Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:26][CH2:27][CH2:28][N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[CH2:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:26][CH2:27][CH2:28][N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCn1ccnc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCn1ccnc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 0.17 g (0.34 mmol) t-butyl 8-(p-chlorophenylsulfonamido)-4-[3-(1-imidazolyl)propyl]-octanoate in 5 ml methylene chloride is added 1 ml trifluoroacetic acid and the solution is stirred at room temperature for 1.5 h. The solvent is evaporated and the residue taken up in 5 ml water. The pH of the solution is adjusted to 6.5 using 1N aqueous sodium hydroxide. Then the aqueous solution is extracted twice with ethyl acetate. The combined organic layer is washed with water and brine, dried, filtered and concentrated to give a pale yellow oil. The product is triturated five times with 2 ml ether each and finally dried to yield 8-(p-chlorophenylsulfonamido)-4-[3-(1-imidazolyl)propyl]-octanoic acid, m.p. 136°-138°.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:39]I>O.C(#N)C>[I:39][CH2:2][CH2:3][CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CC(CCO)C1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(CCI)C1
Reaction time: 18 h
Yield: 69.1 %

Procedure:
A stirred solution of tert-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate (254 mg, 1.26 mmol), Ph3P (381 mg, 1.45 mmol.15), imidazole (129 mg, 1.89 mmol0) and acetonitrile (6.5 mL) at 0° C.; was treated with iodine (368 mg, 1.45 mmol.15). Mixture was allowed to reach 25° C. and stirring continued for 18 h. The reaction mixture was then diluted with water and extracted with hexanes (6×25 mL). The combined organics were dried (MgSO4) and concentrated, then purified by chromatography (40 g column, 50 μm from Analogix, 0-30% EtOAc in hexanes over 15 min to give tert-butyl 3-(2-iodoethyl)azetidine-1-carboxylate (271 mg, 871 μmol, 69.0%) as a colorless oil. 1H NMR (CDCl3) δ: 4.03 (t, J=8.3 Hz, 2H), 3.56 (dd, J=8.7, 5.7 Hz, 2H), 3.10 (t, J=7.0 Hz, 2H), 2.63 (quint, J=7.8, 5.4 Hz, 1H), 2.13 (q, J=7.1 Hz, 2H), 1.42 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](I)=[CH:4][N:3]=1.[NH:10]1[CH:14]=[C:13]([CH2:15][CH2:16][NH2:17])[N:12]=[CH:11]1.CC1(C)C(C)(C)OB([C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)O1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][CH2:16][CH2:15][C:13]2[N:12]=[CH:11][NH:10][CH:14]=2)[C:5]([C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)=[CH:4][N:3]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: NCCc1c[nH]cn1
Reactant: CC1(C)OB(c2cccs2)OC1(C)C
Product: Clc1ncc(-c2cccs2)c(NCCc2c[nH]cn2)n1

Procedure:
Preparation according to procedures 2 and 3 with the use of 2,4-dichloro-5-iodo-pyrimidine, 2-(1H-imidazol-4-yl)-ethylamine and 4,4,5,5-tetramethyl-2-(2-thienyl)-1,3,2-dioxaborolane.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[N+:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20])([O-:15])=[O:14]>N1C=CC=CC=1>[C:4]([C:3]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=1[NH:1][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=1)#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: N#Cc1cc([N+](=O)[O-])ccc1NC(=O)c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 8.16 gm. (0.05 mole) of 2-amino-5-nitrobenzonitrile and 9.28 gm. (0.05 mole) of m-nitro benzoyl chloride in 50 ml. of dry pyridine is refluxed for 3 hours. The pyridine is removed by distillation in vacuo and the solid residue triturated with water. There is obtained 15.3 gm. (95%) of a yellow solid that melts at 203°-205°. Recrystallization from aqueous ethanol (2:1) gives material melting at 205°-206°.
Reaction SMILES: [CH3:1][C:2]1([CH2:19][C:20]#N)[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[C:11](=[O:18])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.Cl.[OH-:23].[Na+].[OH2:25]>>[CH3:1][C:2]1([CH2:19][C:20]([OH:25])=[O:23])[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[C:11](=[O:18])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: CC1(CC#N)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reactant: [OH-]
Reactant: O
Agent: Cl
Agent: [Na+]
Product: CC1(CC(=O)O)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Temperature: 20 °C

Procedure:
The process is performed as in Example 53 but starting with 0.84 g of (10-methyl-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl)-acetonitrile, 7.6 ml of concentrated hydrochloric acid and 1.5 ml of distilled water. The reaction mixture is cooled to a temperature in the region of 20° C., basified with 7 ml of concentrated sodium hydroxide and filtered. Distilled water (qs 50 ml) is added and the filtrate is acidified to pH 4 with acetic acid. The precipitate formed is filtered off, washed with distilled water and then with ethyl ether (2×15 ml), and dried at 60° C. under vacuum (1 mmHg; 0.13 kPa). 0.14 g of (10-methyl-4,5-dihydro-4-oxo-10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-10-yl)acetic acid is obtained in the form of a beige-coloured solid (1H NMR spectrum: (200 MHz; (CD3)2SO-d6 ; δ in ppm): 1.62 (s, 3H: CH3); 3.22 (limiting AB, J=15.5 Hz, 1H: CH2COO); 7.35 (mt, 2H: H 7 and H 8); 7.60 and 8.28 (2 broad s, 1H each: H of the imidazole); 7.65 and 7.85 (2 broad d, J=7.5 Hz, 1H each: H 6 and H 8); from 11.80 to 12.80 (broad mult., 1H: NH 5)).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH2:12][OH:13])[CH2:9][C:10]#[N:11])=[C:4]([O:14][CH3:15])[CH:3]=1.[O:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O.[BH4-].[Na+].C(NCC)C>CO>[C:20]([O:19][C:17](=[O:16])[NH:11][CH2:10][CH2:9][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[O:14][CH3:15])[CH2:12][OH:13])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COc1cc(Br)ccc1[C@@H](CO)CC#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCNCC
Solvent: CO
Product: COc1cc(Br)ccc1[C@@H](CO)CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.7 %

Procedure:
To a solution of (S)-3-(4-bromo-2-methoxy-phenyl)-4-hydroxy-butyronitrile (459 mg, 1.699 mmol) in MeOH (12.1 mL) at 0° C. was added (BOC)2O (736.3 mg, 3.398 mmol), NiCl2.6H2O (40.75 mg, 0.17 mmol), and (in portions) sodium borohydride (450.3 mg, 11.9 mmol). The mixture was stirred at room temperature for 18 hours. Diethylamine (0.183 mL, 1.699 mmol) was then added and the mixture was stirred for 30 minutes. Solvent was evaporated under reduced pressure and a solution of aqueous NaHCO3 (10%) was added. The mixture was extracted with EtOAc, and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified via flash chromatography (hexane/EtOAc, 7/3) to give 405 mg (64% yield) of [(S)-3-(4-bromo-2-methoxy-phenyl)-4-hydroxy-butyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:7](=[O:16])[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.C(=O)([O-])[O-:26].[Na+].[Na+].[I-].[K+].Cl[CH2:34][CH2:35][CH2:36][CH:37]([C:45]1[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=1)[C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1>O.CC(C)CC(=O)C>[O:26]([CH:24]([CH3:23])[CH3:2])[CH:35]([CH3:36])[CH3:34].[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([CH:17]3[CH2:18][CH2:19][N:20]([CH2:34][CH2:35][CH2:36][CH:37]([C:38]4[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=4)[C:45]4[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=4)[CH2:21][CH2:22]3)[C:7](=[O:16])[N:8]([CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:4]=2[CH:3]=1
Reactant: O=c1n(Cc2ccccc2)c2cc(Cl)ccc2n1C1CCNCC1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CC(C)OC(C)C
Product: O=c1n(Cc2ccccc2)c2cc(Cl)ccc2n1C1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 8 h

Procedure:
A mixture of 6.8 parts of 5-chloro-1,3-dihydro-3-(phenylmethyl)-1-(4-piperidinyl)-2H-benzimidazol-2-one, 6.4 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 30 minutes with water-separator. After cooling, 7 parts of 1-chloro-4,4-bis(4-fluorophenyl)butane are added and stirring at reflux temperature is continued overnight. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The oily residue is crystallized twice: first from 2,2'-oxybispropane and then from 2-propanol, yielding 5-chloro-1-{1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl}-1,3-dihydro-3-(phenylmethyl)-2H-benzimidazol-2-one; mp. 141.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[C:9]1(=[O:13])[O:12][CH2:11][CH2:10]1.[H-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:11][CH2:10][C:9]([OH:13])=[O:12])=[CH:4][CH:3]=1
Reactant: Fc1ccc(S)cc1
Reactant: O=C1CCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCSc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
p-Fluorothiophenol (5 g, 40 mmol) and β-propiolactone (2.8 g, 40 mmol) were dissolved in THF (36 mL of freshly distilled) and then placed in an ice bath. 95% sodium hydride (1 g, 42.9 mmol) was added in small portions over 1 hour. The reation was allowed to stir at 0° C. for 2 hours, then placed in the freezer overnight. The reaction was quenched with ice chips and then acidified with concentrated hydrogen chloride until a pH of 2. The product was extracted with ethyl acetate (1×200 mL) and dichloromethane (2×200 mL), dried (sodium sulfate) and concentrated to give 3-(4-fluorophenylthio)propanoic acid (7.08 g, 89%). 1H NMR (CDCl3, 300 MHz): δ7.42-7.35 (m, 2H), 7.02 (t, 2H, J=8.6 Hz), 4.35 (t, 1H, J=6.2 Hz), 3.10 (t, 2H, J=7.3 MHz), 2.63 (t, 2H, J=7.3 Hz) ppm.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=2[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:6]=[CH:7][CH:8]=1.C(Br)(Br)(Br)[Br:27].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>CN(C=O)C>[Br:27][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=2[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)Cc1cc(-c2cccc(CO)c2)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cc1cc(-c2cccc(CBr)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A mixture of 3-(3-hydroxymethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (246 mg, 0.644 mmol; see step (d)), CBr4 (534 mg, 1.61 mmol) and PPh3 (422 mg, 1.61 mmol) in DMF (5.0 mL) was stirred at room temperature overnight. Water (10 mL) was then added and the reaction mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried and concentrated in vacuo. The crude product was purified on column chromatography (Hex/EtOAc 9:1) to give the sub-title compound as a white solid in 95% yield (273 mg, 0.612 mmol).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH:12]([NH:25][C:26](=[O:30])[O:27][CH2:28][CH3:29])[CH:13]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)=[CH:8][CH:7]=1.[CH3:31][N:32]1[CH:36]=[C:35]([S:37](Cl)(=[O:39])=[O:38])[N:34]=[CH:33]1.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[Cl:23])[CH2:16][CH:13]1[C:14]2[C:9](=[CH:8][CH:7]=[C:6]([O:5][CH2:4][CH2:3][NH:2][S:37]([C:35]3[N:34]=[CH:33][N:32]([CH3:31])[CH:36]=3)(=[O:39])=[O:38])[CH:15]=2)[CH2:10][CH2:11][CH:12]1[NH:25][C:26](=[O:30])[O:27][CH2:28][CH3:29]
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CCOC(=O)NC1CCc2ccc(OCCN)cc2C1Cc1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)NC1CCc2ccc(OCCNS(=O)(=O)c3cn(C)cn3)cc2C1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 75.1 %

Procedure:
Ethyl 7-(2-aminoethoxy)-1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate hydrochloride (100 mg, 0.229 mmol) and DMAP (27.9 mg, 0.229 mmol) were dissolved in CH2Cl2 (15 ml) and 1-methyl-1H-imidazole-4-sulfonyl chloride (41.3 mg, 0.229 mmol) dissolved in CH2Cl2 (15 ml) was added. The reaction mixture was stirred over night at RT. After addition of H2O the phases were separated and the aqueous phase was extracted with CH2Cl2. The organic layer was washed with HCl (1N), NaHCO3 solution and NaCl solution, then dried on MgSO4 and the solvent was removed. To the residue EtOAc/diethylether (1:1) was added, stirred, and the precipitate was separated by filtration to obtain a brown solid of product (100 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([SH:13])[CH:6]=1)[CH3:2].C(N(CC)CC)C.Cl[CH2:23][C:24](=[O:26])[CH3:25].CCOC(C)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([S:13][CH2:23][C:24](=[O:26])[CH3:25])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(OC)c(S)c1
Reactant: CC(=O)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OC)c(SCC(C)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Mercapto-4-methoxy-benzoic acid ethyl ester (1.29 g, 6.08 mmol) and triethylamine (2.12 mL, 15.19 mmol) were dissolved in THF (20 mL) at 0° C. Chloroacetone (0.58 mL, 7.29 mmol) was then added and the reaction stirred at room temperature for 30 minutes. It was then allowed to slowly warm to room temperature and stirred an additional 30 minutes. Standard aqueous workup followed by silica gel chromatography (0-70% EtOAc in hexanes) gave the title compound.
Reaction SMILES: Br[C@H:2]1[C@H:11](O)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Br:13])[CH:9]=2)[O:4][CH2:3]1.[OH-:14].[NH4+:15]>C(O)(C)C>[NH2:15][C@@H:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Br:13])[CH:9]=2)[O:4][CH2:3][C@H:2]1[OH:14]
Reactant: [NH4+]
Reactant: [OH-]
Reactant: O[C@@H]1c2cc(Br)ccc2OC[C@H]1Br
Solvent: CC(C)O
Product: N[C@@H]1c2cc(Br)ccc2OC[C@H]1O
Temperature: 2.5 °C
Reaction time: 15 h
Yield: 89.2 %

Procedure:
To a solution of racemic-trans-3,6-dibromochroman-4-ol (30.0 g, 97.4 mmol) in isopropyl alcohol (300 mL) at ambient temperature (500 mL), add ammonium hydroxide (28-30% aq., 150 mL, 2.2 mol). Stir slowly for 15 hr. Filter the reaction mixture and dilute the filtrate with water (200 mL). Concentrate the resulting solution under reduced pressure to one half of its original weight. Add water (100 mL), stir the mixture at ambient temperature for 10 min., then cool to 0-5° C. and stir for an additional 30 min. Collect the precipitate by filtration and wash the solids with water (25 mL) and heptanes (25 mL). Vacuum dry the material at 40° C. to afford the title compound as a pale yellow solid (21.2 g, 89.2%). 1H NMR (DMSO-d6) δ 1.96 (bs, 2H), 3.53 (m, 2H), 3.87 (dd, 1H), 4.11 (dd, 1H), 5.15 (bs, 1H), 6.66 (d, 1H), 7.19 (dd, 1H), 7.48 (dd, 1H). LC-ES/MS m/z (79Br) 244 [M+H].
Reaction SMILES: C([Li:5])CCC.Br[C:7]1[CH:12]=[C:11]([F:13])[C:10]([Cl:14])=[CH:9][C:8]=1[O:15][CH2:16][O:17][CH3:18].[C:19](=[O:21])=[O:20]>C(OCC)C>[Cl:14][C:10]1[C:11]([F:13])=[CH:12][C:7]([C:19]([O-:21])=[O:20])=[C:8]([O:15][CH2:16][O:17][CH3:18])[CH:9]=1.[Li+:5]
Reactant: O=C=O
Reactant: [Li]CCCC
Reactant: COCOc1cc(Cl)c(F)cc1Br
Solvent: CCOCC
Product: COCOc1cc(Cl)c(F)cc1C(=O)[O-]
Product: [Li+]
Reaction time: 1 h

Procedure:
n-butyllithium was added to a diethyl ether solution of 1-bromo-4-chloro-5-fluoro-2-(methoxymethoxy)benzene in a dry ice-acetone bath and stirred for one hour. The reaction solution was added to a mixture of dry ice and diethyl ether and stirred for two hours to give lithium 4-chloro-5-fluoro-2-(methoxymethoxy)benzoate. Phosphorus oxychloride was added to a mixture of the obtained lithium 4-chloro-5-fluoro-2-(methoxymethoxy)benzoate, 3-aminothiophene-2-carboxamide and pyridine in a MeOH ice bath and stirred for one hour to give 3-{[4-chloro-5-fluoro-2-(methoxymethoxy)benzoyl]amino}thiophene-2-carboxamide.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][NH2:17].[Cl:18][CH2:19][CH2:20][N:21]=[C:22]=[O:23]>>[Cl:18][CH2:19][CH2:20][NH:21][C:22]([N:17]([CH2:16][C:12]1[S:11][CH:15]=[CH:14][CH:13]=1)[CH:9]1[O:10][CH2:2][C@H:3]([OH:4])[C@H:5]([OH:6])[C@H:7]1[OH:8])=[O:23]
Reactant: NCc1cccs1
Reactant: O=C=NCCCl
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Product: O=C(NCCCl)N(Cc1cccs1)C1OC[C@H](O)[C@H](O)[C@H]1O

Procedure:
3.0 g of L-arabinose, 2.7 g of (thiophen-2-yl-methyl)amine and 2.5 of 2-chloroethyl isocyanate are treated in the same manner as described in Example 31-(1). 4.1 g of 1-(2-chloroethyl)-3-(thiopen-2-yl-methyl)-3-(L-arabinopyranosyl)urea are thereby obtained as colorless powder.
Reaction SMILES: [C:1]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([NH2:17])=[O:16])=[CH:12][CH:13]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-])=O)[C:7]=1[CH2:28][CH2:29][CH3:30])(=[O:5])[CH:2]([CH3:4])[CH3:3].[ClH:31]>CO.[Pd].C(Cl)(Cl)Cl>[ClH:31].[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([C:15]([NH2:17])=[O:16])[CH:10]=2)[C:6]([C:1](=[O:5])[CH:2]([CH3:3])[CH3:4])=[C:7]1[CH2:28][CH2:29][CH3:30]
Reactant: CCCc1c(C(=O)C(C)C)c2ccc(C(N)=O)cc2n1Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCc1c(C(=O)C(C)C)c2ccc(C(N)=O)cc2n1Cc1ccccc1N
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 3-isobutyryl-1-(2-nitrobenzyl)-2-propylindole-6-carboxamide (316 mg) in methanol (10 ml) was hydrogenated over 10% palladium on carbon at 20° C. for 6 hours. The catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of methanol and chloroform 1:30) to give an oil which was dissolved in a mixture of chloroform (10 ml) and methanol (20 ml). To this solution was added 10% hydrogen chloride in methanol (0.9 ml), and the mixture was stirred at 20° C. for 1 hour and evaporated in vacuo. The residue was recrystallized from a mixture of methanol and diisopropyl ether to give 1-(2-aminobenzyl)-3-isobutyryl-2-propylindole-6-carboxamide hydrochloride (415 mg) as colorless crystals.
Reaction SMILES: C1([NH:7]N)C=CC=CC=1.[Cl:9][C:10]1[CH:16]=[C:15]([CH2:17][CH3:18])[CH:14]=[C:13]([Cl:19])[C:11]=1[NH2:12]>>[Cl:9][C:10]1[CH:16]=[C:15]([CH2:17][CH3:18])[CH:14]=[C:13]([Cl:19])[C:11]=1[NH:12][NH2:7]
Reactant: CCc1cc(Cl)c(N)c(Cl)c1
Reactant: NNc1ccccc1
Product: CCc1cc(Cl)c(NN)c(Cl)c1

Procedure:
The phenylhydrazine used as starting material in Reference Example 10 was prepared by proceeding in a similar manner to that hereinbefore described in Reference Example 5 but replacing the 2-chloro-4-ethylaniline by 2,6-dichloro-4-ethylaniline. 2,6-Dichloro-4-ethylphenylhydrazine, m.p. 48°-50° C., was obtained in the form of a cream-coloured solid.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]3[C:14]([CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:13][NH:12][C:9]3=[CH:10][N:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O[N:34]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C=O)C>[CH2:20]([N:27]1[CH2:32][CH2:31][N:30]([NH:34][C:17](=[O:19])[CH2:16][CH2:15][C:14]2[C:8]3[C:9](=[CH:10][N:11]=[C:6]([N:1]4[CH:5]=[N:4][CH:3]=[N:2]4)[CH:7]=3)[NH:12][CH:13]=2)[CH2:29][CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)CCc1c[nH]c2cnc(-n3cncn3)cc12
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCc1c[nH]c2cnc(-n3cncn3)cc12)NN1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.4 %

Procedure:
To a suspension of 3-(5-(1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)propionic acid (0.65 g) in dry DMF (5 mL) was added 1-benzylpiperazine (0.36 mL, 2.3 mmol), 1-hydroxybenzotriazole (0.255 g, 1.9 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (0.362 g, 1.9 mmol) and triethylamine (0.26 mL, 1.9 mmol) and this mixture was stirred at ambient temperature under nitrogen for 16 hours. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (25 mL) and water (25 mL) and Na2CO3 (sat., 1 mL). The two phases were separated and the aqueous phase was extracted with ethyl acetate (3×25 mL). The combined organics were dried (Na2 SO4) and evaporated in vacuo. The residue was chromatographed on silica eluting with a gradient of 5 to 10% MeOH in DCM to give the title compound (0.625 g, 100%) as a pale yellow foam. 1H NMR (360 MHz, CDCl3) δ 2.28-2.46 (4H, m), 2.70 (2H, t, J=7.1Hz), 3.15 (2H, t, J=7.2Hz), 3.37-3.43 (2H, m), 3.50 (2H, s), 3.60-3.68 (2H, m), 7.23-7.34 (6H, m), 8.05 (1H, s), 8.10 (1H, s), 8.58 (1H, s), 8.69 (1H, br s) and 9.14 (1H, s).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1.[OH-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CO>[OH:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7](=[O:9])[CH:8]=1
Reactant: O=c1cc(CO)occ1O
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1cc(CO)occ1OCc1ccccc1

Procedure:
A suspension of 2-(hydroxymethyl)-5-hydroxy-4H-pyran-4-one (56.8 g, 0.4 mole) in 400 ml of methanol was treated with sodium hydroxide (16 g, 0.4 mole) in 200 ml of warm methanol followed by 50.6 g (46 ml, 0.4 mole) of benzyl chloride. The mixture was heated to reflux for 3.5 hours, cooled, and poured into 1 L of water. The resulting solid was filtered and washed with ca. 1.5 L of water, 200 ml of ethanol and 400 ml of hexane. After drying under high vacuum, the weight of product was 55.7 g.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH3:16])[N:14]=1)[C:9]([OH:11])=O)[CH2:4][CH3:5])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:48]([C:50]1[CH:51]=[C:52]([CH:57]=[C:58]([CH3:61])[C:59]=1[OH:60])[C:53]([NH:55]O)=[NH:54])[CH3:49]>CN(C=O)C.C(Cl)Cl>[CH2:48]([C:50]1[CH:51]=[C:52]([C:53]2[N:55]=[C:9]([C:8]3[CH:12]=[C:13]([O:15][CH3:16])[N:14]=[C:6]([CH:3]([CH2:1][CH3:2])[CH2:4][CH3:5])[CH:7]=3)[O:11][N:54]=2)[CH:57]=[C:58]([CH3:61])[C:59]=1[OH:60])[CH3:49]
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Reactant: CCC(CC)c1cc(C(=O)O)cc(OC)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C(CC)CC)c3)n2)cc(C)c1O
Reaction time: 2 h
Yield: 47.7 %

Procedure:
To a solution of 2-(1-ethyl-propyl)-6-methoxy-isonicotinic acid (436 mg, 1.95 mmol) and DIPEA (759 mg, 5.86 mmol) in DMF (30 mL), TBTU (627 mg, 1.95 mmol) is added. The mixture is stirred at rt for 15 min before 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine (379 mg, 1.95 mmol) is added. Stirring is continued at rt for 2 h. The mixture is diluted with DCM (100 mL) and washed three times with sat. aq. NaHCO3 solution. The org. extract is dried over MgSO4, filtered and concentrated. The residue is dissolved in dioxane (20 mL) and the mixture is stirred at 100° C. for 18 h. The mixture is concentrated and the crude product is purified by prep. HPLC to give 2-ethyl-4-{5-[2-(1-ethyl-propyl)-6-methoxy-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenol (355 mg) as a beige solid; LC-MS: tR=1.20 min, [M+H]+=382.04; 1H NMR (CDCl3): δ0.84 (t, J=7.3 Hz, 6H), 1.34 (t, J=7.5 Hz, 3H), 1.68-1.89 (m, 4H), 2.36 (s, 3H), 2.57-2.65 (m, 1H), 2.74 (q, J=7.8 Hz, 2H), 4.02 (s, 3H), 5.00 (s br, 1H), 7.33 (s, 1H), 7.45 (s, 1H), 7.85 (s, 2H).