Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][S:15][C:8]=2[C:7]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH2:18][CH2:17]1)=[O:5])[CH3:2].[C:29]([O-])([O-])=O.[Cs+].[Cs+].Cl.ClC[C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1>CN1C(=O)CCC1>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[C:9]2[CH:13]=[C:14]([CH3:29])[S:15][C:8]=2[C:7]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH2:18][CH2:17]1)=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2sccc2[nH]c1=O
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2sc(C)cc2n(-c2cccnc2)c1=O
Temperature: 0 °C

Procedure:
A solution of 5-oxo-7-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (5) (856 mg, 2.05 mmol), Cs2CO3 (2.75 g, 8.4 mmol), 3-chloromethyl pyridine hydrochloride (0.370 g, 2.25 mmol) and KI (1 g) in dry NMP was heated overnight at 90° C. The solution was poured into ice water and the solids formed were filtered, washed by cold water, and dried. The crude product was purified by reverse phase flash chromatography in combiflash eluting with water/acetonitrile gradient. 1H-NMR (DMSO-d6) δ 3.13 (t, J=7.2 Hz, 3H), 3.80 (m, 4H), 4.27 (q, J=7.2 Hz, 2H), 5.40 (s, 2H), 7.15 (m, 1H), 7.35 (m, 1H), 7.44 (d, J=6.0 Hz, 1H), 7.48 (dd, J=1.2, 3.6 Hz, 1H), 7.60 (m, 1H), 7.79 (dd, J=0.8, 4.8 Hz, 1H), 8.06 (d, J=5.6 Hz, 1H), 8.47 (dd, J=1.6, 4.8 Hz, 1H), 8.56 (d, J=1.6 Hz, 1H); EIMS m/z 509 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]([C:13]2[S:14][CH:15]=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=[CH:9][CH:8]=1.C([Li])CCC.CCCCCC.Br[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=2)[N:43]=1>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]([C:13]2[S:14][C:15]([C:50]3[CH:51]=[CH:52][CH:53]=[C:48]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:42][N:43]=4)[N:49]=3)=[C:16]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: Brc1cccc(-c2ccccn2)n1
Reactant: c1ccc(-c2csc(-c3cccc(-c4ccccn4)n3)c2-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1ccc(-c2c(-c3cccc(-c4ccccn4)n3)sc(-c3cccc(-c4ccccn4)n3)c2-c2ccccc2)cc1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
After placing 3.5 g of 3,4-diphenylthiophene and 60 ml of tetrahydrofuran in a flask and cooling to −30° C. in an argon atmosphere, 11 ml of a 1.5 mol/l concentration n-butyllithium/n-hexane solution was added dropwise. The mixture was stirred at −30° C. for 2 hours, and then 4.1 g of a zinc chloride/tetramethylethylenediamine complex was added before raising the temperature to room temperature. After stirring for 30 minutes, 3.8 g of 2-bromo-6-(2-pyridyl)pyridine and 0.52 g of a palladium chloride/bistriphenylphosphine complex were added and the mixture was stirred for 2 hours at reflux temperature. After completion of the reaction, the product was cooled to room temperature, purified water was added, the organic layer was extracted, and the concentrate obtained using an evaporator was purified by recrystallization to obtain 4.5 g of 2-(6-(2-pyridyl)-2-pyridyl)-3,4-diphenylthiophene. After placing 3.3 g of the 2-(6-(2-pyridyl)-2-pyridyl)-3,4-diphenylthiophene and 80 ml of tetrahydrofuran in a flask and cooling to −30° C. in an argon atmosphere, 6.2 ml of a 1.5 mol/l concentration n-butyllithium/n-hexane solution was added dropwise. The mixture was stirred at −30° C. for 2 hours, and then 2.4 g of a zinc chloride/tetramethyl-ethylenediamine complex was added before raising the temperature to room temperature. After stirring for 30 minutes, 2.2 g of 2-bromo-6-(2-pyridyl)pyridine and 0.30 g of a palladium chloride/bistriphenylphosphine complex were added and the mixture was stirred for 2 hours at reflux temperature. After completion of the reaction, the product was cooled to room temperature, purified water was added, and the organic layer was extracted. The organic layer was concentrated with an evaporator and purified by column chromatography and recrystallization to obtain 1.1 g of BPPDPT.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:21])[CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[N:14]=2)[C:9](=[O:17])[C:8]([C:18](O)=O)=[CH:7]1.[NH2:22][C:23]1[NH:27][N:26]=[N:25][N:24]=1.CN(C)[CH:30]=[O:31]>>[CH3:2][N:3]([CH3:21])[CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[N:14]=2)[C:9](=[O:17])[C:8]([CH2:18][C:30]([NH:22][C:23]2[NH:27][N:26]=[N:25][N:24]=2)=[O:31])=[CH:7]1
Reactant: CN(C)C=O
Reactant: Nc1nnn[nH]1
Reactant: Cc1ccc2c(=O)c(C(=O)O)cn(CCN(C)C)c2n1
Agent: Cl
Product: Cc1ccc2c(=O)c(CC(=O)Nc3nnn[nH]3)cn(CCN(C)C)c2n1
Reaction time: 36 h

Procedure:
1(2-Dimethylaminoethyl)-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid, hydrochloride (4.6 g) and N,N'-carbonyldiimidazole (2.75 g) in dimethylformamide (40 ml) were stirred and heated to 90° for 2 hours. 5-Amino-1H-tetrazole (1.45 g) was added and the mixture was heated to 40° and stirred for 36 hours. The solid was collected, m.p. 305°-307° (d). (30%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:29][CH2:30][CH2:31][O:32][C:33]4[N:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=4)=[N:12][N:13]([CH3:28])[C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][N:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1.C[OH:41]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:29][CH2:30][CH2:31][O:32][C:33]4[N:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=4)=[N:12][N:13]([CH3:28])[C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH2:26][OH:41])=[CH:21][N:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CO
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCOc3ncc(Cl)cn3)nn2C)nc1
Product: CC(CO)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCOc3ncc(Cl)cn3)nn2C)nc1
Reaction time: 48 h

Procedure:
Streptomyces rimosus subsp. rimosus ATCC10970 maintained on a ¼ strength ATCC172 agar slope was inoculated as a loopful of spores into a 300 ml Erlenmeyer flask containing 50 ml of AS7-H inoculum medium. This was allowed to incubate for 2 days at 28° C., 200 rpm on an Infors Multitron Shaker™ with 1″ throw. 2 mls of this inoculum medium was then transferred to each of twenty 300 ml Erlenmeyer flask containing 50 ml of AP-5H production medium and incubated under the same conditions for a further 24 hours. At this point 5 mg of N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-yl)-5-isopropyl-2-pyridinesulfonamide (Example 103) dissolved in 0.5 ml of methanol was added to each of the flasks and the fermentation allowed to continue under the same conditions for a further 96 hours. Each flask was then extracted with 200 mls of ethyl acetate and the combined ethyl acetate solubles concentrated to dryness to give a gum solid.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:25])[C:4]2[C:9]([C:10](=[O:24])[C:11]=1[CH2:12][CH2:13][CH:14]([CH3:23])[CH2:15][CH:16](C(O)=O)[C:17]([OH:19])=[O:18])=[CH:8][CH:7]=[CH:6][CH:5]=2>C(Cl)(Cl)Cl.C(O)C>[CH3:1][C:2]1[C:3](=[O:25])[C:4]2[C:9]([C:10](=[O:24])[C:11]=1[CH2:12][CH2:13][CH:14]([CH3:23])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CC1=C(CCC(C)CC(C(=O)O)C(=O)O)C(=O)c2ccccc2C1=O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC1=C(CCC(C)CCC(=O)O)C(=O)c2ccccc2C1=O
Temperature: 140 °C

Procedure:
4.3 Parts of 2,3,5-trimethyl-6-(5',5'-dicarboxy-3'-methylpentyl)-1,4-benzoquinone (Formula (IV) wherein R=H3C; Z=H) obtained in Reference Example 1 is heated at 140°C for 1 hour. It is then subjected to thin-layer chromatography with chloroform-ethanol (19:1) as the developer and recrystallized from ligroine. Th described procedure gives 2.97 parts of 2,3,5-trimethyl-6-(5'-carboxy-3'-methylpentyl)-1,4-benzoquinone (Formula (I) wherein R=H3C; Z=H) as yellowish needles. melting point 58°C-61°C.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:21]4=[N:22][C:23](I)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:45]2[CH:50]=[CH:49][C:48]([C@H:51]3[CH2:56][CH2:55][C@H:54]([OH:57])[CH2:53][CH2:52]3)=[CH:47][CH:46]=2)O1>>[Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:21]4=[N:22][C:23]([C:45]5[CH:50]=[CH:49][C:48]([C@H:51]6[CH2:52][CH2:53][C@H:54]([OH:57])[CH2:55][CH2:56]6)=[CH:47][CH:46]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc([C@H]3CC[C@H](O)CC3)cc2)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(I)nc2n1COCC[Si](C)(C)C
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](O)CC4)cc3)nc2n1COCC[Si](C)(C)C

Procedure:
The title compound is prepared from 2-((3R,3aR,6R,6aS)-6-(tert-butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-5-iodo-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine and (trans)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexanol following a procedure analogous to that described for Intermediate 7 Step 2. LC (method 5): tR=1.16 min; Mass spectrum (ESI+): m/z=716 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([CH:11]([CH:18]([CH3:20])[CH3:19])[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)(Cl)Cl.ClCCCl>[CH3:19][CH:18]([CH:11]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1)[CH3:20]
Reactant: CC(C)C(CCCC(=O)O)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CC(C)C1CCCC(=O)c2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.1 %

Procedure:
Thionyl chloride (5.6 ml, 77 mmol) was added to a solution of 5-phenyl-5-(2-propyl)pentanoic acid (8.35 g, 37.9 mmol) in chloroform (50 ml), followed by heating under reflux for 3.5 hours. Then, thionyl chloride (3.0 ml, 41 mmol) was added thereto and the resulting mixture was heated under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in 1,2-dichloroethane (20 ml). The resulting solution was added dropwise to a suspension of aluminum chloride (10.1 g, 75.8 mmol) in 1,2-dichloroethane (100 ml) which had been cooled to 0° C., and the resulting mixture was stirred at 0° C. for 10 minutes. The reaction mixture was poured into a cold 1N hydrochloric acid and extracted twice with ethyl acetate, and the extract solution was washed twice with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to obtain 6.83 g of 9-(2-propyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one.
Reaction SMILES: [CH2:1]([CH:4]([CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9])[CH2:2][CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:18]>ClCCl>[CH2:10]([CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH:8]1[CH2:9][O:18]1)[CH2:11][CH3:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCCC(CCC)CCC
Solvent: ClCCl
Product: CCCC(CCC)CCCC1CO1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88.1 %

Procedure:
To a 250 ml flask containing 6-propylnon-1-ene (4 g, 23,76 mmol, purified by distillation) and anhydrous dichloromethane (260 mL) under nitrogen atmosphere, was added at 0 ° C. meta-chloroperoxybenzoic acid (77%, 10,65 g, 47,53 mmol, 2 eq) and the reaction was stirred for 20 minutes at 0 ° C. before warming to room temperature. The disappearance of starting material is monitored by TLC. The reaction was evaporated almost to dryness and cyclohexane (260 ml) was added and the remaining solid in the flask was extracted several times with cyclohexane. The combined organic phases were then washed with saturated aqueous sodium bicarbonate (5×25 mL). After evaporation of the solvent, the crude was purified by column chromatography (eluent dichloromethane) to give the desired product (3,86 g, 88%) as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1S.COC1C=C(S)C=CC=1.COC1C=CC=CC=1[S:27][Cl:28].COC1C=C(SCl)C=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:27][Cl:28])=[CH:5][CH:4]=1
Reactant: COc1ccccc1S
Reactant: COc1ccccc1SCl
Agent: COc1cccc(S)c1
Agent: COc1cccc(SCl)c1
Product: COc1ccc(SCl)cc1

Procedure:
By the same procedure or by the procedure of Example 13, o-methoxythiophenol and m-methoxythiophenol are converted, respectively, to o-methoxybenzenesulfenyl chloride and m-methoxybenzenesulfenyl chloride.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([NH:13][C:14](=[O:26])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[CH2:27]([O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:14]([NH:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]=2)=[O:26])=[CH:17][C:18]=1[N+:23]([O-:25])=[O:24])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cc1ccc(O)c([N+](=O)[O-])c1)Nc1cccc(C2CCCCC2)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1)Nc1cccc(C2CCCCC2)c1

Procedure:
A mixture of N-(3-cyclohexylphenyl)-4-hydroxy-3-nitrophenylacetamide (the compound of Example 29) (300 mg), benzyl bromide (287 mg), potassium carbonate (500 mg) and acetone (10 ml) is heated under reflux for 18 hours. After cooling, water is added to the mixture, and the mixture is extracted with ethyl acetate. The organic layer is dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give 4-benzyloxy-N-(3-cyclohexylphenyl)-3-nitrophenylacetamide (320 mg). This product is dissolved in ethanol (5 ml), and thereto are added reduced iron (200 mg), ammonium chloride (80 mg) and water (5 ml), and the mixture is heated under reflux for one hour. The reaction solution is filtered through Celite, and the filtrate is concentrated, and the residue is dissolved in chloroform. The organic layer is washed with water, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the desired compound (240 mg).
Reaction SMILES: [N:1]1([C:7]([NH:9][C:10]2([C:16]([OH:18])=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[OH:33][C@H:34]1[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]1[NH:40][C:41](=[O:50])[C@@H:42]([OH:49])[C@@H:43]([NH2:48])[CH2:44][CH2:45][CH2:46][CH3:47]>C(Cl)(Cl)Cl.O1CCCC1>[OH:49][C@@H:42]([C@@H:43]([NH:48][C:16]([C:10]1([NH:9][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:8])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)=[O:18])[CH2:44][CH2:45][CH2:46][CH3:47])[C:41]([NH:40][C@H:35]1[CH2:36][CH2:37][CH2:38][CH2:39][C@@H:34]1[OH:33])=[O:50]
Reactant: CCCC[C@H](N)[C@H](O)C(=O)N[C@H]1CCCC[C@@H]1O
Reactant: O=C(NC1(C(=O)O)CCCCC1)N1CCOCC1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC[C@H](NC(=O)C1(NC(=O)N2CCOCC2)CCCCC1)[C@H](O)C(=O)N[C@H]1CCCC[C@@H]1O
Reaction time: 2 h
Yield: 94.2 %

Procedure:
Under ice-cooling, to 10 ml of an anhydrous tetrahydro-furan solution containing 256 mg (1 mmol) of 1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarboxylic acid and 202 mg (2 mmol) of triethylamine was added 1 ml of an anhydrous tetrahydrofuran solution containing 121 mg (1 mmol) of pivaloyl chloride, and the resulting mixture was stirred at the same temperature for 2 hours. Moreover, the temperature of the reaction mixture was returned to room temperature and the mixture was stirred for 18 hours. Insoluble material in the reaction mixture was filtered off, and the filtrate was added to 80 ml of a chloroform solution containing 258 mg (1 mmol) of (2S,3S)-N-[(1S,2S)-2-hydroxycyclohexane-1-yl]-3-amino-2-hydroxyheptanamide, and the resulting mixture was stirred for 3 hours. Chloroform was additionally added to the reaction mixture, and the resulting mixture was washed successively with a 10% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution and then a saturated NaCl solution, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 468 mg (Yield: 94%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13]>>[CH2:17]([O:16][C:10](=[O:15])[C:11](=[C:6]([NH2:7])[C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)[C:12](=[O:13])[CH3:14])[CH3:18]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1ccc(F)cc1
Product: CCOC(=O)C(C(C)=O)=C(N)c1ccc(F)cc1

Procedure:
The title compound was synthesized in analogy to Example 1 from 4-fluorobenzonitrile and ethyl acetoacetate: MS (m/z) 252.2 (M+1).
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([C:17]2[CH:27]=[C:26]([O:28][C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=3)[C:20]3[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=3[CH:18]=2)=[O:16])=[N:12][CH:13]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C(Cl)Cl>[OH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([C:17]2[CH:27]=[C:26]([O:28][C:29]3[CH:30]=[CH:31][C:32]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:33][CH:34]=3)[C:20]3[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=3[CH:18]=2)=[O:16])=[N:12][CH:13]=1
Reactant: CC1(C)Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)Nc3ccc(C(C)(C)O[SiH2]C(C)(C)C)cn3)cc2O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1(C)Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)Nc3ccc(CO)cn3)cc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
To a solution of 4-(4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid[5-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-yl]-amide (22b) (85 mg, 0.15 mmol) in CH2Cl2 (5 mL) was added TBAF in THF (220 uL, 0.22 mmol). The reaction mixture was stirred at room temperature for 1 hr, quenched with H2O (20 mL), and extracted with CH2Cl2 (2×20 mL). The organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 50% EtOAc in hexanes to give a white solid (23 mg, 34% yield). 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1 H) 8.34 (d, J=8.34 Hz, 1 H) 8.30 (s, 1 H) 7.93 (d, J=8.84 Hz, 2 H) 7.74-7.83 (m, 1 H) 7.08-7.17 (m, 4 H) 4.72 (s, 2 H) 3.09 (s, 3 H) 2.91 (s, 2 H) 1.51 (s, 6 H); LCMS for C24H24N2O6S m/z 469.10 (M+H)+.
Reaction SMILES: C(N[C:5]1([CH2:10][C:11]([OH:13])=O)CCCC1)(=O)C.[NH2:14][C:15]1([CH2:20][C:21]([OH:23])=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16]1.[CH3:24]C#N.O.CC#N>O>[C:11]([NH:14][C:15]1([CH2:20][C:21]([OH:23])=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16]1)(=[O:13])[CH:10]([CH3:5])[CH3:24]
Reactant: NC1(CC(=O)O)CCCC1
Reactant: CC#N
Reactant: CC(=O)NC1(CC(=O)O)CCCC1
Solvent: O
Product: CC(C)C(=O)NC1(CC(=O)O)CCCC1

Procedure:
The title compound is prepared analogously as described for (1-acetylamino-cyclopentyl)-acetic acid from (1-amino-cyclopentyl)-acetic acid. MS (LC-MS): [M+H]+=214.2. tR (HPLC, Waters Symmetry C18 column, 20-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 3.08 min.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[C:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9][C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]1=2>[Ni].C(O)C>[CH3:25][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[C:14]([S:17]([CH3:20])(=[O:18])=[O:19])[CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]1=2
Reactant: CN(C)CCC=C1c2ccccc2C=Cc2ccc(S(C)(=O)=O)cc21
Agent: [Ni]
Solvent: CCO
Product: CN(C)CCC=C1c2ccccc2CCc2ccc(S(C)(=O)=O)cc21

Procedure:
5-(3-Dimethylaminopropylidene)-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene (α-isomer), (1.39 g., 0.0039 mole), dissolved in 20 ml. of ethanol, is hydrogenated over Raney nickel at 65°C. under an initial hydrogen pressure of 440 p.s.i. The catalyst is separated and the solvent evaporated under reduced pressure. Recrystallization from cyclohexane gives 10,11-dihydro-5-(3-dimethylaminopropylidene)-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene (α-isomer), m.p. 121°-121.5°C. (sintered, 120°C.; cleared, 122.5°C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9](O)=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[SH-].[Na+].[S:30](=O)(=O)(O)O>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9](=[O:10])[SH:30])=[CH:4][CH:3]=1
Reactant: CC(C)C(C(=O)O)c1ccc(Cl)cc1
Reactant: O=S(=O)(O)O
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [SH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C(C(=O)S)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Three grams (14.1 mmol) of 2-(4-chlorophenyl)-3-methylbutanoic acid is dissolved in approximately 50 ml of dry dimethylformamide, after which 1.43 g (14.1 mmol) of triethylamine is added in one portion. The solution is cooled to 0° and 1.59 g (14.1 mmol) of ethyl chloroformate is slowly added over 30 seconds. After 0.5 hour 3.15 g (28.2 mmol) of sodium hydrosulfide is added. The mixture is stirred overnight at room temperature. The reaction mixture is then poured into 150 ml of water and adjusted to pH 3 with 5% aqueous sulfuric acid. Extraction with 50 ml methylene chloride (3×) is followed by drying and stripping. Dimethylforamide is still present, so the product is taken up in ether and washed with 200 ml of water, dried and stripped to yield 2-(4-chlorophenyl)-3-methylbutanethioic S-acid.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].C([O-])(=O)C.[Na+:15]>C(O)(=O)C>[C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=[O:7].[Na+:15]
Reactant: O=C(O)CCCCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C([O-])CCCCC(=O)O

Procedure:
In reaction ii, sodium bisulfate is reacted with sodium acetate to produce sodium sulfate and solid acetic acid. In reaction iii., malic acid is reacted with sodium acetate to produce sodium hydrogen diglycolate and solid acetic acid. In reaction iv., fumaric acid is reacted with sodium acetate to produce sodium hydrogen fumarate and solid acetic acid. In reaction v., tartaric acid is reacted with sodium acetate to produce sodium hydrogen tartrate and solid acetic acid. In reaction vi., adipic acid is reacted with sodium acetate to produce sodium hydrogen adipate and solid acetic acid. In reaction vii, sulfamic acid is reacted with sodium acetate to produce sulpher sodium nitrate and solid acetic acid.