Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([CH:15]2[CH2:17][CH2:16]2)[OH:14])[CH2:9]1)=O)(C)(C)C.CN(C=O)C.[H-].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](F)[C:27]=1[CH3:33].Cl.CCO>>[Cl:25][C:26]1[C:27]([CH3:33])=[C:28]([CH:29]=[CH:30][CH:31]=1)[O:14][C@H:13]([CH:15]1[CH2:16][CH2:17]1)[C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: Cc1c(F)cccc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@H](O)C2CC2)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1O[C@H](C1CC1)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((R)-Cyclopropylhydroxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester (1.0 g, 4.1 mmol) was dissolved in DMF (15 mL, 200 mmol). Washed and dried sodium hydride (298 mg, 12.4 mmol) was added carefully in three separate portions and the resulting mixture was stirred at room temperature for 15 minutes. 2-Chloro-6-fluorotoluene (749 μL, 6.2 mmol) was added, and the mixture was stirred overnight at 70° C. The mixture was concentrated and the BOC-protected intermediate was purified by silica gel chromatography (0-10% EtOAc in hexanes for 10 minutes, 10-50% in 10 minutes) and the desired fractions were isolated and concentrated. The crude material was then treated with 1.25M HCl in EtOH (23.2 mL, 29.0 mmol) and stirred overnight at room temperature. The product was concentrated under vacuum and purified by preparative HPLC to yield the title compound as a mono-TFA salt (240 mg, 99.4% purity). MS m/z: [M+H]+ calcd for C15H20ClNO, 266.12; found 266.0.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]4[CH:19]=[CH:20][C:21]([C:23](O)=[O:24])=[CH:22][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][NH2:42])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][NH:42][C:23]([C:21]2[CH:20]=[CH:19][C:13]3[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:27]=[CH:26][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:22]=2)=[O:24])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Yield: 59.8 %

Procedure:
4-({[2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbonyl]-amino}methyl)-piperidine-1-carboxylic acid tert-butyl ester (160 mg) was prepared by following General Procedure F starting from 2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylic acid (180 mg), 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (150 mg), HBTU (200 mg), and DIEA (1.2 mL) in DMF (2 mL).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([N:18](C(OCC2C=CC=CC=2)=O)[CH3:19])[CH3:17])=[CH:11][C:10]=1[C:30]([CH3:33])([CH3:32])[CH3:31])C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].CO>[C:30]([C:10]1[CH:11]=[C:12]([CH2:15][CH:16]([NH:18][CH3:19])[CH3:17])[CH:13]=[CH:14][C:9]=1[OH:8])([CH3:32])([CH3:31])[CH3:33]
Reactant: [H][H]
Reactant: CC(Cc1ccc(OCc2ccccc2)c(C(C)(C)C)c1)N(C)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CNC(C)Cc1ccc(O)c(C(C)(C)C)c1
Yield: 99.6 %

Procedure:
A suspension of 2-(4-benzyloxy-3-tert-butylphenyl)-N-benzyloxycarbonyl-N-methyl-1-methylethylamine (3.30 g, 7.35 mmol) and 20% palladium hydroxide/carbon catalyst (350 mg) in methanol (100 ml) was stirred in a hydrogen atmosphere for 1.5 hours. The mixture was filtered to remove the catalyst and the filtrate was evaporated to remove the solvent under reduced pressure, giving 2-(3-tert-butyl-4-hydroxyphenyl)-N-methyl-1-methylethylamine (T20) (1.62 g, 100%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:11]2[O:12][CH2:13][O:14][CH2:15][C:10]=2[CH:9]=[C:8]([NH:16][C:17](=[O:22])[O:18][CH:19]([CH3:21])[CH3:20])[CH:7]=1)[CH3:4].[C:23]1([S:29]Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[C:23]1([S:29][N:16]([C:8]2[CH:7]=[C:6]([O:5][CH2:3][CH3:4])[C:11]3[O:12][CH2:13][O:14][CH2:15][C:10]=3[CH:9]=2)[C:17](=[O:22])[O:18][CH:19]([CH3:21])[CH3:20])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOc1cc(NC(=O)OC(C)C)cc2c1OCOC2
Reactant: ClSc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(N(Sc2ccccc2)C(=O)OC(C)C)cc2c1OCOC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Sodium hydride (0.107 g; 60% dispersion in mineral oil) was dispersed in N,N-dimethylformamide (20 ml). To this solution was added isopropyl N-(8-ethoxy-1,3-benzodioxan-6-yl)carbamate (0.75 g) under ice-cooling. After being stirred at room temperature for 1 hour, phenylsulfenyl chloride (0.39 g) was added thereto under ice-cooling, and stirring was continued at room temperature overnight. The resulting mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-phenylthio-N-(8-ethoxy-1,3-benzodioxan-6-yl)carbamate (Compound 25) (0.91 g) in a yield of 87.5%. M.P., 120°-123° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([C:9]#[N:10])[C:7]([NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>O1CCOCC1>[C:9]([C:8]1[CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[N:12]=[CH:15][N:16]([CH3:18])[CH3:17])#[N:10]
Reactant: COC(OC)N(C)C
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Solvent: C1COCCO1
Product: CN(C)C=Nc1ccc([N+](=O)[O-])cc1C#N
Temperature: 100 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of 5-nitroanthranilonitrile (1.00 g, 6.13 mmol) in dioxane (25 mL) was added dimethylformamide dimethyl acetal (0.88 g, 7.36 mmol). Th reaction mixture was stirred at 100° C. for 2 h and then cooled to room temperature and refrigerated. The precipitate was filtered out, washed with cold ether several time, and then dried in vacuo to give 1.30 g (97%) of N′-(2-cyano-4-nitrophenyl)-N,N-dimethylformamidine as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.Cl[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15].CC(C)([O-])C.[K+]>CN(C=O)C.C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:15])=[O:16])[C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])cn1
Reactant: Cc1ccc(S(=O)(=O)CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(CS(=O)(=O)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.2 %

Procedure:
A mixture of 15.4 g (0.1 mol) of 6-methoxy-3-nitropyridine and 20.4 g (0.1 mol) of 1-chloromethane-sulfonyl-4-methyl-benzene is dissolved in 100 mL of DMF and cooled to 5 C. To this solution is added, dropwise, 100 mL (0.1 mol) of a 1M solution of potassium t-butoxide in THF, keeping the temperature ≦10 C. The dark reaction mixture is stirred for 18 hours at room temperature. The reaction mixture is evaporated to remove the THF, and to the remaining solution is added 100 mL of water. A dark brown precipitate formed which is collected by filtration. This solid is triturated with isopropyl ether for 1 hour and refiltered to yield 12 grams of 6-methoxy-3-nitro-2-(toluene-4-sulfonylmethyl)-pyridine. 1H NMR (CDCl3) δ 8.25 (d, 1H), 7.60 (m, 2H), 7.30 (m, 2H), 6.80 (d, 1H), 5.10 (s, 1H), 3.75 (s, 3H), 2.40 (s, 3H). Mass Spectrum: m/e=323.1 (p+1), TLC (CDCl3) Rf=0.45 Step 2:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH2:20])=[CH:7]2.[NH2:21][C:22]1[N:30]=[C:29]2[C:25]([NH:26][CH:27]=[N:28]2)=[C:24](Cl)[N:23]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH:20][C:24]1[N:23]=[C:22]([NH2:21])[N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)=[CH:7]2
Reactant: NCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NCc2cc3cccc(Cl)c3nc2-c2ccccc2Cl)c2nc[nH]c2n1
Reaction time: 8 h

Procedure:
A mixture of (8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methanamine (144.8 mg, 0.478 mmol), 2-amino-6-chloropurine (89.1 mg, 0.525 mmol) and N,N-diiso-propylethylamine, redestilled, 99.5% (0.166 mL, 0.955 mmol) in 1-butanol, anhydrous, 99.8% (5.24 mL) was heated to reflux and stirred overnight. The reaction was cooled solvents removed and subjected to chromatography, 89:9:1(DCM/MeOH,NH4OH)gradient,
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]1=2.[BH:16]([OH:18])[OH:17]>>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([B:16]([OH:18])[OH:17])[CH:5]=[CH:4][C:3]1=2
Reactant: OBO
Reactant: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Product: CC1(C)CCC(C)(C)c2cc(B(O)O)ccc21

Procedure:
In a similar manner to Example 3(a), starting with 5 g (18.7 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-bromonaphthalene, 4.3 g (100%) of the expected boronic acid are obtained.
Reaction SMILES: [N+](C1C=CC(COC(C2N3[C@H](SC=2)C(C(OC(=O)C)[C:21]2[N:22]=[C:23]4[CH2:28][N:27]([CH3:29])[C:26](=[O:30])[CH2:25][N:24]4[CH:31]=2)(Br)C3=O)=O)=CC=1)([O-])=O.P([O-])([O-])([O-])=O.[C:44](OCC)(=[O:46])C>C1COCC1.C(#N)C.[Zn]>[CH3:29][N:27]1[C:26](=[O:30])[CH2:25][N:24]2[C:31]([CH:44]=[O:46])=[CH:21][N:22]=[C:23]2[CH2:28]1
Reactant: CC(=O)OC(c1cn2c(n1)CN(C)C(=O)C2)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Reactant: CCOC(C)=O
Agent: O=P([O-])([O-])[O-]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC#N
Product: CN1Cc2ncc(C=O)n2CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(5R,6RS)-6-[Acetoxy-(7-methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-2-yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (481 mg) was dissolved in THF (6.7 mL) and acetonitrile (3.1 mL). Freshly activated Zn dust (1.92 g) and 0.5 M phosphate buffer (pH 6.5, 9.9 mL) were added to the mixture. The reaction vessel was covered with foil to exclude light. The reaction mixture was vigorously stirred for 2 h at room temperature. The reaction solution was mixed with ethyl acetate and filtered through a pad of Celite. The pad was washed with water and the aqueous layer was separated. The aqueous layer was cooled to 3° C. and 1 M NaOH was added to adjust pH to 8.0. The mixture was concentrated under high vacuum at 35° C. and lyophilized. The residue was separated by the preparative HPLC (Inertsil ODS-2, GL Science Inc., 10×250 mm, 0.05 mol/L phosphate buffer (pH 7.1): CH3CN=93:7, 4.0 mL/min.). The separated fractions of (5R),(6Z)-6-(7-Methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt and (5R),(6E)-6-(7-Methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt were cooled to 3° C. and 1 M NaOH was added to adjust pH to 8.0 respectively. Each solution was concentrated under high vacuum at 35° C. Each concentrate was applied to Diaion HP-21 (60 mL, Mitsubishi Kasei Co. Ltd.) resin column chromatography. After adsorbing, the column was eluted with water and then with 5% acetonitrile-water. The combined fractions were concentrated under high vacuum at 35° C. and lyophilized to give the title compound (5R),(6Z)-6-(7-Methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt as a yellow amorphous solid (125 mg, 44.4%, Mp 115-117° C. (dec)) and compound (5R),(6E)-6-(7-Methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt as yellow amorphous solid (19 mg, 6.7%) respectively.
Reaction SMILES: C([O:7][C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([N:17]([CH3:27])[S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)(=[O:20])=[O:19])[CH:16]=1)[NH:13][C:12]([C:28]1[S:29][CH:30]([CH:33](OC)OC)[CH2:31][N:32]=1)=[CH:11]2)(=O)C(C)(C)C.O.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].F[C:50](F)(F)[C:51](O)=O>>[OH:7][C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([N:17]([CH3:27])[S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)(=[O:19])=[O:20])[CH:16]=1)[NH:13][C:12]([C:28]1[S:29][CH:30]([CH2:33][N:13]3[CH2:51][CH2:50][S:29][CH2:28][CH2:12]3)[CH2:31][N:32]=1)=[CH:11]2
Reactant: COC(OC)C1CN=C(c2cc3cc(OC(=O)C(C)(C)C)cc(N(C)S(=O)(=O)c4ccccn4)c3[nH]2)S1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CN(c1cc(O)cc2cc(C3=NCC(CN4CCSCC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 80 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
To a solution of 2-[5-(dimethoxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-5-yl pivalate (273 mg) in trifluoroacetic acid (2 mL) were added water (4 mL) and concentrated sulfuric acid (2 mL), and the mixture was stirred at 80° C. for 5 hr, basified with saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was diluted with ethyl acetate, washed with water and saturated brine, dried (MgSO4), and concentrated under reduced pressure. To a tetrahydrofuran solution (5 mL) of the residue were added thiomorpholine (0.041 mL) and sodium triacetoxyborohydride (215 mg), and the mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogencarbonate and ethyl acetate were added to the reaction solution, and the organic layer was washed with water and saturated brine, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1-1:2) to give the title compound (145 mg, yield 85%) as a colorless amorphous powder. MS: 504 (MH+).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.[C:34]([O:38][C:39]([NH:41][C@H:42]([C:46]([O:48][CH:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1)=[O:47])[CH2:43][CH2:44]O)=[O:40])([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[Br:1][CH2:44][CH2:43][C@H:42]([NH:41][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])[C:46]([O:48][CH:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1)=[O:47]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OC1CCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCBr)C(=O)OC1CCCC1
Reaction time: 0.08 h
Yield: 84 %

Procedure:
To a slurry of N-bromosuccinimide (1.86 g, 10.4 mmol) in DCM (16.2 ml) was added a solution of triphenylphosphine (2.56 g, 9.74 mmol) in DCM (7.2 ml). The solution was stirred for a further 5 minutes after addition. Pyridine (338 μl, 4.18 mmol) was added, followed by a solution of Stage 4 product (Scheme 7) (1.00 g, 3.48 mmol) in DCM (8.8 ml). The solution was stirred for 18 hours, concentrated under reduced pressure and the residual solvent azeotroped with toluene (3×16 ml). The residue was triturated with diethyl ether (10 ml) and ethyl acetate:heptane (1:9, 2×10 ml). The combined ether and heptane solutions was concentrated onto silica and purified by column chromatography using ethyl acetate/heptane (1:9 to 2:8) to provide 1.02 g (84% yield) of title compound. 1H NMR (300 MHz, CDCl3), δ: 5.30-5.05 (2H, m), 4.45-4.30 (1H, m), 3.45 (2H, t, J=7.3 Hz), 2.50-2.30 (1H, m), 2.25-2.10 (1H, m), 1.95-1.60 (8H, br m), 1.47 (9H, s).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[CH:24]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1>[OH:16][CH2:15][C:3]1([CH2:2][O:1][C:31](=[O:32])[NH:30][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14]
Reactant: O=C1c2ccccc2SCCC1(CO)CO
Reactant: O=C=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)OCC1(CO)CCSc2ccccc2C1=O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 4,4-bis(hydroxymethyl)-3,4-dihydro-2H-benzo[b]thiepin-5-one (424 mg, 1.78 mmol) in 22 ml of tetrahydrofuran were added, at 0° C., triethylamine (0.27 ml, 1.96 mmol) and cyclohexyl isocyanate (1.0 ml, 7.84 mmol). The mixture was stirred at 80° C. for 18 hours, concentrated and purified by column chromatography on silica (eluent: 1:2 tert-butyl methyl ether/cyclohexane). The product was obtained in a yield of 366 mg (57%).
Reaction SMILES: [O:1]=[C:2]1[N:7]([Na])[C:6](=[O:9])[CH:5]=[N:4][NH:3]1.[CH2:10](Br)[C:11]#[CH:12]>C(O)CO>[O:1]=[C:2]1[N:7]([CH2:12][C:11]#[CH:10])[C:6](=[O:9])[CH:5]=[N:4][NH:3]1
Reactant: O=c1cn[nH]c(=O)n1[Na]
Reactant: C#CCBr
Solvent: OCCO
Product: C#CCn1c(=O)cn[nH]c1=O
Temperature: 80 °C

Procedure:
A mixture of 4.59 g 3,5-dioxo-4-sodio-2,3,4,5-tetrahydro-1,2,4-triazine, 4.64 g propargyl bromide and 40 ml ethylene glycol was heated to 80° C. for 3 hours.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([O:8][CH3:9])[CH:7]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH2:21])=[N:17][CH:18]=1>>[Cl:10][C:5]1[CH:4]=[CH:3][C:2]([NH:21][CH2:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:23])([F:11])[F:22])=[CH:18][N:17]=2)=[CH:7][C:6]=1[O:8][CH3:9]
Reactant: COc1cc(Br)ccc1Cl
Reactant: NCCc1ccc(C(F)(F)F)cn1
Product: COc1cc(NCCc2ccc(C(F)(F)F)cn2)ccc1Cl

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (4-chloro-3-methoxy-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 331.1 [M+H]+) was prepared from 5-bromo-2-chloro-anisol instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=[C:16]([O:29][CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:39])C.[OH-].[Na+].Cl>C(O)C>[CH3:39][C:8]1[CH:9]=[C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=[C:16]([O:29][CH2:30][CH2:31][CH2:32][N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[CH:15]=2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:40])=[O:3]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#CCc3ccccc3)cc(OCCCN3CCOCC3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#CCc3ccccc3)cc(OCCCN3CCOCC3)c2)ccc1OCC(=O)O
Reaction time: 1 h

Procedure:
{2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-1-ynyl)-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (200 mg; 0.36 mmol) was dissolved in ethanol (20 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 150 mg. HPLC-MS: m/z: 532.1 (M+); Rt: 1.87 min.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([F:19])[CH:8]=2)[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3]1.N1C=CC=CC=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([N:16]1[CH2:15][CH2:14][CH:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3][C:2]3=[O:1])=[CH:8][C:9]=2[F:19])[CH2:18][CH2:17]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(S(C)(=O)=O)CC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of (S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20, 125 mg) and pyridine (60 μL) in dry methylene chloride (1.9 mL) at 0° C. is treated with methanesulfonyl chloride (32 μL), and the resulting mixture was stirred at 0° C. for one hour and at ambient temperature for 16 hours. The reaction mixture is then diluted with methylene chloride (30 mL), washed with water (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is recrystallized from methylene chloride/diethyl ether to give the title compound, mp 240-242° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH3:11])[CH:3]=1.[F:12][CH:13]([F:23])[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1>>[CH2:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:22]#[C:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH:13]([F:23])[F:12])=[CH:16][CH:17]=2)[CH:3]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCc1cccc(Br)c1
Reactant: C#Cc1ccc(OC(F)F)cc1
Product: CCCCc1cccc(C#Cc2ccc(OC(F)F)cc2)c1

Procedure:
Using essentially the same procedure described in Example 1, step a, and employing 1-bromo-3-butylbenzene and 1-(difluoromethoxy)-4-ethynylbenzene, the phenylethynylbenzene product was obtained. This product was purified on silica gel (Biotage) using hexanes/EtOAc 50/1 as the eluting solvents to give 1-butyl-3-{[4-(difluoromethoxy)phenyl]ethynyl}benzene as a colorless oil (0.56 g, 28% yield), MS m/e M+ 300; 1H NMR (400 MHz, DMSO-d6) 0.82 (t, J=7.19 Hz, 3H), 1.25 (m, 2H), 1.55 (m, 2H), 2.56 (t, J=7.56 Hz, 2H), 7.2 (m, 3H), 7.35-7.45 (m, 4H), 7.58 (d, J=8.79 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(Cl)Cl>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:29][CH2:28]1
Reactant: CN1CCNCC1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 0.17 h

Procedure:
To a 0° C. cooled solution of 4-nitrobenzaldehyde in DCM (40 mL) was added Na(OAc)3BH (10.526 gm, 49.66 mmol) and the reacton was stirred for 10 min. To the reaction mixture was added N-methylpiperazine (9.93 g, 99.3 mmol) under nitrogen atmosphere and the reaction mixture was continued stirring at room temperature for 4 h. The progress of the reaction was monitored by TLC and upon completion of the reaction, the mixture was partitioned between DCM (20 mL) and water (15 mL) and the organic layer was separated, washed with water (2×15 mL), dried over sodium sulphate, filtered and the solvent was removed under reduced pressure to give crude residue. Washing with ether gave 1-methyl-4-(4-nitrobenzyl)piperazine (4 g). 1H NMR (CDCl3, 200 MHz) δ: 8.19 (2H, d, J=8.4 Hz), 7.53 (2H, d, J=8.4 Hz), 3.59 (2H, s), 2.47 (8H, bm), 2.29 (3H, s); m/e=236 (M+1).