15]>CN(C)C=O>[CH2:1]([O:3][CH2:4][C:5]([NH:8][C:9]1[O:10][CH:11]=[C:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]=1[C:14]#[N:15])=[O:6])[CH3:2]
Reactant: CC(C)(C)c1coc(N)c1C#N
Reactant: CCOCC(=O)Cl
Solvent: CN(C)C=O
Product: CCOCC(=O)Nc1occ(C(C)(C)C)c1C#N
Temperature: 0 °C
Yield: 78.5 %

Procedure:
26.2 g (0.2 mole) of ethoxyacetyl chloride were added dropwise to a solution of 32.8 g (0.2 mole) of 2-amino-3-cyano-4-tert.-butyl-furan in 200 ml of dimethylformamide at room temperature. After the moderately exothermic reaction had subsided (rise in temperature from 23° C. to 38°), the reaction mixture was poured into ice-water. The solid product thereby obtained was filtered off and recrystallized, in the moist state, from a little methanol. 39.3 g of 2-ethoxyacetylamino-3-cyano-4-tert.-butyl-furan of melting point 98° C. were obtained in this manner.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1.[CH2:31](O)[CH2:32][OH:33]>C(Cl)Cl>[O:33]1[C:2]2([CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)[O:1][CH2:31][CH2:32]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1CCC2(CC1)OCCO2
Yield: 64.9 %

Procedure:
Ethyl 4-oxocyclohexane carboxylate (122.56 mmol, 20.86 g) and para-toluenesulfonic acid monohydrate (12.56 mmol, 2.33 g) are charged to a 1000 mL roundbottom flask. To this flask was added benzene (300 mL) followed by ethylene glycol (0.37 mol, 20.5 mL). The resulting bi-layer reaction mixture was refluxed overnight in a Dean-Stark trap. Upon cooling, the reaction mixture was diluted in 300 mL DCM and washed with 300 mL saturated NaHCO3(aq). The aqueous layer was washed with DCM (3×) and the combined organics are dried over Na2SO4. The residue was dissolved in DCM and purified by silica gel chromatography on 0% to 50% ethyl acetate in hexanes gradient. The product is tracked via PMA stain. Chromatography yields 17.05 grams (79.58 mmol, 65% yield) ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].O.[C:19](Cl)(=[O:21])[CH3:20]>C(OCC)(=O)C>[C:19]([NH:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)(=[O:21])[CH3:20]
Reactant: NC1Cc2ccccc2C1
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)NC1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 88.4 %

Procedure:
To a mixture of 2-aminoindan hydrochloride (10.40 g), potassium carbonate (34.2 g), water (100 ml) and ethyl acetate (150 ml) is added dropwise acetyl chloride (9.68 g) under ice cooling. The mixture is stirred at 0° C. for 1.5 hour, and the ethyl acetate layer is separated, washed with aqueous saline solution, dried, and then the solvent is distilled off under reduced pressure. The residue is recrystallized from ethyl acetate - n-hexane to give 2-acetylaminoindan (9.5 g) as colorless crystals. m.p. 126.5°-127.5° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([C:12]#[N:13])[CH:6]=1.C([BH3-])#N.[Na+]>>[C:12]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[F:11])[CH2:4][NH:3][O:2][CH3:1])#[N:13]
Reactant: CON=Cc1ccc(F)c(C#N)c1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccc(F)c(C#N)c1

Procedure:
Reduction of 3-cyano-4-fluorobenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of compound 3-B gave the title hydroxylamine as a clear oil after chromatography on silica gel (elution hexane-ethyl acetate 8: 2) (73% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.46 (3H, s, OCH3), 4.02 (2H, s, NCH2), 7.18 (1H, t, aromatic), 7.58-7.66 (2H, m, aromatics). The hydrochloride salt was obtained as a white solid: mp 152-158° C. Anal. calcd for C9H9FN2O—HCl: C, 49.89; H, 4.65; N, 12.93. Found: C, 50.04; H, 4.64; N, 12.84.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:12](=[C:14]([C:18]([OH:20])=O)[CH:15]=[CH:16][CH:17]=2)[N:13]=1.Cl.Cl.[NH2:23][C@H:24]1[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:26]12[CH2:31][CH2:30][CH:29]([CH2:28][CH2:27]1)[C@H:24]([NH:23][C:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:11]3[O:10][C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])=[N:13][C:12]=13)=[O:20])[CH2:25]2
Reactant: O=C(O)c1cccc2oc(-c3ccc(Cl)cc3Cl)nc12
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cccc2oc(-c3ccc(Cl)cc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.3 %

Procedure:
A mixture of 2-(2,4-dichlorophenyl)benzo[d]oxazole-4-carboxylic acid (100 mg, 0.32 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (64 mg, 0.32 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (123 mg, 0.64 mmol) and 1-hydroxybenzotriazole (86 mg, 0.64 mmol) in DMF (1.5 mL) was stirred at room temperature for 5 min, then triethylamine (0.17 mL, 1.28 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (20 mL), then washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 89:10:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2,4-dichlorophenyl)benzoxazole-4-carboxamide (63 mg, 47%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.40 (d, J=7.0 Hz, 1H), 8.25 (dd, J=7.5, 1.0 Hz, 1H), 8.17 (d, J=8.5 Hz, 1H), 7.75 (dd, J=8.0, 1.0 Hz, 1H), 7.65 (d, J=2.0 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.47 (dd, J=8.5, 2.0 Hz, 1H), 4.32-4.26 (m, 1H), 3.50 (ddd, J=11.5, 9.5, 2.0 Hz, 1H), 3.10-2.72 (m, 5H), 2.15-2.10 (m, 1H), 2.02-1.95 (m, 1H), 1.82-1.70 (m, 2H), 1.60-1.51 (m, 1H); MS (ESI+) m/z 416 (M+H); HPLC>99% (AUC), tR=13.23 min.
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[NH:30]([CH2:34][CH2:35][OH:36])[CH2:31][CH2:32][OH:33]>>[OH:33][CH2:32][CH2:31][N:30]([CH2:34][CH2:35][OH:36])[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1
Reactant: OCCNCCO
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(N(CCO)CCO)nc1

Procedure:
6-[Bis-(2-hydroxy-ethyl)-amino]-N-(7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-yl-methyl)-nicotinamide was prepared starting from intermediate E and diethanolamine. MS calcd. for C26H25ClN4O4 [(M+H)+] 493, obsd. 493.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([NH2:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH2:9]1[CH2:15][S:12](=[O:14])(=[O:13])[O:11][CH2:10]1>C(#N)C>[NH2:8][C:6]([C@H:2]([NH:1][CH2:10][CH2:9][CH2:15][S:12]([OH:14])(=[O:13])=[O:11])[CH:3]([CH3:5])[CH3:4])=[O:7]
Reactant: O=S1(=O)CCCO1
Reactant: CC(C)[C@@H](N)C(N)=O
Solvent: CC#N
Product: CC(C)[C@@H](NCCCS(=O)(=O)O)C(N)=O
Temperature: 25 °C
Yield: 45.8 %

Procedure:
To a solution of D-valinamide (1.76 g, 14.7 mmol) in acetonitrile (30 mL) was slowly added 1,3-propanesultone (1.75 g, 14.4 mmol). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with acetonitrile (2×25 mL). The solid product was dissolved in water (75 mL). Dowex Marathon C resin (strongly acidic) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure. The solid material was suspended in acetone (50 mL), filtered and dried in vacuo, affording the title compound (1.57 g, 51%). 1H NMR (D2O, 500 MHz) δ ppm 3.80 (m, 1H), 3.19 (m, 2H), 3.00 (m, 2H), 2.25 (m, 1H), 2.16 (m, 2H), 1.08 (d, 3H, J=6.8 Hz), 1.02 (d, 3H, J=6.8 Hz). 13C (D2O, 125 MHz) δ ppm 169.94, 65.86, 48.10, 46.27, 29.54, 21.23, 17.99, 17.02. [α]D=−12.4° (c=0.0037 in water), ES-MS 237 (M−1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1)[NH2:7].[N:17]#[C:18][NH2:19].Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:7][C:18]([NH2:19])=[NH:17])[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1
Reactant: N#CN
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1

Procedure:
3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline hydrochloride (3 g, 12.52 mmol), cyanamide (0.684 g, 16.27 mmol) and hydrochloric acid (1.564 mL, 18.77 mmol) in ethanol (20 mL) were heated to reflux o.n. The reaction mixture was concentrated under reduced pressure before the resulting mixture was poured on a solution of potassium carbonate (1.730 g, 12.52 mmol) in water (60 mL) and left in refrigerator o.n. The formed carbonate-salt was filtered off, and dried in vacuum oven o.n. The solid was washed with several portions of DCM, dried and used as such in next step.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.FC(F)(F)C(O)=O.[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:9])=[CH:6][CH:5]=[C:4]([NH:35][CH:32]2[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: Nc1nc(Cl)ccc1C(=O)c1ccccc1F
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCC(Nc2ccc(C(=O)c3ccccc3F)c(N)n2)CC1

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(2-fluoro-phenyl)-methanone (Example 7) and 1-methanesulfonyl-piperidin-4-ylamine (Step A, Example 6) using the procedure described in Step B. Example 6. HRMS, observed: 392.1329, calcd for M+: 392.1318.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-bromobenzoic acid (5 g) and thionyl chloride (15 mL) was stirred at the room temperature for 16 hours, heated to reflux for 6 hours and then stirred at room temperature for 16 hours. At the end of this period, the reaction mixture was diluted with chloroform and evaporated. The residue was treated with toluene, evaporated and the process was repeated three times. The product was obtained as a solid (5.63 g); MS: 221; NMR: 7,5 (m, 2), 7.9-8.1 (m, 2).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH2:7][CH2:6][N:5](C(OCC)=O)[CH2:4]1.Cl>>[CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: CCOC(=O)N1CC[C@H](NC(C)c2ccccc2)[C@H](OC)C1
Agent: Cl
Product: CO[C@@H]1CNCC[C@@H]1NC(C)c1ccccc1
Yield: 100 %

Procedure:
A solution of 16 parts of (+)-ethyl cis-3-methoxy-4-[(1-phenylethyl)amino]-1-piperidinecarboxylate in 170 parts of a hydrochloric acid solution 6N was stirred and refluxed for 45 hours. The reaction mixture was cooled and washed with dichloromethane. The aqueous phase was cooled in an ice-bath and treated with ammonium hydroxide. The product was extracted three times with 130 parts of dichloromethane. The combined extracts were washed with 10 parts of water, dried, filtered and evaporated. The residue was dissolved in methylbenzene and the latter was evaporated again, yielding 12.2 parts (100%) of (+)-cis-3-methoxy-N-(1-phenylethyl)-4-piperidinamine as a residue (intermediate 105).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[O:9].C([O-])(=S)C.[K+].O>CC(C)=O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9]
Reactant: O=CCCCCCCBr
Agent: CC([O-])=S
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: OCCCCCCCBr
Temperature: 25 °C

Procedure:
To a solution of crude 7-bromoheptanal (Enders and Bartzen (1991) Liebigs Ann. Chem, 569-574) (3.32 g, 17.2 mmol) in acetone (50 mL) was added potassium thioacetate (2.36 g, 21 mmol) under stirring at rt. Then the mixture was refluxed, yielding a precipitate after a few minutes. The reaction was monitored by TLC and cooled to rt when no starting material was detectable (4 h). Water (50 mL) was added, the mixture was extracted with ethyl ether until the organic phase was colorless, and the combined organic phases were dried (Na2SO4) and evaporated. Distillation at 98° C. with a water suction pump afforded 1.66 g (51%, 42% from 7-bromoheptanol) of a yellow oil. IR (neat): {tilde over (v)} 2938, 2857, 2721, 1725, 1694; 1H NMR δ 1.28-1.43 (m, 4H), 1.53-1.69 (m, 4H), 2.33 (s, 3H), 2.43 (dt, 3J=7.3Hz, 3J=1.5Hz, 2H), 2.86 (t, 3J=7.3 Hz, 2H), 9.77 (t, 3J=1.5 Hz, 1H); 13C NMR (APT) δ 21.6 (+), 28.1 (+), 28.3 (+), 28.6 (+), 29.0 (+), 30.3 (−), 43.3 (+), 195.4 (+), 202.0 (−); GC-MS (EI) obsd 188, 187, 145, 128, 112, 94, 43.