Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.COB(OC)OC.C(#N)C>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: C1CCNCC1
Agent: COB(OC)OC
Solvent: O
Solvent: CC#N
Product: COc1c(N2CCCCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Yield: 79.9 %

Procedure:
A mixture of 1.48 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (5 mmol), 0.85 g of piperidine (10 mmol), 1.04 g of trimethoxyborane (10 mmol) and 7.5 ml of acetonitrile was refluxed with heating for 4 hours. The reaction solution was cooled to room temperature, 20 ml of water was added therein, and separated crystals were filtered and dried to obtain 1.44 g of the objective compound.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:3][CH2:4][C:5]#N.[H-].C([Al+]CC(C)C)C(C)C.C([O:29]CC)C.Cl>C(Cl)Cl>[CH3:1][C:2]([CH3:16])([CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:3][CH2:4][CH:5]=[O:29]
Reactant: CCOCC
Reactant: CC(C)(CCC#N)CO[Si](C)(C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: CC(C)(CCC=O)CO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a cooled (-78° C.) solution of 4.5 g (18.6 mmol) of 4,4-dimethyl-5-t-butyldimethylsilyloxyvaleronitrile in 36 mL of dry CH2Cl2 was added dropwise, over 30 min., 20.4 mL (20.4 mmol; 1.1 eq) of a 1.0 M solution of diisobutyl-aluminum hydride in CH2Cl2. After stirring for 2 h at -78° C., the cooling bath was removed and the solution allowed to warm to 0° C. To the crude (0° C.) reaction mixture was added 50-60 mL of ethyl ether, followed by the cautious addition of 10% HCl, until the mixture became strongly acidic (pH=1-2). Separation of the layers and three extractions of the aqueous phase with 100 mL ether, drying over MgSO4 and concentrating the combined organic layers gave 3.6 g (79%) of the title compound as a faint yellow oil, sufficiently pure to be used in the next step. TLC: (Silica) Rf 0.28 (CH2 /Cl2 /pentane 3:7), detection with Purpald.
Reaction SMILES: [CH:1]1([C:6]#[N:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:17][Cl:18].O>C1COCC1.CCCCCC>[Cl:18][CH2:17][C:1]1([C:6]#[N:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CC1CCCC1
Reactant: ClCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: N#CC1(CCl)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
A solution of cyclopentanecarbonitrile (14.3 g, 150 mmol) in THF (25 ml) was added dropwise to a stirred solution of lithium diisopropylamide (158 mmol) in THF (150 ml) and hexane (100 ml), under dry nitrogen, keeping the temperature below -65°. After 0.5 h, the solution was warmed to ambient temperature and added to a stirred solution of bromochloromethane (49.4 ml, 750 mmol) in THF (50 ml) keeping the temperature below -65°. The solution was allowed to warm to ambient temperature and, after 18 h, poured into water (500 ml). The aqueous mixture was extracted with CHCl3 (3×250 ml). The extracts were washed with 2N HCl (100 ml) and H2O (100 ml), dried (MgSO4), and evaporated under reduced pressure to give an oil which was distilled to give a pale yellow oil (8.9 g) b.p. 96° at 10 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[O:7][CH2:8][C:9]1[CH:19]=[C:18]([C:20]([C:22]3[N:26]4[CH:27]=[CH:28][C:29]([C:31]([F:34])([F:33])[F:32])=[CH:30][C:25]4=[N:24][C:23]=3[O:35][CH3:36])=[O:21])[CH:17]=[CH:16][C:10]=1/[C:11]/2=[C:12](/[CH3:15])\[C:13]#[N:14].[BH4-].[Li+].O>C(O)C.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[O:7][CH2:8][C:9]1[CH:19]=[C:18]([CH:20]([OH:21])[C:22]3[N:26]4[CH:27]=[CH:28][C:29]([C:31]([F:34])([F:33])[F:32])=[CH:30][C:25]4=[N:24][C:23]=3[O:35][CH3:36])[CH:17]=[CH:16][C:10]=1/[C:11]/2=[C:12](/[CH3:15])\[C:13]#[N:14]
Reactant: COc1nc2cc(C(F)(F)F)ccn2c1C(=O)c1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COc1nc2cc(C(F)(F)F)ccn2c1C(O)c1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
[step 5] (E)-2-{3-fluoro-8-[2-methoxy-7-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carbonyl)dibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (0.100 g, 0.197 mmol) obtained in step 4 was dissolved in ethanol (0.985 mL) and THF (0.985 mL), lithium borohydride (0.44 g, 1.2 mmol) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was discontinued with water, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give (E)-2-(3-fluoro-8-{hydroxy[2-methoxy-7-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}dibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (100 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:13])[CH2:11][CH3:12])[CH:5]=[CH:6][C:7]=1[F:8].[Br:14]Br>C(O)(=O)C>[Br:14][C:5]1[CH:6]=[C:7]([F:8])[C:2]([Cl:1])=[CH:3][C:4]=1[NH:9][C:10](=[O:13])[CH2:11][CH3:12]
Reactant: BrBr
Reactant: CCC(=O)Nc1ccc(F)c(Cl)c1
Solvent: CC(=O)O
Product: CCC(=O)Nc1cc(Cl)c(F)cc1Br
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 97.2 %

Procedure:
The solid (10 g, 49.60 mmol) from step 1 dissolved in acetic acid (70 mL) was added with Br2 (12.7 mL, 247.93 mmol) dropwise for 2 h. Then the reaction mixture was kept stirring at rt for 5.5 h. The resulting mixture was poured to ice water (1 L) and quenched with excess of NaHSO3 until the solution became clear with yellow suspension. The quenched solution was filtered to get title compound (13.52 g, 97.2%). 1H NMR (400 MHz, DMSO-d6) δ 1.07 (t, J=7.6 Hz, 3H), 2.36 (q, J=7.6 Hz, 2H), 7.80 (d, J=7.6 Hz, 1H), 7.84 (d, J=8.8 Hz, 1H), 9.50 (br s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 10.1, 29.3, 117.3, 117.4, 119.0, 119.2, 121.0, 121.2, 128.4, 134.45, 134.49, 153.4, 155.9, 173.0;
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2I)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].I[C:24]1[C:32]2[C:27](=[N:28][CH:29]=[CH:30][CH:31]=2)[NH:26][N:25]=1.C[Sn](C)C.C[Sn](C)C>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:24]2[C:32]3[C:27](=[N:28][CH:29]=[CH:30][CH:31]=3)[NH:26][N:25]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2I)cc1
Reactant: Ic1n[nH]c2ncccc12
Agent: C[Sn](C)C
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-c2n[nH]c3ncccc23)cc1
Temperature: 100 °C

Procedure:
4-tert-butyl-N-(4-chloro-2-iodo-phenyl)-benzenesulfonamide (100 mg, 0.22 mmol), 3-iodo-1H-pyrazolo[3,4-b]pyridine (71 mg, 0.29 mmol), bis(triphenylphosphine)Pd(II)dichloride (20 mg, 0.03 mmol), and hexamethylditin (70 μL, 0.33 mmol) were suspended in 0.7 mL of dioxane and heated to 100° C. for 24 hours in a sealed 4 mL scintillation vial. The black crude residue obtained was purified by preparative TLC to afford 4-tert-butyl-N-[4-chloro-2-(1H-pyrazolo[3,4-b]pyridin-3-yl)-phenyl]-benzenesulfonamide: MS (ES) M+H expected 441.1, found 441.0.
Reaction SMILES: [CH3:1][C:2]([OH:20])([CH2:9][CH2:10][CH2:11][CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:3]#[C:4][CH2:5][CH:6]([OH:8])[CH3:7].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([O:8][CH:6]([CH2:5][C:4]#[C:3][C:2]([CH3:1])([OH:20])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH3:7])(=[O:23])[CH3:22]
Reactant: CC(C)CCCC(C)CCCC(C)(O)C#CCC(C)O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(C)CC#CC(C)(O)CCCC(C)CCCC(C)C
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A solution of 230 mg (0.814 mmole) of 6,10,14-trimethyl-4-pentadecyne-2,6-diol (produced in accordance with Example XVI) and 0.25 mL (2.65 mmoles) of acetic anhydride in 0.25 mL of pyridine (A.C.S. reagent-grade, purchased from Aldrich Chemical Co., Milwaukee, Wis.) was stirred, while being maintained under a nitrogen atmosphere, at room temperature for 8 hours. After destroying excess acetic anhydride by addition of 10 mL of icecold 1M aqueous sodium hydroxide, the mixture was diluted with 20 mL of hexane and 25 mL of 10% aqueous sodium chloride. The layers were then separated, and the organic layer washed in successive order with 1:1 (v/v) 1M aqueous sodium hydroxide: 10% aqueous sodium chloride (1×10 mL), 1:1 (v/v) 2M aqueous hydrochloric acid: saturated brine (2×20 mL), saturated aqueous sodium bicarbonate (1×10 mL), and saturated brine (1×10 mL). The washed organic layer was subsequently dried over anhydrous magnesium sulfate and filtered. Removal of the volatile organic material by evaporation at reduced pressure afforded 249 mg (94% yield) of 2-acetoxy-6,10,14-trimethyl-4-pentadecyn-6-ol (i.e., the product derived by selective acetylation of the 2° alcohol functionality in the starting alkynediol).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]1([S:16]([O-:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Na+]>CS(C)=O>[C:10]1([S:16]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Product: O=Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: 180 °C
Yield: 76.5 %

Procedure:
A microwave vessel was charged with 1 g of 4-chlorobenzaldehyde in 6 mL of DMSO and 1.75 g of sodium benzenesulfinate. The vessel was sealed and heated in a microwave reactor at 180° C. for 1.5 hours. The mixture was cooled and poured into 12 mL of ice water. Filtered and the solid was purified by flash chromatography using ethyl acetate/hexane as eluent mixtures to afford 1.34 g of the title compound. 76% yield.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([CH3:11])[CH:5]=1)[CH3:2].[C:12]([N:15]1[CH2:17][CH2:16]1)(=[O:14])[CH3:13]>CO>[C:12]([NH:15][CH2:17][CH2:16][N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([CH3:11])[CH:5]=1)(=[O:14])[CH3:13]
Reactant: CCNc1ccc(F)c(C)c1
Reactant: CC(=O)N1CC1
Solvent: CO
Product: CCN(CCNC(C)=O)c1ccc(F)c(C)c1

Procedure:
7.66 g (50 mMol) N-ethyl-4-fluoro-3-methyl-aniline and 4.68 g (55 mMol) N-acetylaziridine are refluxed in 100 ml methanol (abs.) for 15 hours. Then the reaction mixture is evaporated on a rotary evaporator and the residue is digested with diisopropylether. The solid thus obtained is filtered with suction, washed with diisopropylether and dried.
Reaction SMILES: C([Li])CCC.[CH:6]#[C:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH:13]([CH:15]1[CH2:19][CH2:18][CH:17]([O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:16]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:14]>CCCCCC.C1(C)C=CC=CC=1.CCOCC>[OH:14][CH:13]([CH:15]1[CH2:19][CH2:18][CH:17]([O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:16]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:6]#[C:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C#CCCCCC
Reactant: O=CC1CCC(OC2CCCCO2)C1CCCCCCC(=O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCC#CC(O)C1CCC(OC2CCCCO2)C1CCCCCCC(=O)O
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
Under a nitrogen atmosphere at -40° C, a solution of 70.4 ml of n-butyl lithium in hexane (2.3 molar) is added dropwise to a solution of 1-heptyne (14.78 g, 2.2 equivalents) in 50 ml of toluene. The mixture is stirred at the same temperature for 10 minutes. The solution is transferred carefully to an addition funnel and added at to a solution of 2-formyl-5 -(tetrahydropyran-2-yloxy)-cyclopentaneheptanoic acid (22.82 g, 1 equivalent), described in Example 1, in 50 ml of toluene cooled to -70° C. The reaction is stirred at the same temperature for 2 hr. The mixture then is diluted with ether and washed with water. The aqueous layer is acidified with acetic acid and extracted with ether. The ether extract is washed with water, dried and concentrated to give the title compound, nmr (CDCl3) δ0.89 (+, 3H), 3.90 (broad, 1H), 4.33 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:29])[C:13]3[C:14](=[C:16]([CH2:26][CH2:27][CH3:28])[N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:30]([N:33]2[CH2:38][CH2:37][N:36]([CH2:39][CH3:40])[CH2:35][CH2:34]2)(=[O:32])=[O:31])=[CH:6][N:5]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:51][N:52](C)[CH2:53]CO>O>[CH3:51][N:52]([CH3:53])[CH2:2][CH2:1][O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:29])[C:13]3[C:14](=[C:16]([CH2:26][CH2:27][CH3:28])[N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:30]([N:33]2[CH2:38][CH2:37][N:36]([CH2:39][CH3:40])[CH2:35][CH2:34]2)(=[O:31])=[O:32])=[CH:6][N:5]=1
Reactant: CN(C)CCO
Reactant: CCCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCC)[nH]c(=O)c2nn1Cc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Product: CCCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCCN(C)C)[nH]c(=O)c2nn1Cc1ccccn1
Temperature: 90 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
A mixture of the title compound of Example 26 (200 mg, 0.35 mmol), potassium bis(trimethylsilyl)amide (352 mg, 1.76 mmol) and 2-dimethylaminoethanol (1.5 ml) was stirred at 90° C. for 18 hours, then allowed to cool. Water (5 ml) was added, the mixture extracted with ethyl acetate (3×5 ml) and the combined extracts dried (MgSO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using an elution gradient of dichloromethane:methanol (95:5 to 90:10), to give the title compound (147 mg, 68%) as an off-white foam. Found: C, 56.35; H, 6.37; N, 20.12. C29H39N9O4S; 0.50H2O requires C, 56.29; H, 6.52; N, 20.37%. δ (CDCl3): 0.94 (3H, t), 1.04 (3H, t), 1.72 (2H, m), 2.43 (8H, m), 2.56 (4H, m), 2.74 (2H, t), 2.95 (2H, t), 3.15 (4H, m), 4.80 (2H, t), 5.67 (2H, s), 7.07 (1H, d), 7.21 (1H, m), 7.61 (1H. m), 8.56 (1H, d), 8.62 (1H, s), 8.75 (1H, s), 12.23 (1H, s). LRMS: m/z 610 (M+1)+.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:18])/[CH2:11][CH2:12][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15])=[CH:3]\[C:4]([NH2:6])=[O:5].S[CH2:20][CH2:21][OH:22].C(N(CC)CC)C>CO>[OH:22][CH2:21][CH2:20][CH2:15][CH:14]([CH3:16])[C:13](=[O:17])[CH2:12][CH2:11]/[C:10](/[CH3:18])=[CH:9]/[CH2:8][CH2:7]/[C:2](/[CH3:1])=[CH:3]/[C:4]([NH2:6])=[O:5]
Reactant: OCCS
Reactant: C=C(C)C(=O)CC/C(C)=C/CC/C(C)=C/C(N)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: C/C(=C\C(N)=O)CC/C=C(\C)CCC(=O)C(C)CCCO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4.1 g (0.016 mol) of (E,E)-3,7,11-trimethyl-10-oxo-2,6,11-dodecatrienamide in 125 ml of methanol is treated with 3.5 ml of 2-mercaptoethanol and 7 ml of triethylamine. The solution is stirred at room temperature for 18 hours. After removing the solvent the residue is taken up three times in toluene and freed from solvent on a rotary evaporator. The residue is chromatographed on silica gel with ether-methanol 10:1. There is obtained (2E,6E)-12-(2-hydroxyethyl)-3,7,11-trimethyl-10-oxo-2,6-dodecadienamide which exhibits the following absorption bands in the IR spectrum: 3340 cm-1, 3201 cm-1, 2924 cm-1, 1707 cm-1, 1669 cm-1, 1608 cm-1, 1409 cm-1, 1369 cm-1, 1305 cm-1, 1046 cm-1, 1012 cm-1.
Reaction SMILES: [OH:1][C:2]1[C:18]([OH:19])=[C:17]([OH:20])[CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([S:13][CH3:14])=[S:12])[CH2:7][CH2:6]1.C(O[C:25](=[O:27])[CH3:26])(=O)C>C(Cl)(Cl)Cl>[C:2]([O:1][C:2]1[C:18]([O:19][C:18](=[O:19])[CH3:17])=[C:17]([O:20][C:25](=[O:27])[CH3:26])[CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C:11]([S:13][CH3:14])=[S:12])[CH2:9][CH2:10]1)(=[O:1])[CH3:3]
Reactant: CSC(=S)N1CCN(Cc2ccc(O)c(O)c2O)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CSC(=S)N1CCN(Cc2ccc(OC(C)=O)c(OC(C)=O)c2OC(C)=O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
In 520 ml of chloroform was suspended 50 g of methyl 4-(2,3,4-trihydroxybenzyl)-1-piperazinecarbodithioate, and to the suspension was dropwise added under chilling with ice 97.3 g of acetic anhydride over a period of 15 min. The mixture was then stirred for one hour. The reaction mixture was washed successively with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residual oil was crystallized by addition of 250 ml of ethyl acetate. After stirring for one hour, the crystals were collected by filtration. The crystals were washed with ethyl acetate to give 48.8 g of the desired compound as white crystals, m.p. 148°-150° C. (decomp.), yield 69.7%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([NH:10][CH:11]1[CH2:15][S:14](=[O:17])(=[O:16])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]1=2)[CH2:7][CH2:8][CH3:9].C(N(CC)CC)C>C1COCC1>[CH2:6]([N:10]([CH:11]1[CH2:15][S:14](=[O:17])(=[O:16])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]1=2)[S:2]([CH3:1])(=[O:4])=[O:3])[CH2:7][CH2:8][CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCNC1CS(=O)(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCN(C1CS(=O)(=O)c2ccccc21)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 106 %

Procedure:
6.63 g (57 mmol) of methanesulfonyl chloride were added dropwise to a solution of 11.7 g (41 mmol) of butyl-(1,1-dioxo-2,3-dihydro-1H-benzo[b]thiophen-3-yl)-amine and 15.5 g (153 mmol) of triethylamine in 120 ml of THF, and the reaction mixture was stirred at RT overnight. Most of the THF was distilled off, the residue was diluted with 250 ml of water and the precipitate was filtered off with suction. Drying under reduced pressure gave 13.8 g of N-butyl-N-(1,1-dioxo-2,3-dihydro-1H-benzo[b]thiophen-3-yl)methanesulfonamide; m.p. 171-173° C.
Reaction SMILES: C(O[C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[CH2:8]N1CCC(=O)CC1C)(C)C.Cl.[NH2:21][OH:22].[CH3:23]C([O-])=O.[Na+]>C(O)C.O>[CH2:8]1[C:7]2([CH2:6][CH2:5][C:19](=[N:21][OH:22])[CH2:18][CH2:17]2)[CH2:23]1
Reactant: NO
Reactant: CC(=O)[O-]
Reactant: CC(C)Oc1cccc(CN2CCC(=O)CC2C)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C1CCC2(CC1)CC2

Procedure:
To a solution containing 2.1 g (16.9 mmol) of the ketone from step 3 in 10 mL of ethanol was added 2.0 g (28.7 mmol) of hydroxylamine hydrochloride followed by 4.0 g (29 mmol) of NaOAc in 20 mL of water. The resulting mixture was refluxed for 3 h, cooled and concentrated to one-half volume and the precipitate was collected.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[N:21][C:20]([NH:23][C:24]4[CH:25]=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[OH-].[Li+].Cl>C1COCC1.O>[F:33][C:30]([F:31])([F:32])[C:27]1[N:26]=[CH:25][C:24]([NH:23][C:20]2[N:21]=[CH:22][C:17]([C:14]3[CH:13]=[CH:12][C:11]([CH:8]4[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:34])=[O:2])[CH2:10][CH2:9]4)=[CH:16][CH:15]=3)=[N:18][CH:19]=2)=[CH:29][CH:28]=1
Reactant: COC(=O)CC1CCC(c2ccc(-c3cnc(Nc4ccc(C(F)(F)F)nc4)cn3)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1CCC(c2ccc(-c3cnc(Nc4ccc(C(F)(F)F)nc4)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (4-{4-[5-(6-trifluoromethyl-pyridin-3-ylamino)-pyrazin-2-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester (0.051 g) in 4 Ml THF/water (1:1) was added solid lithium hydroxide (0.030 g). The reaction was stirred at room temperature for 48 h, then heated to 45° C. for 24 h. The reaction was neutralized with 6 N hydrochloric acid and then purified by reverse-phase preparative HPLC to afford the title compound: 1H NMR (400 MHz, DMSO-D6) δ ppm 1.1 (s, 2 H) 1.3 (s, 1 H) 1.6 (s, 2 H) 1.9 (s, 6 H) 3.5 (s, 6 H) 7.4 (s, 2 H) 7.9 (s, 1 H) 8.0 (s, 2 H) 8.6 (s, 1 H), 8.6 (s, 1 H) 8.9 (s, 1 H) 9.1 (s, 1 H) 10.9 (s, 1 H); (M+H)+ 457.1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[N:5][C:4]=1[C:14]([N:16]([CH2:38][CH:39]([CH3:41])[CH3:40])[C@H:17]1[CH2:22][C@@H:21]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])[CH2:20][N:19]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:18]1)=[O:15].[H-].[Na+].Br[CH2:45][CH2:46][O:47][CH3:48]>CN(C=O)C.C(=O)([O-])O.[Na+]>[CH3:48][O:47][CH2:46][CH2:45][O:1][CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[N:5][C:4]=1[C:14]([N:16]([CH2:38][CH:39]([CH3:41])[CH3:40])[C@H:17]1[CH2:22][C@@H:21]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])[CH2:20][N:19]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:18]1)=[O:15]
Reactant: CC(C)CN(C(=O)c1nnn(-c2ccccc2)c1CO)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: COCCBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl(3S,5R)-3-[{[5-(hydroxymethyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (215 mg) was dissolved in DMF (3 ml), sodium hydride (50% in oil, 30 mg) was added under ice-cooling. The reaction mixture was stirred at room temperature for 30 min, 1-bromo-2-methoxyethane (55 μl) was added under ice-cooling, and the mixture was further stirred at room temperature for 14 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (149 mg).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19])C.[OH-].[K+]>C(O)C.O>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[NH:11][C:10]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:5][C:4]([OH:20])=[O:3]
Reactant: CCOC(=O)Cc1sccc1Nc1c(Cl)cccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1sccc1Nc1c(Cl)cccc1Cl

Procedure:
330 mg (1 mmole) of 3-(2,6-dichloroanilino)-2-thiophenacetic acid ethyl ester are boiled with 1 g of potassium hydroxide in 5 ml of ethanol for one hour. The mixture is then diluted with 20 ml of water and extracted with 20 ml of methylene chloride. The aqueous solution is acidified, and the precipitate which has formed is filtered off and washed with 3 ml of diisopropyl ether. 3-(2,6-Dichloroanilino)-2-thiophenacetic acid (m. 164° to 168°) is obtained.