Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH2:5]2.[CH3:19][N:20](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:12]=[C:7]1[N:6]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:19]#[N:20])[CH:3]=2)[NH:8]1
Reactant: CN(C)C=O
Reactant: O=C1Nc2ccc(Br)cc2CN1C1CCNCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(c1)CN(C1CCNCC1)C(=O)N2
Temperature: 90 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
6-Bromo-3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (0.16 g, 0.52 mmol), zinc cyanide (37 mg, 0.31 mmol) and tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.05 mmol) were combined in dimethylformamide (4 mL). The reaction flask was connected to high vacuum and degassed (3×) by a freeze-thawing method, before being heated at 90° C. with stirring under nitrogen for 1 h. After cooling to room temperature, the solution was evaporated in vacuo and the crude mixture purified by preparative HPLC to afford 50 mg (38%) of the desired nitrile. 1H-NMR (CD3OD) δ 1.99 (m, 2H), 2.08-2.23 (m, 2H), 3.15 (m, 2H), 3.50 (bs, 1H), 3.55 (bs, 1H), 4.40 (m, 1H), 4.47 (s, 2H), 6.93 (d, J=8.1, 1H), 4.10 (m, 2H). Mass spec.: 257.13 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:31])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:30])=[CH:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](/[CH:23]=[CH:24]/[CH:25]=[C:26](/[CH:28]=O)\[CH3:27])\[CH3:22].[CH3:32][O-:33].[Na+].S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(C)C>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:31])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:30])=[CH:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](/[CH:23]=[CH:24]/[CH:25]=[C:26](/[CH:28]=[CH:1]/[CH:2]=[C:3](/[CH:32]=[O:33])\[CH3:4])\[CH3:27])\[CH3:22]
Reactant: C[O-]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(\C)C=O)C(C)(C)CCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C=C(\C)C=O)C(C)(C)CCC1
Temperature: 70 °C

Procedure:
For the performance of the Wittig reaction, 75 g (0.18 mol) of β-apo-8'-carotenal were placed in a 2.5 l sulphonation flask equipped with a stirrer, condenser, thermometer, automatic dosage device (Dosimat) and argon gasification. The β-apo-8'-carotenal was then suspended in 900 ml of dry isopropanol and the resulting red, not very thick suspension was heated to 70° C. The freshly prepared alkaline acetal solution from the previously process step was then added and rinsed in with 100 ml of dry isopropanol. 38.99 ml of sodium methylate solution (containing 0.2080 mol of base) were subsequently dosed in within 30 minutes using the Dosimat. Subsequently, the mixture was stirred at 70° for a further hour and thereafter 342.3 mol of 0.5N sulphuric acid (0.0858 mol of acid) were dosed in at 70° C. within one hour using the Dosimat. Then the oil bath was replaced by a water bath, 342.3 ml of 0.5N sodium hydroxide solution (0.1711 mol of base) were added within 15 minutes using the Dosimat and thereby the reaction mixture was cooled to 25° C. The red-brown crystal slurry was stirred for a further 60 minutes, thereafter filtered over a slotted glass suction filter having a paper filter and the filter cake was washed in sequence twice with 340 ml each time of isopropanol and three times with 340 ml each time of deionized water. The thus-obtained wine-red crystals were subsequently dried for 2 days at 50° C. in a vacuum drying oven at 20-30 mbar (2-3 kPa). There were obtained 82.7 g of a cystallizate of the desired product, β-apo-4'-carotenal. The weight yield was 95.2% based on β-apo-8'-carotenal used. The composition of the product according to HPLC or, respectively, Karl-Fischer titration was as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14]([O:16]C)=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(-c2ccc(C(=O)O)s2)cc1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
A solution of methyl 5-(4-methoxyphenyl)thiophene-2-carboxylate (1.4 g, 5.6 mmol), and 1 M sodium hydroxide (55 mL) in methanol (55 mL) was heated at 80° C. for 18 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid and aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the desired product (1.2 g, 93%) as an off-white solid: ESI MS m/z 325 [C12H10O3S+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[N:13][OH:14])[CH3:12].[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[C:29]([O:30][CH3:31])=[N:28][N:27]([CH3:32])[C:26]1=[O:33]>CN(C=O)C>[CH3:31][O:30][C:29]1[N:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][O:14][N:13]=[C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH3:12])[C:26](=[O:33])[N:27]([CH3:32])[N:28]=1
Reactant: CC(=NO)c1ccc2ccccc2c1
Reactant: COc1nn(C)c(=O)n1-c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nn(C)c(=O)n1-c1ccccc1CON=C(C)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution of 0.56 g (3.02 mmol) of 1-(2-naphthalenyl)ethanone oxime in 10 mL of DMF was added 0.13 g (3.28 mmol) of NaH. 0.75 (2.52 mmol) of the title compound of Step D was then added to the reaction and the mixture was stirred at room temperature for 3 h. The reaction mixture was washed successively with water and saturated NaCl and then extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel using 60% ethyl acetate/hexane as eluent to give 0.80 g (79% yield) of the title compound of Step E, a compound of the invention, as a solid melting at 91-94° C.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]([CH3:4])[OH:3].[CH:9]([O:12][CH2:13][CH3:14])=[CH:10][CH3:11]>Cl>[CH2:13]([O:12][CH:9]([O:3][CH:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH2:10][CH3:11])[CH3:14]
Reactant: CCOC(=O)C(C)O
Reactant: CC=COCC
Agent: Cl
Product: CCOC(=O)C(C)OC(CC)OCC
Temperature: 75 °C
Yield: 82.6 %

Procedure:
To a 250 mL flask containing 37.0 g (0.31 mole) ethyl lactate and four drops 32% hydrochloric acid at 30° C. is added 71 g (0.82 mole) ethyl propenyl ether. The mixture is heated to 75° C. for thirty minutes, cooled to 25° C., then quenched with 100 g 5% sodium bicarbonate solution. The organic material was flash distilled yielding 52.3 g (90%) ethyl 2-[(1'-ethoxy)propoxy]propanoate.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=O)=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH3:32])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl.[NH2:40][OH:41]>O>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:40][OH:41])=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH3:32])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c1C=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c1C=NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
Intermediate (17b) (4.3 g, 10 mmol) was dissolved in pyridine (40 mL, 500 mmol). Hydroxylamine hydrochloride (1.7 g, 25 mmol) was added, followed by the addition of water (20 mL, 1000 mmol). The mixture was stirred at room temperature overnight. Water (30 mL) was added and the mixture was stirred for 20 minutes. The precipitant was filtered off and dried to yield intermediate (17c) (3.5 g). MS m/z: [M+H+] calcd for C26H29N3O4, 448.2. found 448.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[N:35]1([CH2:40][CH2:41][NH2:42])[CH2:39][CH2:38][CH2:37][CH2:36]1>O1CCOCC1>[F:34][C:20]1[C:19]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][CH2:41][CH2:40][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[N:7]=2)=[CH:24][CH:23]=[CH:22][C:21]=1[NH:25][S:26]([C:29]1[CH:33]=[CH:32][O:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccoc1
Reactant: NCCN1CCCC1
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(NCCN3CCCC3)n2)c1F)c1ccoc1

Procedure:
Following a procedure analogous to the procedure described in example 300 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide (110 mg, 0.211 mmol), [2-(1-pyrrolidinyl)ethyl]amine (121 mg, 1.056 mmol) in 1,4-dioxane (2 mL)), the title compound was obtained as a white foam (30 mg, 22%). 1H NMR (400 MHz, DMSO-d6) ppm 1.58-1.87 (m, 6H), 2.01 (dd, J=12.88, 2.02 Hz, 2H), 2.54-2.88 (m, 6H), 3.12-3.43 (m, 3H), 3.47 (td, J=11.62, 2.02 Hz, 2H), 3.93 (dt, J=9.47, 2.21 Hz, 2H), 5.77 (s, 1H), 5.91-6.31 (m, 1H), 6.56 (d, J=1.26 Hz, 1H), 6.92 (br. s., 1H), 7.07 (t, J=7.71 Hz, 1H), 7.18 (br. s., 1H), 7.41 (td, J=8.02, 1.64 Hz, 1H), 7.70 (t, J=1.77 Hz, 1H), 8.05 (s, 1H), 8.11 (d, J=5.05 Hz, 1H); MS (ESI): 599.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.BrCCCC[C:22]1[CH:32]=[CH:31][CH:30]=[C:24]2[C:25]([NH:27][C:28](=[O:29])[C:23]=12)=[O:26]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:16][CH2:2][CH2:3][CH2:4][N:27]4[C:28](=[O:29])[C:23]5=[CH:22][CH:32]=[CH:31][CH:30]=[C:24]5[C:25]4=[O:26])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C1NC(=O)c2c(CCCCBr)cccc21
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 47.1 %

Procedure:
A mixture of 6 -fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (5.5 g, 25 mmol), 4-bromobutylphthalimide (8.0 g, 28.3 mmol, 1.13 eq), K2 CO3 (4.55 g, 32 mmol) in acetonitrile (100 ml) was heated at reflux for 3 hours. At the end of the reaction, the mixture was filtered. The insolubles were washed with dichloromethane (200 ml). The organic solution was concentrated gradually to allow cystallization. The crude crystals (5.9 g) were collected. The mother liquor was concentrated to a solid (5.5 g,). Purification was by flash chromatography over a silica gel column. The product (3.8 g) thus purified was recrystallized from ethanol (70 ml) to give 2.48 g of N-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butyl]phthalimide as white crystals, m.p.=144°-146° C.
Reaction SMILES: [N+:1]([CH2:4][CH:5]1[CH2:13][C:8]2(OCC[O:9]2)[CH:7]([CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:6]1[CH:23]=[CH:24][C:25]([OH:37])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([O-:3])=[O:2].O1CCCC1.Cl>O>[OH:37][C:25]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:24]=[CH:23][CH:6]1[CH:5]([CH2:4][N+:1]([O-:3])=[O:2])[CH2:13][C:8](=[O:9])[CH:7]1[CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: CCCCCC(O)(C=CC1C(C[N+](=O)[O-])CC2(OCCO2)C1CC=CCCCC(=O)O)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC(O)(C=CC1C(C[N+](=O)[O-])CC(=O)C1CC=CCCCC(=O)O)c1ccccc1

Procedure:
A solution of 0.3 g. of 7-[8-nitromethyl-7-(3-hydroxy-3-phenyl-1-octenyl)-1,4-dioxaspiro[4.4]-non-6-yl]-5-heptenoic acid in 6 ml. of dry tetrahydrofuran was treated at 0° C. with 0.6 ml. of concentrated hydrochloric acid and stirred at 0° C. for 1.5 hours. The reaction mixture was added to water and extracted with ether. After washing with water and drying over magnesium sulfate, the extract was evaporated and the residue chromatographed on silica. Elution with 33% ethyl acetate in hexane gave 0.08 g. of the title product as an oil, λmaxfilm 3.00 (shoulder), 3.40, 5.75, 6.40, 7.20, 10.20, 13.20, 14.18 μ. NMR: δ4.45 (m, 2, --CH2NO2), 5.40 (m, 2, 5 and 6-H), 5.85 (m, 2, 13 and 14-H), 5.90 (s, 2, OH), 7.40 (s, 5, aromatic -H ppm. Mass spectrum: M+ at m/e 471 (theory 471), M+ --H2O at m/e 453 (theory 453).
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:39][C:40]1[CH:45]=[C:44]([S:46]([CH3:49])(=[O:48])=[O:47])[CH:43]=[CH:42][C:41]=1[N:50]1[C:54]2=[N:55][CH:56]=[N:57][C:58]([O:59][CH:60]3[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]3)=[C:53]2[CH:52]=[N:51]1.C(N(CC)CC)C>CN(C=O)C>[F:13][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:63]2[CH2:64][CH2:65][CH:60]([O:59][C:58]3[N:57]=[CH:56][N:55]=[C:54]4[N:50]([C:41]5[CH:42]=[CH:43][C:44]([S:46]([CH3:49])(=[O:48])=[O:47])=[CH:45][C:40]=5[F:39])[N:51]=[CH:52][C:53]=34)[CH2:61][CH2:62]2)=[O:10])=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)c(F)c1
Reactant: O=C(O)c1ccc(OC(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCN(C(=O)c5ccc(OC(F)F)cc5)CC4)ncnc32)c(F)c1
Reaction time: 24 h
Yield: 12.1 %

Procedure:
4-Difluoromethoxy-benzoic acid (527 mg, 2.8 mmol) and HATU (1.06 g, 2.8 mmol) were stirred together in DMF at room temperature for 30 min. 1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (800 mg, 1.87 mmol) and triethylamine (785 μL, 5.61 mmol) were added next. The resulting mixture was allowed to stir for 24 hours. Progress of the reaction was monitored by TLC and LCMS. Removal of organic solvents in vacuo and purification by HPLC afforded Compound A193 as a beige solid (127 mg, 32%). Exact mass calculated for C25H22F2N5O5S 561.53, found 562.2 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:17](O)(=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)c1ccncc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)c2ccncc2)cc1
Temperature: 23 °C
Reaction time: 4 h
Yield: 87.6 %

Procedure:
A solution of p-anisidine (2.46 g, 20 mmol) and triethylamine (13.9 mL, 100 mmol) in ethyl acetate (200 mL) was treated with isonicotinic acid (2.46 g, 20 mmol) followed by 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 15.1 mL, 24 mmol). After stirring at 23° C. for 4 h, the reaction mixture was diluted with ethyl acetate, was washed with water and with brine, and the organic layer was dried (MgSO4), was filtered, and was concentrated in vacuo. Purification by silica gel chromatography with chloroform-methanol (40:1) gave 4 g (88% yield) of the title compound; diagnostic 13C NMR signals (100 MHz, CD3OD/CDCl3) δ 164.825, 157.213, 149.758, 143.349, 130.989, 123.085, 122.068, 55.285; MS (AP/CI) 229.3 (M+H)+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([C:12]([NH2:14])=[O:13])[CH:11]=1)[NH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[Cl:21][CH2:22][CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([C:12]([NH2:14])=[O:13])[CH:11]=1)[NH:8][N:7]=[C:6]2[CH:15]1[CH2:16][CH2:17][N:18]([S:25]([CH2:24][CH2:23][CH2:22][Cl:21])(=[O:27])=[O:26])[CH2:19][CH2:20]1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCNCC3)n[nH]c12
Reactant: O=S(=O)(Cl)CCCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Yield: 97.4 %

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 5-bromo-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (100 mg, 0.31 mmol) was reacted with 3-chloro-1-propanesulfonyl chloride (63 uL, 0.46 mmol) in the presence of diisopropylethylamine (0.24 mL, 1.38 mmol) in methylene chloride (5 mL) to give the crude title compound (140 mg, 98%), which was used in the next step without further purification.
Reaction SMILES: [CH:1]([N:4]([C:12](=[O:17])[CH2:13][C:14]([CH3:16])=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:18]N(C)C=O.[H-].[Na+].CI>O>[CH:1]([N:4]([C:12](=[O:17])[CH:13]([CH3:18])[C:14]([CH3:16])=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)CC(=O)N(c1ccc(Cl)cc1)C(C)C
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC(=O)C(C)C(=O)N(c1ccc(Cl)cc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A one liter reaction flask equipped with a power stirrer, condener, drying tube, thermometer and nitrogen inlet tube was charged with 48.5 g (0.19 mole) of N-isopropyl-4'-chloroacetoacetanilide and 145 ml of dry dimethylformamide. With efficient stirring in a nitrogen atmosphere, portionwise addition of 7.2 g of 57% sodium hydride in mineral oil (0.17 mole) was completed in one hour (excessive foaming). Methyl iodide (24.1 g, 0.17 mole) was added dropwise and the reaction mixture was stirred for two hours at ambient temperature. The mixture was poured into one liter of cold water and stirred. The organic material was extracted into toluene and the latter was water washed. Most of the toluene was removed on the rotary evaporator. Hexane was added which caused the mass to crystallize. There was obtained 36.4 g (80%) of white material, M.P. 77°-79°. N.M.R. (CDCl3) ∂0.9-1.4 (CH3, 9 protons), 2.0 (0=C--CH3), 2.9-3.2 (CH), 4.7-5.2 (CH, isopropyl), 6.9-7.5. (aromatic).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([NH:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][N:13]=2)[S:8][C:7]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:4].[C:22](=O)([O-])[O-].[K+].[K+].IC.[NH4+].[Cl-]>CC(C)=O>[F:21][C:2]([F:20])([F:1])[C:3]([N:5]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][N:13]=2)[S:8][C:7]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:22])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1sc2nccnc2c1NC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)c1sc2nccnc2c1N(C)C(=O)C(F)(F)F
Temperature: 50 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of ethyl 7-(2,2,2-trifluoroacetamido)thieno[2,3-b]pyrazine-6-carboxylate 10 (9.22 g, 28.9 mmol) and potassium carbonate (7.98 g, 57.8 mmol) in acetone (140 mL) was added iodomethane (3.60 mL, 57.8 mmol). The reaction was stirred at 50° C. for 1 h. NH4Cl solution(aq) was added and extracted with EtOAc. Organic layer was washed with brine, dried and evaporated to give crude ethyl 7-(2,2,2-trifluoro-N-methylacetamido)thieno[2,3-b]pyrazine-6-carboxylate 11 (9.1 g, 95%). (m/z)=334 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([OH:5])=[O:4].O=[C:13](CCCCCC)[C:14](O)=O>>[O:1]=[C:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:13][CH3:14])=[O:4]
Reactant: CCCCCCC(=O)C(=O)O
Reactant: CCCCCCC(O)C(=O)O
Product: CCCCCCC(=O)C(=O)OCC

Procedure:
The diglycerides and the triglycerides of 2-hydroxyoctanoic acid and 2-ketooctanoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH:6]2[OH:11].C(N(CC)CC)C.[CH3:23][Si:24](Cl)([CH3:26])[CH3:25].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH:6]2[O:11][Si:24]([CH3:26])([CH3:25])[CH3:23]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)CC1Cc2c(Br)cccc2C1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC1Cc2c(Br)cccc2C1O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
A 300-ml three-necked round flask equipped with a stirring bar, a Dimroth condenser, a dropping funnel and a thermometer was charged with 34.4 g (127.8 mmol) of 4-bromo-2-i-butyl-1-hydoxyindane, 23.1 ml (166.2 mmol) of triethylamine and 118 ml of methylene chloride. To the mixture was added dropwise 20 ml of a methylene chloride solution containing 19.45 ml (153.4 mmol) of trimethylsilyl chloride under a nitrogen atmosphere while cooling with ice bath. After the addition was completed, the temperature was elevated to room temperature, and the mixture was further stirred for 1.5 hours. The reaction mixture was poured onto a mixture of 200 ml of ice water and 20 ml of a saturated aqueous solution of sodium bicarbonate. Then, the organic phase was separated, and the aqueous phase was further extracted with 50 ml of methylene chloride two times. The combined organic phase was washed with 100 ml of a saturated NaCl aq., followed by dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure. The residue was distilled under reduced pressure to obtain 41.8 g of the desired product (mixture of two isomers) as a pale yellow liquid (yield: 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[CH2:13]([SH:17])[CH2:14][CH2:15][SH:16].B(F)(F)F.CCOCC>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]2[S:17][CH2:13][CH2:14][CH2:15][S:16]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: SCCCS
Reactant: COc1ccc(C=O)cc1OC
Agent: FB(F)F
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COc1ccc(C2SCCCS2)cc1OC
Temperature: 0 °C
Reaction time: 18 h

Procedure:
74.7 g of 3,4-dimethoxybenzaldehyde are dissolved in 1250 ml of chloroform, treated with 50 ml of 1,3-propanedithiol and cooled at 0° C with stirring. 20 ml of boron trifluoride etherate are added and the mixture is left to stand in a refrigerator for 18 hours. The mixture is then washed three times successively with 500 ml of a 7% potassium hydroxide solution and 500 ml of a 10% sodium chloride solution. The organic extracts are combined, dried over magnesium sulphate and evaporated. The residue is recrystallized twice from ether. There are obtained 102.6 g of 2-(3,4-dimethoxyphenyl)-m-dithiane of melting point 99° - 101° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][CH2:15][CH2:14][N:13]([CH3:17])[CH3:12])=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: CN(C)CCN
Reactant: Cc1cc(C(=O)O)ccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)NCCN(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-bromo-3-methylbenzoic acid (430 mg), N, N-dimethylethylenediamine (180 mg), 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride (600 mg) and 4-dimethylaminopyridine (244 mg) in dichloromethane (20 mL) was stirred at ambient temperature for 4 hours, diluted with ethyl acetate (200 mL), washed with water and brine, and dried (Na2SO4), filtered and concentrated. The concentrate was purified by flash column chromatography with 10% ethyl acetate in ammonia saturated dichloromethane.