Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:16]([NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:17].[OH-].[Na+].Br[CH2:33][C:34]([OH:36])=[O:35].Cl>CCO.O>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:16]([NH:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:33][C:34]([OH:36])=[O:35])[CH2:21][CH2:20]1)=[O:17]
Reactant: O=C(O)CBr
Reactant: COc1ccc(C(=O)NC2CCNCC2)cc1OCCc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)NC2CCN(CC(=O)O)CC2)cc1OCCc1ccc(Cl)cc1Cl

Procedure:
To 360 mg 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-yl-benzamide hydrochloride and 162 mg NaOH in 20 ml EtOH/H2O 1:1 142 mg bromo acetic acid was added at RT. After stirring over night the reaction mixture was acidified with half concentrated HCl. After evaporation of the solvent the residue was coevaporated with toluene. The waxy brown solid was subjected to the subsequent reaction without further purification.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=O)[C:7]([CH3:16])=[CH:6]2)#[N:2].[F:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=O)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]2[O:15][C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:20])([F:18])[F:19])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[C:7]3[CH3:16])=[N:29][N:28]=2)=[CH:24][CH:23]=1
Reactant: NNC(=O)c1ccc(F)cc1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=O)O
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1nnc(-c2ccc(F)cc2)o1

Procedure:
Synthesized as described in Example 35C using [5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]acetic acid and 4-fluorobenzohydrazide: 1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J=8.4 Hz, 1H), 7.96 (dd, J=8.7 and 5.4 Hz, 2H), 7.77 (d, J=8.4 Hz, 1H), 7.41 (t, J=8.7 Hz, 2H), 6.65 (s, 1H), 5.97 (s, 2H), 2.57 (s, 3H); MS (ES) m/z 401 (M+1).
Reaction SMILES: [K].[F:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.[CH3:10]I>CN(C)C=O>[CH3:10][N:5]1[CH:4]=[C:3]([F:2])[CH:8]=[N:7][C:6]1=[O:9]
Reactant: O=c1ncc(F)c[nH]1
Reactant: CI
Agent: [K]
Solvent: CN(C)C=O
Product: Cn1cc(F)cnc1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 40 %

Procedure:
A mixture of the potassium salt of 5-fluoropyrimid-2-one (prepared as described in Undeheim, K. and Gacek, M. Acta. Chem. Scand. 23 (1969) 294 or Budesinsky, Z., Prikyl, J. and Svatek, E. Coll. Czech. Chem. Commun. 30 (1965) 3895) (0.01 mol) and methyl iodide (0.013 mol) in dimethylformamide (40 ml) was stirred at room temperature for 20 hours. The solvent was then removed under reduced pressure (1 mm Hg) and the said residue triturated with chloroform (4×50 ml). The chloroform solution containing the desired product was washed with aqueous 1 N NaOH (3 ml) and with water (3 ml). The dried (MgSO4) chloroform solution was then evaporated and the solid residue recrystallised from benzene; yield 40%, m.p.=177°-178° C. (Found: C, 47.21; H, 3.95; Calc. for C5H5FN2O: C, 46.88; H, 3.93)
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[C:9]([C:13]1[CH:14]=[CH:15][C:16]([S:19][C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:18]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1ccc(S)cc1
Reactant: Oc1cccc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: CC(C)(C)c1ccc(Sc2cccc(O)c2)cc1
Yield: 89.8 %

Procedure:
The general procedure in example 39 was followed. 3-Iodophenol (220 mg, 1.0 mmol), 4-tert-butylthiophenol (168 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 3-(4-tert-butylphenyl)sulfanylphenol (232 mg, 90% yield) as the colorless oil. Workup procedure: ethyl acetate (approx. 5 mL) and dodecane (227 μL, GC standard) were added to the reaction mixture after the reaction was completed. The organic layer was neutralized by dilute HCl to pH 8. The aqueous layer was extracted by ethyl acetate (4×10 mL). The combined organic layers were concentrated and purified by column chromatography on silica gel using hexane/ethyl acetate=10/1 as the eluent to afford the titled product. Rf=0.2 (hexane/ethyl acetate=10/1) (Note: same Rf value as the starting material). 1H NMR (CDCl3, 300 MHz) δ 7.21-7.34 (m, 2 H), 7.14 (t, 1 H, J=8.1 Hz), 6.95 (t, 1 H, J=8.1 Hz), 6.84-6.88 (m, 1 H), 6.78-6.81 (m, 1 H), 6.64-6.71 (m, 2 H). 13C NMR (CDCl3, 75 MHz) δ 156.0, 132.5, 131.2, 130.3, 130.1, 124.8, 122.1, 116.3, 115.2, 113.8, 35.0, 31.7. IR (neat, cm−1) 3375 (broad), 2962, 2904, 2867. MS (EI) m/z (relative intensity) 258 (100). HRMS (EI), Cald. for C16H18OS, 258.1073. Found 258.1068.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[NH:21][C:22](=[O:39])[C@@H:23]([NH:31]C(=O)OC(C)(C)C)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO>[NH2:31][C@@H:23]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:22]([NH:21][C:10]1[CH:11]=[C:12]([C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:39]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1cc(-c2ccncc2)ccc1OCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccccc1)C(=O)Nc1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (S)-1-(3-(1H-pyrazol-4-yl)phenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate 13.E (1.25 g, 2.39 mmol) in MeOH (10 mL) was added 4M HCl in dioxane solution (10 ml, 40 mmol). The resulting mixture was stirred for 2 hours at room temperature. The mixture was then concentrated to afford crude (S)-2-amino-N-(2-(benzyloxy)-5-(pyridin-4-yl)phenyl)-3-phenylpropanamide 13.F which was used in the next step without any further purification.
Reaction SMILES: [Cl:1][CH2:2][CH:3]=O.[SH2:5]>>[Cl:1][CH2:2][CH:3]1[S:5][CH:3]([CH2:2][Cl:1])[S:5][CH:3]([CH2:2][Cl:1])[S:5]1
Reactant: O=CCCl
Reactant: S
Product: ClCC1SC(CCl)SC(CCl)S1

Procedure:
reacting chloroacetaldehyde with hydrogen sulfide to obtain 2,4,6-tris(chloromethyl)-1,3,5-trithiane;
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([S:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]=[CH:9][N:8]=1>>[Cl:3][CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([S:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]=[CH:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(SCCN2CCCCC2)ccnc1CO
Product: Cc1c(SCCN2CCCCC2)ccnc1CCl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (15 ml) was dropwise added to 2-hydroxymethyl-3-methyl-4-(2-piperidinoethylthio)pyridine (2.5 g) under ice-cooling and the mixture was stirred at room temperature for 3 hours. After the completion of the reaction, thionyl chloride was distilled away. The residue was alkali-oversaturated with potassium carbonate and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled away to give 2.0 g of 2-chloromethyl-3-methyl-4-(2-piperidinoethylthio)pyridine as an oily substance. The substance was added to ethanol (50 ml) containing a solution of 2-mercaptobenzimidazole (1.0 g) and sodium hydroxide (0.6 g) in water (10 ml) and the mixture was refluxed under heating for 5 hours. After the completion of the reaction, the ethanol was distilled away and water was added to the residue, followed by extraction with chloroform. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled away. The residue was recrystallized to give 2-((3-methyl-4-(2-piperidinoethylthio)-2-pyridyl)methylthio)-1H-benzimidazole, melting point 138°-140° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[NH2-].[Na+]>C1C=CC=CC=1>[CH3:16][CH2:15][O:14][C:12]([CH:11]1[O:3][C:1]1([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2])=[O:13]
Reactant: CC(=O)c1ccccc1
Reactant: CCOC(=O)CCl
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)C1OC1(C)c1ccccc1
Temperature: 25 °C
Yield: 63.1 %

Procedure:
To a mixture of 120 g of acetophenone, 123 g of ethyl chloroacetate, and 200 ml of benzene was added 47.2 g of powder sodium amide over a period of 2 hours at 15° C. At the end of a 2-hour stirring at room temperature, the resulting red colored mixture was poured into 700 g of ice water. The organic phase was extracted with benzene, dried, and stripped of the solvent. The residue was fractionally distilled, yielding 130 g of ethyl 3-methyl-3-phenylglycidate having a boiling point of 107°-113° C./3 mmHg.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].C(O)(=O)C.[I:16]N1C(=O)CCC1=O>>[CH2:1]([C:3]1[C:11]([I:16])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCc1cc2ccccn2n1
Solvent: CC(=O)O
Product: CCc1nn2ccccc2c1I
Yield: 75.2 %

Procedure:
2-Ethylpyrazolo[1,5-a]pyridine (4.1 g, 22 mmol) was stirred in acetic acid (2.6 g, 18 mmol) and N-iodosuccinimide (8 g, 40 mmol) was added in portions over 5 hrs. The mixture was evaporated and purified on silica gel with ethyl acetate in hexanes (0-15%) to give the desired compound (4.5 g, 93%). LCMS for C9H10IN2 (M+H)+: m/z=273.1. 1H NMR (300 MHz, DMSO-d6): δ 8.62 (m, 1 H), 7.40 (m, 1 H), 7.27 (m, 1 H), 6.82 (m, 1 H), 2.72 (m, 2 H), 1.22 (m, 3 H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][SH:12])=[CH:7][CH:6]=1.Br[C:14]1[CH:15]=[C:16]([CH2:21][OH:22])[S:17](=[O:20])(=[O:19])[CH:18]=1>O1CCCC1.O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12][CH:14]2[CH2:18][S:17](=[O:20])(=[O:19])[CH:16]([CH2:21][OH:22])[CH2:15]2)=[CH:7][CH:6]=1
Reactant: COc1ccc(CS)cc1
Reactant: O=S1(=O)C=C(Br)C=C1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CSC2CC(CO)S(=O)(=O)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. slurry, under argon, of 0.502 g of sodium hydride (60% oil dispersion) in 9 ml of dry tetrahydrofuran is added, dropwise over 5 minutes, 1.69 mi of p-methoxy-α-toluenethiol in 9 ml of dry tetrahydrofuran. The reaction is warmed to room temperature for 30 minutes, recooled to 0° C. and a solution of 2.31 g of product from Example 176 in 10 ml of dry tetrahydrofuran is added. The reaction mixture is allowed to warm to room temperature and stirred overnight. The mixture is diluted with 100 ml of water and extracted with diethyl ether. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo to give an oil. The oil is purified by chromatography (silica gel: 0-90% ethyl acetate/hexane) to give 3.0 g of the desired product (1:1 mixture of isomers).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH:13]=O)[C@H:10]([CH2:15][N:16]([C:20](=[O:34])[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH3:33])[CH:22]=2)[CH:17]([CH3:19])[CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:35]1([NH2:38])[CH2:37][CH2:36]1>CCOC(C)=O.CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:38][CH:35]2[CH2:37][CH2:36]2)[C@H:10]([CH2:15][N:16]([C:20](=[O:34])[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH3:33])[CH:22]=2)[CH:17]([CH3:18])[CH3:19])[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1C
Reactant: NC1CC1
Solvent: CO
Solvent: CCOC(C)=O
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC2CC2)C(C)C)ccc1C

Procedure:
From (3R,4S)-3-({[4-methyl-3-(3-methoxy-propoxy)-benzoyl]-isopropyl-amino}-methyl)-4-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (3 g, 6.29 mmol), cyclopropyl amine (0.395 mL, 6.92 mmol) and NaBHOAc3 (1.87 g, 8.81 mmol) and purification by flash chromatography on silica gel (AcOEt/MeOH 100:0 to 85:15) to give the title compound as colorless oil. TLC, Rf (AcOEt)=0.63. MS (LC-MS): 518.3 [M+H]+; tR (HPLC, Nucleosil C-18HD (4×70 mm, 3 μm), 20-100% CH3CN/H2O/6 min, 100% CH3CN/1.5 min; flow: 1 mL/min): 5.37 min.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][CH2:14][O:15][CH2:16][Sn](CCCC)(CCCC)CCCC)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:30]/[C:31](/[CH2:35][CH2:36]/[CH:37]=[C:38](\[CH3:45])/[CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43])=[CH:32]\[CH2:33]Br.O>C1COCC1>[CH3:30]/[C:31](/[CH2:35][CH2:36]/[CH:37]=[C:38](\[CH3:45])/[CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43])=[CH:32]\[CH2:33][CH2:16][O:15][CH2:14][O:13][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCC[Sn](CCCC)(CCCC)COCOCc1ccccc1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCOCOCc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 54.5 %

Procedure:
n-Butyl lithium (1.6M in hexane, 8.6 mL, 13.8 mmol) was added under nitrogen to a stirred solution of (benzyloxymethoxy)methyl-tri-(n-butyl) tin (6.1 g, 13.8 mmol) in THF (56 mL) at -78° C. The resulting mixture was stirred at -78° C. for 10 min, then added a solution of (E,E)-3,7,11-trimethyl-2,6,10-dodecatrienylbromide (3.5 g, 12.3 mmol) in THF (4 mL) via a dropping funnel. The resulting mixture was stirred at -78° C. for 0.5 hours, then poured into cold water and extracted with ether. The ethereal extract was dried, filtered and evaporated to afford a residue, which was purified by flash chromatography on a silica gel column. Elution of the column with hexane:ether (25:1, v:v) provided the title compound as a colorless oil (2.39 g, 6.7 mmol, 54.5%).
Reaction SMILES: CN(C)C=O.[C:6]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][CH:18]=[C:19]([C:22]([CH3:24])=O)[C:20]=2[OH:21])=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].[NH:25]([C:27]([NH:29][C:30]1[S:34][C:33]([C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:31]=1)=[S:28])[NH2:26]>Cl.O>[C:6]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][CH:18]=[C:19]([C:22](=[N:26][NH:25][C:27]([NH:29][C:30]3[S:34][C:33]([C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:31]=3)=[S:28])[CH3:24])[C:20]=2[OH:21])=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: COC(=O)c1ccc(NC(=S)NN)s1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=S)NN=C(C)c2csc(-c3ccc(C(C)(C)C)cc3)c2O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
Dimethylformamide (1.3 ml) and conc. hydrochloric acid (1 drop) were added to 2-(4-t-butylphenyl)-3-hydroxy-4-methylcarbonylthiophene (70 mg, 0.26 mmol) synthesized in Reference Synthetic Example 33 and methyl 5-hydrazinocarbonothioylamino-2-thiophenecarboxylate (59 mg, 0.26 mmol) synthesized in Reference Synthetic Example 57, and the mixture was stirred overnight at room temperature. Water was added, and the precipitated solid was filtered. The obtained solid was extracted with chloroform, dried over anhydrous sodium sulfate. The organic layer was concentrated, and purified with a silica gel column chromatography (chloroform/methanol=95/5) to obtain the desired product as a pale yellow solid (112 mg, yield 90%).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]([OH:18])=O)[CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1.[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:25][C:16]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]2[CH2:5][CH2:4][CH:3]([N:2]([CH3:1])[CH3:19])[CH2:15][C:14]3=2)=[O:18])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CN(C)C1CCc2[nH]c3ccc(C(=O)O)cc3c2C1
Reactant: NC1CCCC1
Product: CN(C)C1CCc2[nH]c3ccc(C(=O)NC4CCCC4)cc3c2C1
Yield: 41 %

Procedure:
Beginning with 7.4 mg (0.029 mMol) 3-dimethylamino-1,2,3,4-tetrahydro-9H-carbazole-6-carboxylic acid and cyclopentylamine, 4.1 mg (41%) of the title compound were recovered.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6](=O)[CH2:7][NH:8][C:9]([C:11]2[S:12][C:13]3[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:18][CH:17]=[C:16]([O:26][CH3:27])[C:14]=3[N:15]=2)=O)[C:3]2[CH:29]=[CH:30][CH:31]=[CH:32][C:2]1=2.FC(F)(F)C([O-])=O.[NH4+:40]>O>[S:1]1[CH:5]=[C:4]([C:6]2[NH:40][C:9]([C:11]3[S:12][C:13]4[C:19]([N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)=[CH:18][CH:17]=[C:16]([O:26][CH3:27])[C:14]=4[N:15]=3)=[N:8][CH:7]=2)[C:3]2[CH:29]=[CH:30][CH:31]=[CH:32][C:2]1=2
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)NCC(=O)c3csc4ccccc34)nc12
Reactant: [NH4+]
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: COc1ccc(N2CCOCC2)c2sc(-c3ncc(-c4csc5ccccc45)[nH]3)nc12
Temperature: 25 °C
Yield: 69.5 %

Procedure:
A mixture of 0.15 g 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid (2-benzo[b]thiophen-3-yl-2-oxo-ethyl)-amide and 0.43 g ammonium triflouroacetate was melted at 210° C. for 30 minutes and, after cooling to room temperature, suspended in water. Extraction with dichloromethane and chromatography on silicagel with ethylacetate/hexane 1:1 gave 0.10 g (69%) 2-(5-benzo[b]thiophen-3-yl-1H-imidazol-2-yl)-4-methoxy-7-morpholin-4-yl-benzothiazole as yellow solid; M.p.: 161–162° C.; MS (ISP): m/e=449 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:24])/[CH:14]([OH:23])[C:15]([CH3:22])([CH3:21])[C:16]([O:18]CC)=[O:17])=[C:9]([O:25][CH3:26])[C:8]([CH3:27])=[C:7]2[C:3]=1[C:4](=[O:28])[O:5][CH2:6]2>CCOCC.C(OCC)(=O)C>[OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:24])/[CH:14]([OH:23])[C:15]([CH3:21])([CH3:22])[C:16]([OH:18])=[O:17])=[C:9]([O:25][CH3:26])[C:8]([CH3:27])=[C:7]2[C:3]=1[C:4](=[O:28])[O:5][CH2:6]2
Reactant: CCOC(=O)C(C)(C)C(O)/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1c(C)c2c(c(O)c1C/C=C(\C)C(O)C(C)(C)C(=O)O)C(=O)OC2

Procedure:
By following the procedure of Example ZA-6A and substituting methyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) 2,4-dimethyl-4-hexenoate with ethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2,2,4-trimethyl-3-hydroxy-4-hexenoate and the corresponding compounds of Formula I-ZA-M1 prepared as described in Part A above, there are obtained (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy -7-methyl-3-oxoisobenzofuran-5-yl)-2,2,4-trimethyl-3-hydroxy-4-hexenoic acid, m.p. 180°-181° C. (ether/ethyl acetate) and the corresponding compounds of Formula I-ZA-M2 (where Z2 is OH) as identified in the following table.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([O:18]C)[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([OH:18])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)ccc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2ccc(F)c(O)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.1 %

Procedure:
To a solution of Example 82 (0.075 g, 0.142 mmoles) in dichloromethane (15 ml), BBr3 (1M in dichloromethane, 1 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N Hal solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as pale green solid (0.040 g, 55% yield). MP: 241-244° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 10.15(s,1H), 8.05(s, 1H), 8.05(dd, J=8.6,1.5Hz, 1H), 7.86(m, 1H), 7.68(d, J=8.4Hz, 1H),7.53(t, J=7.4Hz, 1H), 7.28(m,2H), 7.20(dd, J=8.5,1.9 Hz, 1H), 7.05(m,4H),6.04(q, J=7.1Hz, 1H),1.88(d, J=7.1Hz, 3H). Mass: 511.94(M+).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.C1(C)C=CC=CC=1.[BH4-].[Na+]>O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][NH:18][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COc1ccc(CN)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(CNCc2ccc(OC)cc2)cc1
Temperature: 5 °C

Procedure:
p-Anisaldehyde (411 mmol), 4-methoxybenzylamine (411 mmol) and toluene (500 mL) were combined in a round bottomed flask fitted with a condenser and a Dean-Stark trap. The reaction was refluxed for 1 h during which water was removed from the reaction mixture. The reaction was cooled and concentrated. The residue was dissolved in MeOH (120 mL). The mixture was cooled to 5° C. and NaBH4 (205 mmol) was added in portions over 45 min. The reaction was slowly heated to reflux. After 2 h at reflux, the reaction was cooled to room temperature and concentrated. The residue was dissolved in EtOAc. The organic layer was washed (3×H2O and brine), dried (Na2SO4) and concentrated to yield the desired product.
Reaction SMILES: S([O-])([O-])=O.[Na+:5].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[Na+:5]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S([O-])c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 1009.6 %

Procedure:
To a mixture of 504 g of sodium sulfite and 1.8 l of water was added portionwise 16 g of p-chlorobenzenesulfonyl chloride at 50° C. After being stirred at 55°-60° C. for 3 hours, the mixture was cooled with ice and white crystals which separated out were collected and washed with cold water to obtain 152 g of sodium p-chlorobenzenesulfinate. In a manner similar to Synthesis Example 1, sodium p-chlorobenzenesulfinate and ethyl chloroacetate were reacted to obtain ethyl p-chlorophenylsulfonyl acetate. The ester thus obtained (110 g) was added portionwise to a 20% sodium hydroxide aqueous solution while cooling with ice. During this procedure, white crystals separated out quickly. After stirring at room temperature for 1 hour, the mixture was cooled with ice and white crystals were collected by filtration and washed with isopropanol. The crystals thus obtained were dissolved in 300 ml of water and the solution was neutralized with diluted hydrochloric acid. The white crystals which separated out were collected by filtration, washed with water to obtain 90 g of p-chlorophenylsulfonylacetic acid.
Reaction SMILES: Cl[CH:2]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22].Cl>CN(C=O)C.O>[CH:8]1([CH:2]([C:19]2[CH:18]=[CH:17][C:16]([N+:21]([O-:23])=[O:22])=[C:15]([F:14])[CH:20]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)C(Cl)C1CCCCC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(c1ccc([N+](=O)[O-])c(F)c1)C1CCCCC1
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 48.6 %

Procedure:
8.2 g of potassium tert.butylate were dissolved in 70 ml of DMF and cooled to −45° C. For this purpose, a mix of ethyl 2-chloro-2-cyclohexylacetate (36.6 mmol, 7.5 g) and 1-fluoro-2-nitrobenzene (36.6 mmol, 3.9 ml) was carefully added dropwise and stirred for a further 20 minutes. The reaction mix was set to pH 4 using 16% HCl, diluted with 25 ml of water and extracted with EtOAc (3×50 ml). Once combined, the organic phases were washed with water and sat. aq. NaCl sol., dried over MgSO4 and concentrated under vacuum. The resulting residue was purified by column chromatography (silica gel: mesh 100-200, eluent: 10% EtOAc in cyclohexane) and produced 5.5 g (49%) of product.