Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][C@@H:7]([CH3:19])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH:11]=[N:10]1)([CH3:4])([CH3:3])[CH3:2].[Br:22]N1C(=O)CCC1=O.S(=O)(O)[O-].[Na+]>C1COCC1>[Br:22][C:16]1[C:15]([OH:18])=[CH:14][CH:13]=[C:12]2[C:17]=1[N:9]([CH2:8][C@@H:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:21])[CH3:20])[CH3:19])[N:10]=[CH:11]2
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@@H](Cn1ncc2ccc(O)cc21)O[Si](C)(C)C(C)(C)C
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](Cn1ncc2ccc(O)c(Br)c21)O[Si](C)(C)C(C)(C)C
Yield: 76.6 %

Procedure:
To a solution of the product from Step B (3.79 g, 12.4 mmol) in anhydrous THF (100 mL) at 0° C. was added N-bromosuccinimide (2.20 g, 12.4 mmol) in 3 portions over 10 min. After 20 min the mixture was poured into a saturated aqueous solution of sodium bisulfite (100 mL) and extracted with EtOAc (3×200 mL). The combined extracts were dried (MgSO4) and evaporated to a residue (4.79 g). Chromatography (silica, 10% EtOAc/hexane) gave a solid (3.66 g, 77%): mp 103-105° C.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10](=[O:29])[CH:11]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]3[O:25][CH2:24][C:23]([CH3:27])([CH3:26])[C:22]=3[CH:28]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1>CCOCC.[Cl-].[Zn+2].[Cl-]>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]([OH:29])[CH:11]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]3[O:25][CH2:24][C:23]([CH3:26])([CH3:27])[C:22]=3[CH:28]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(Cc1ccc2c(c1)C(C)(C)CO2)C(=O)c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc2c(c1)C(C)(C)CO2)C(O)c1cccc(Cl)c1
Reaction time: 2 h
Yield: 85.5 %

Procedure:
To a suspension (140 ml) of zinc chloride (9.90 g, 72.6 mmol) in ether was added sodium borohydride (5.50 g, 145.2 mmol) at room temperature, and the mixture was stirred as it was for 2 hrs. Insoluble material was filtered off, and to the filtrate was added a solution of ethyl 3-(3-chlorophenyl)-2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-3-oxopropionate (14.04 g, 36.3 mmol) in ether (50 ml), and the mixture was stirred at room temperature for 1.5 hrs. The reaction was quenched with 3N hydrochloric acid, and the reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The mixture was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1, 5:1) to give ethyl (2RS,3RS)-3-(3-chlorophenyl)-2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-3-hydroxypropionate (12.07 g, 86%) as a pale-yellow oil.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](Cl)=[O:15].[OH-].[Na+]>O>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([N:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:15]
Reactant: O=C(Cl)c1ccco1
Reactant: C1CNCCNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(c1ccco1)N1CCCNCC1

Procedure:
Homopiperazine (70 g., 0.70 mole) in 160 ml. water was treated with 6 N hydrochloric acid to adjust to pH 5.5 Furoyl chloride (79.5 g., 0.60 mole) and 25% (w/w) aqueous sodium hydroxide solution were added simultaneously to maintain a pH of 4.5-5.5. Then additional sodium hydroxide was added to bring the mixture to pH 9.5. The solution was extracted with chloroform, dried over anhydrous potassium carbonate and distilled to afford 63 g. of product, B.P. 124°-130° C. at 10 mm.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=1[NH2:18].CCN(CC)CC>CN(C=O)C>[N+:8]([C:7]1[C:2]([NH:18][C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:11])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Cc1ccccc1N
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccccc1Nc1ncccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (4.13 g, 26.1 mmol), o-tolylamine (3.4 mL, 31.3 mmol) and Et3N (4.4 mL, 31.3 mmol) in DMF (10 mL) was stirred at 90° C. for 1 h under a nitrogen atmosphere. Additional o-tolylamine (2 mL, 18.2 mmol) was added and stirring continued for 16 h. The mixture was partitioned between DCM and water. The aqueous phase was further extracted with DCM (×3) and the combined organic fractions washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 20-100% DCM in cyclohexane) to afford the title compound as an orange solid (3.96 g, 66%). LCMS (Method C): RT 3.60 min [M+H]+ 230.3
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]=[C:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][CH2:15][C:16](=[O:24])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:9]1[CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]#[N:32]>C1COCC1>[OH:24][CH:16]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][CH2:14][C@H:10]1[CH2:11][CH2:12][CH2:13][C:8](=[O:7])[N:9]1[CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]#[N:32]
Reactant: N#CCOCCCCN1C(=O)CCC[C@@H]1CCC(=O)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CCOCCCCN1C(=O)CCC[C@@H]1CCC(O)Cc1ccccc1
Yield: 78 %

Procedure:
Lithium aluminum hydride (1.0 M in THF, 0.02 mL, 0.02 mmol) was added to a solution of {4-[(R)-2-oxo-6-(3-oxo-4-phenyl-butyl)-piperidin-1-yl]-butoxy}-acetonitrile (15.7 mg, 0.044 mmol) in THF (0.75 mL) at 0° C. After 2 h at 0° C. the reaction was quenched with saturated aqueous NH4Cl (5 mL) and extracted with (3×5 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo to afford 12.3 mg (78%) of the title compound.
Reaction SMILES: [C:1](=[S:6])([S-:5])[S:2][CH2:3][CH3:4].[K+].C(O[CH:12]1[NH:15][C:14](=[O:16])[CH:13]1[CH:17]([CH3:19])[CH3:18])(=O)C.CC(C)=O.C1(C)C=CC=CC=1.C(OCC)(=O)C>O>[CH2:3]([S:2][C:1]([S:5][CH:12]1[NH:15][C:14](=[O:16])[CH:13]1[CH:17]([CH3:19])[CH3:18])=[S:6])[CH3:4]
Reactant: CC(=O)OC1NC(=O)C1C(C)C
Reactant: CCSC(=S)[S-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCSC(=S)SC1NC(=O)C1C(C)C

Procedure:
A solution of 230 mg of potassium ethyl trithiocarbonate in 1.5 ml of water is added dropwise at room temperature, in a nitrogen atmosphere, to a solution of 195 mg (1.14 mmole) of 4-acetoxy-3-isopropylazetidin-2-one (racemic mixture of cis- and trans-isomer in the ratio of 1:3) in 1 ml of water and 0.2 ml of acetone and the mixture is stirred at the same temperature for 120 minutes. The reaction mixture is exhaustively extracted with methylene chloride. The combined organic phases are dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed over 12 g of silica gel with toluene/ethyl acetate (9:1) and yields the trans-title compound. Melting point: 65°-66° TLC: Rf =0.5 (toluene/ethyl acetate 2:3]; IR spectrum (CH2Cl2): absorption bands at 2.95, 3.37, 5.62 and 9.25μ. NMR spectrum (in CDCl3 /100 Mc, in ppm): 6.65, 1H, m (exchange with D2O); 5.4, 1 H, d (J=2.5 Hz): 3.39, 2H, q; 3.05, 1H, m; 2.15, 1H, m: 1.38, 3H, t; 1.1, 6H, m.
Reaction SMILES: CN(C)C=O.[N:6]1([CH2:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([NH2:24])=[N:16]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.Br.Br[CH2:27][CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[N:6]1([CH2:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([NH:24][CH2:27][CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[N:16]2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CCN(CC)CCCBr
Reactant: Nc1nn(CCCN2CCCCC2)c2ccccc12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCCNc1nn(CCCN2CCCCC2)c2ccccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 51.5 %

Procedure:
To 60 ml of anhydrous N,N-dimethylformamide were added 8.4 g of the 1-(3-piperidinopropyl)-3-aminoindazole, 8.98 g of 3-bromopropyldiethylamine hydrobromide and 7.89 g of anhydrous potassium carbonate, and the mixture was stirred for 12 hours at 80° C. After cooling, the mixture was added with 80 ml of water and extracted with diethyl ether. The diethyl ether layer was extracted three times with 2N hydrochloric acid, and the hydrochloric acid layer was washed with diethyl ether. The pH of the layer was adjusted to at least 11 with potassium carbonate, and the alkali layer was extracted three times with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography (alumina: 200 g) using chloroform as the developing solvent to give 6.22 g of 1-(3-piperidinopropyl)-3-(3-diethylaminopropylamino)indazole having the following analytical values in a yield of 53%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][O:21][C:3]=12.[CH2:22]([O:29][CH2:30][CH:31]([CH:41]1[CH2:44][CH:43]([S:45](Cl)(=[O:47])=[O:46])[CH2:42]1)[CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[CH2:34]([O:33][CH2:32][CH:31]([CH:41]1[CH2:42][CH:43]([S:45]([NH:1][C:2]2[C:7]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=3[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]3[CH2:19][CH2:20][O:21][C:3]=23)(=[O:47])=[O:46])[CH2:44]1)[CH2:30][O:29][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=S(=O)(Cl)C1CC(C(COCc2ccccc2)COCc2ccccc2)C1
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCO2
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC(C(COCc3ccccc3)COCc3ccccc3)C2)c2n(c1=O)CCO2
Yield: 71.9 %

Procedure:
Using the same reaction conditions and procedure as described for the preparation of Example 7A, 8-Amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one (I-7f: 0.22 g, 0.539 mmol) was reacted with 3-(1,3-bis(benzyloxy)propan-2-yl)cyclobutane-1-sulfonyl chloride (0.21 g, 0.539 mmol) in dry pyridine (2 mL) to afford the crude product. Purification by column chromatography on silica gel (80% ethyl acetate in hexane) afforded 0.3 g of the product (71% yield). LCMS: 80%, m/z=773 (M+1)
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=O)[O:3][C:2]1=O.[Br:13][C:14]1[C:15]([CH3:21])=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].COC(OC)OC>C1COCC1>[Br:13][C:14]1[C:15]([CH3:21])=[C:16]([N:17]2[C:4](=[O:3])[C:5]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:1]=[CH:2]2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Cc1c(N)cccc1Br
Solvent: COC(OC)OC
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1-n1cnc2ccccc2c1=O
Temperature: 100 °C
Yield: 36.2 %

Procedure:
A mixture of 1H-benzo[d][1,3]oxazine-2,4-dione (200 mg, 1.226 mmol), 3-bromo-2-methylaniline (228 mg, 1.226 mmol), and trimethoxymethane (390 mg, 3.68 mmol) in THF (2 mL) was heated overnight in a sealed tube at 100° C. The mixture was cooled to rt and concentrated, and the residue was purified by column chromatography (eluting with 90:10 to 50:50 hexane-EtOAc) to give 3-(3-bromo-2-methylphenyl)quinazolin-4(3H)-one (140 mg, 36%). 1H NMR (400 MHz, chloroform-d) δ 8.37 (1H, dd, J=8.3, 1.2 Hz), 7.97 (1H, s), 7.76-7.86 (2H, m), 7.72 (1H, t, J=4.6 Hz), 7.57 (1H, ddd, J=8.0, 6.7, 1.5 Hz), 7.21-7.28 (2H, m), 2.26 (3H, s). Mass spectrum m/z 315, 317 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][O:5][CH2:6][CH:7]1[O:9][CH2:8]1)[CH3:2].[NH:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][OH:17].C(OCC1OC1)C1OC1>>[OH:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][OH:20])[CH2:8][CH:7]([OH:9])[CH2:6][O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: OCCNCCO
Reactant: CCCCC(CC)COCC1CO1
Agent: C(OCC1CO1)C1CO1
Product: CCCCC(CC)COCC(O)CN(CCO)CCO
Temperature: 77.5 °C

Procedure:
A three-necked, septum capped, 250 mL, round-bottom flask equipped with an addition funnel and containing a magnetic stirring bar is flushed with argon and charged with 2-ethylhexylglycidyl ether (66.53 g, 0.35 mol). Diethanolamine (40.89 g, 0.38 mol) is added during 10 min to the glycidyl ether, with stirring. The flask is placed in an oil bath and heated at a bath temperature of 75-80° C. overnight. The reaction is cooled and checked by 1H NMR to ensure the complete consumption of the glycidyl ether. A colorless viscous liquid is obtained.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([C:10](=[N:12][OH:13])[CH3:11])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C([Li])CCC.[CH2:19]([C:27]1[CH:36]=[CH:35][C:30]([C:31](OC)=O)=[CH:29][CH:28]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].Cl>O1CCCC1>[CH2:1]([C:5]1[S:9][C:8]([C:10]2[CH:11]=[C:31]([C:30]3[CH:35]=[CH:36][C:27]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:28][CH:29]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C(C)=NO)s1
Reactant: CCCCCCCCc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(-c2cc(-c3ccc(CCCC)s3)no2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The 1-(5-butylthiophen-2-yl)-ethanone oxime obtained in step 2 is dissolved in tetrahydrofuran under an inert gas atmosphere and doubly deprotonated with 2 equivalents of n-butyllithium at 0° C. The solution is admixed with a solution of 0.5 equivalents of methyl 4-octylbenzoate in tetrahydrofuran, and the mixture is stirred for 30 min at 0° C., then admixed with 3 M HCl and refluxed for 1 h. Customary work-up followed by purification by column chromatography over silica gel 60 (eluent: dichloromethane/heptane 1:1) and recrystallizsation affords 3-(5-butylthiophen-2-yl)-5-(4-octylphenyl)-isoxazole; X 63 SC 82 SA 88 N 89 I.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([C:25](=[O:27])[CH3:26])[CH:17]2[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH2:18]2)[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.[NH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([C:25](=[O:27])[CH3:26])[CH:17]2[CH2:18][CH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][CH2:22]2)[CH2:13][C@H:9]1[C:10]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:12])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CC(=O)N(C1CCC(C)(C)CC1)[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: C1CNCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(C1CCC(C)(C)CC1)[C@H]1C[C@@H](C(=O)N2CCNCC2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
(4S)-1-BOC-4-[acetyl(4,4-dimethylcyclohexyl)amino]-L-proline (0.92 g, 2.41 mmol) obtained in Step C of Example 1, was dissolved in DMF (10 mL) and DIPEA (1.05 mL, 6.01 mmol) was added thereto. Piperazine (0.25 g, 2.89 mmol) and HBTU (0.91 g, 2.41 mmol) were also added thereto in order. After the reaction solution was stirred at room temperature for 2 hours, the solution was concentrated in vacuo. The residue was diluted with EtOAc and washed with saturated NaHCO3 aqueous solution. The extracted organic solution was dried over MgSO4, concentrated in vacuo. The residue was purified by column chromatography (eluent: MC/MeOH=10/1) to give the title compound (1.01 g, 93%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH:12]([C@@H:14]1[O:32][CH2:31][C@:17]2([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[F:40])[N:18]=[C:19]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:20][CH2:21][C@@H:16]2[CH2:15]1)[OH:13])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1>[F:40][C:34]1[CH:35]=[C:36]([F:39])[CH:37]=[CH:38][C:33]=1[C@:17]12[CH2:31][O:32][C@@H:14]([CH:12]([OH:13])[CH2:11][CH2:10][CH2:9][OH:8])[CH2:15][C@H:16]1[CH2:21][S:20][C:19]([NH:22][C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[N:18]2
Reactant: CC(C)(C)[Si](C)(C)OCCCC(O)[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](C(O)CCCO)C[C@H]2CS1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-[(4aR,6R,8aS)-6-(4-{[tert-Butyl(dimethyl)silyl]oxy}-1-hydroxybutyl)-8a-(2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C11) (28 mg, 47 μmol) was dissolved in tetrahydrofuran (0.3 mL) and cooled to 0° C. A solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 61 μL, 61 μmol) was added drop-wise, and the reaction mixture was allowed to warm to room temperature and then stir for 1 hour. After addition of saturated aqueous ammonium chloride solution, the mixture was extracted with ethyl acetate (3×5 mL); the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via chromatography on silica gel (Gradient: 35% to 100% ethyl acetate in heptane) provided the product as a white foam. Yield: 19 mg, 40 μmol, 85%. LCMS m/z 477.2 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.22 (br d, J=7.4 Hz, 2H), 7.49-7.56 (m, 1H), 7.42-7.49 (m, 2H), 7.39 (ddd, J=9.0, 9.0, 6.3 Hz, 1H), 6.85-6.97 (m, 2H), 4.16 (dd, J=12.1, 1.4 Hz, 1H), 3.85 (br d, J=12.1 Hz, 1H), 3.53-3.74 (m, 4H), 3.10-3.19 (m, 1H), 3.02 (dd, J=12.9, 4.1 Hz, 1H), 2.65 (dd, J=12.9, 2.5 Hz, 1H), 1.94-2.06 (m, 1H), 1.63-1.80 (m, 4H), 1.49-1.60 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=[C:21]([C:22]([NH2:24])=[O:23])[C:4]=2[N:3]=1>CN(C(OC)OC)C>[CH3:5][N:6](/[CH:7]=[N:24]/[C:22]([C:21]1[C:4]2[N:3]=[C:2]([CH3:1])[N:6]([CH2:7][C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:11]=[CH:10][CH:9]=3)[C:5]=2[CH:18]=[C:19]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:23])[CH3:2]
Reactant: Cc1nc2c(C(N)=O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Agent: COC(OC)N(C)C
Product: Cc1nc2c(C(=O)/N=C/N(C)C)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 25 °C
Yield: 150.2 %

Procedure:
A solution of combined batches of 2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole-4-carboxamide (150 mg, 0.38 mmol) in DMF-DMA (10 mL) was stirred at 130° C. for 2 h. When TLC showed no starting material remaining, the mixture was cooled to rt and the solvent was removed under reduced pressure to give the crude product (130 mg, 76%), as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 2.39 (s, 3H), 3.02 (t, 4H, J=4.5 Hz), 3.13 (s, 3H), 3.20 (s, 3H), 3.69 (t, 4H, J=4.5 Hz), 5.99 (s, 2H), 6.30 (d, 1H, J=7.8 Hz), 7.12 (d, 1H, J=2.4 Hz), 7.33 (t, 1H, J=7.8 Hz), 7.54 (d, 1H, J=2.4 Hz), 7.60-7.71 (m, 2H), 7.85 (d, 1H, J=7.8 Hz), 8.01 (d, 1H, J=7.8 Hz), 8.25 (d, 1H, J=7.8 Hz), 8.54 (s, 1H); LC-MS: m/e=456 [M+1]+
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([CH2:10][C:11]([OH:13])=[O:12])[CH:8]=[CH:9][C:2]1=2.[CH3:14]O>Cl>[CH3:14][O:12][C:11](=[O:13])[CH2:10][C:7]1[CH:8]=[CH:9][C:2]2[S:1][CH2:5][CH2:4][C:3]=2[CH:6]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc2c(c1)CCS2
Agent: Cl
Product: COC(=O)Cc1ccc2c(c1)CCS2
Temperature: 65 °C
Yield: 94 %

Procedure:
In a round bottom flask was placed (2,3-dihydro-benzo[b]thiophen-5-yl)-acetic acid (525 mg, 2.70 mmol), methanol (15 mL) and hydrochloric acid (2 drops). The reaction mixture was heated to 65° C. for 16 h. It was then concentrated in vacuo to remove the methanol, diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The organic layers were combined and washed with a saturated aqueous sodium bicarbonate solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford (2,3-dihydro-benzo[b]thiophen-5-yl)-acetic acid methyl ester (528 mg, 94%) as a yellow oil: ES-HRMS m/e calcd for C11H12O2S (M+H)+ 209.0631, observed 209.0631.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[N:12]=[N:13][N:14]([CH3:16])[CH:15]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>N1C=CC=CC=1>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[N:12]=[N:13][N:14]([CH3:16])[CH:15]=2)=[O:10])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: Cn1cc(C(=O)c2cc(Cl)ccc2N)nn1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cn1cc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nn1

Procedure:
Following the general procedure for synthesis of N-arylbenzenesulfonamides, 28 mg (0.12 mmol) of (2-Amino-5-chloro-phenyl)-(1-methyl-[1,2,3]triazol-4-yl) methanone and 56 mg (0.24 mmol) of 4-tert-butylphenylsulfonyl chloride were combined in 0.5 ml of anhydrous pyridine at 60° C. to give, after purification, the title product as a pale yellow solid: 1H NMR CD3OD δ (ppm): 1.21 (s, 9H), 4.25 (s, 3H), 7.38 (d, 2H), 7.53 (d, 2H), 7.54-7.63 (m, 2H), 8.11 (s, 1H), 8.22 (d, 1H); MS: (M+H)/z=433.1.
Reaction SMILES: [C:1]1([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21](=O)[O:22]C4C=CC=CC=4)=[CH:14][CH:13]=3)[N:10]=[C:9]([C:30]([F:33])([F:32])[F:31])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([S:40]([NH2:43])(=[O:42])=[O:41])[CH:35]=1>>[C:1]1([C:7]2[N:11]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:43][S:40]([C:36]4[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=4)(=[O:42])=[O:41])=[O:22])=[CH:16][CH:17]=3)[N:10]=[C:9]([C:30]([F:33])([F:32])[F:31])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NCCc1ccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)cc1)Oc1ccccc1
Reactant: NS(=O)(=O)c1cccnc1
Product: O=C(NCCc1ccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)cc1)NS(=O)(=O)c1cccnc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 0.42 from phenyl 2-{4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}ethylcarbamate (step 4) and pyridine-3-sulfonamide: 1H-NMR (CDCl3) δ 9.04 (1H, d, J=2.0 Hz), 8.78 (1H, d, J=3.7 Hz), 8.08-8.04 (1H, m), 7.48-7.44 (1H, m), 7.34-7.10 (9H, m), 6.76 (1H, s), 6.28 (1H, br.s), 3.48-3.42 (2H, m), 2.83-2.78 (2H, m).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:14][CH2:15][C:16](=[O:18])[CH3:17].N1C=CC=CC=1.[Mn]([O-])(=O)(=O)=[O:26].[K+]>O>[O:26]=[C:12]1[C:13]2[CH:1]=[C:2]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(=O)CCc1ccc2c(c1)Cc1ccccc1-2
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)CCc1ccc2c(c1)C(=O)c1ccccc1-2
Temperature: 60 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
4-(2-Fluorenyl)-butan-2-one (4.72grams) was dissolvedin a mixture of 60 ml of pyridine and 5 ml of water, the mixture was heated at 60° C., and stirred. Potassium permanganate (6.8 grams) was added thereto little by little during 2 hours. When the addition was finished, the mixture was stirred for 2 hours more. The reaction solution was filtered, the filtrate was concentrated, and the resulting residue was dissolved in chlroform, the solution was washed with in the order of 10% hydrochloric acid, water, saturated sodium bicarbonate, and water, then dried with magensium sulfate, the solvent was evaporated therefrom, and the residue was recrystallized from ethanol to give 1.3 grams of 4-(9-oxo-2fluorenyl)-butan-2-one, yellow crystals, m.p. 75°-77° C.