Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][S:12][CH3:13])=[CH:7][CH:6]=1)[OH:4].[S:16](Cl)([C:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[C:24]([N:25]([CH3:27])[CH3:26])[C:23]=2[CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17].C1N2CCN(CC2)C1.O>C(Cl)Cl>[F:15][C:2]([F:1])([F:14])[CH:3]([O:4][S:16]([C:19]1[C:31]2[C:23](=[C:24]([N:25]([CH3:27])[CH3:26])[CH:28]=[CH:29][CH:30]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:5]1[CH:6]=[CH:7][C:8]([S:11][S:12][CH3:13])=[CH:9][CH:10]=1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: CSSc1ccc(C(O)C(F)(F)F)cc1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Solvent: O
Product: CSSc1ccc(C(OS(=O)(=O)c2cccc3c(N(C)C)cccc23)C(F)(F)F)cc1
Reaction time: 4 h
Yield: 28.4 %

Procedure:
2,2,2-Trifluoro-1-(4-methyldisulfanyl-phenyl)-ethanol (6) (12 mg, 0.047 mmol) and dansyl chloride (15 mg, 0.057 mmol) were dissolved in dry CH2Cl2 (0.2 mL). A solution of DABCO (63 mg, 0.56 mmol) dissolved in dry CH2Cl2 (0.1 mL) was added dropwise to the above solution. After 4 hours at room temperature, the reaction was poured into H2O (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with H2O (3×30 mL), followed by brine (1×30 mL) and then dried over Na2SO4. The organic phase was collected by filtration and concentrated by rotary evaporation. Flash chromatography on silica gel using 0-15% acetone/hexanes to yield Compound 1 as a yellow solid (6.5 mg, 28%). 1H NMR (400 MHz, CDCl3): δ 8.46 (d, J=8.5 Hz, 1H), 8.2 (d, J=8.7 Hz, 1H), 8.07 (d, J=7.3 Hz, 1H), 7.57 (t, J=7.9 Hz, 1H), 7.37 (t, J=8.2 Hz, 1H), 7.16 (d, J=7.2 Hz, 1H), 7.13 (d, J=8.4 Hz, 2H), 7.03 (d, J=8.3 Hz, 2H), 5.59 (q, J=6.3 Hz, 1H), 2.84 (s, 6H), 2.37 (s, 3H); 19F NMR (376 MHz, CDCl3): δ −76.3 (d, J=6.3 Hz). HRMS calc'd for C21H21F3NO3S3: 488.0636. found: 488.0647.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][C:8]3([CH2:14][CH2:13][N:12]([CH:15]([C:19]4[CH:24]=[CH:23][C:22]([C:25]5[CH:34]=[C:33]6[C:28]([CH:29]=[CH:30][CH:31]=[N:32]6)=[CH:27][CH:26]=5)=[CH:21][C:20]=4[F:35])[C:16](O)=[O:17])[CH2:11][CH2:10]3)[O:7][CH2:6][C:5]2=[O:36])[CH2:3][CH2:2]1.Cl.[CH3:38][N:39](C)[CH2:40]CCN=C=NCC.Cl.CNC>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]1([N:4]2[CH2:9][C:8]3([CH2:10][CH2:11][N:12]([CH:15]([C:19]4[CH:24]=[CH:23][C:22]([C:25]5[CH:34]=[C:33]6[C:28]([CH:29]=[CH:30][CH:31]=[N:32]6)=[CH:27][CH:26]=5)=[CH:21][C:20]=4[F:35])[C:16]([N:39]([CH3:40])[CH3:38])=[O:17])[CH2:13][CH2:14]3)[O:7][CH2:6][C:5]2=[O:36])[CH2:3][CH2:2]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)C(c1ccc(-c2ccc3cccnc3c2)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Agent: CN(C)c1ccncc1
Agent: CNC
Agent: Cl
Solvent: ClCCl
Product: CN(C)C(=O)C(c1ccc(-c2ccc3cccnc3c2)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
A solution of 2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)acetic acid (0.153 mmol) in dichloromethane (1 mL) was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.230 mmol) and 4-(dimethylamino)pyridine (0.766 mmol). This mixture was stirred at room temperature for 10 min at which point dimethylamine hydrochloride (0.306 mmol) was added. The reaction vessel was sealed and the reaction was stirred at room temperature overnight. At this point an additional portion of N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.230 mmol) was added. The reaction vessel was sealed and the reaction was stirred at room temperature overnight. The resulting reaction mixture was concentrated to dryness under a stream of nitrogen. Purification of the residue by reverse phase HPLC (20-65% acetonitrile/water with 0.1% NH4OH) followed by chiral HPLC (Chromegachiral CC4, methanol) and lyophilization from water (w/25% acetonitrile) afforded the title compound as a solid (25 mg, 30%). MS(ES)+ m/e 517.4 [M+H]+, >99% ee, αD=−69 deg (c=0.01, methanol).
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([O:12][CH3:13])[CH3:11])[CH:5]=1.[OH-].[Na+]>CO>[CH3:13][O:12][CH:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:14])=[O:2])[CH3:11]
Reactant: COC(=O)c1cccc(C(C)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(C)c1cccc(C(=O)O)c1

Procedure:
1.30 g (6.69 mmol) 3-(1-methoxy-ethyl)-benzoic acid methyl ester was dissolved in 20 mL MeOH and treated with 3.35 mL 4 M aqueous NaOH solution at RT for 5 h. The solvent was removed by distillation, the residue taken up in water and acidified with 4 M aqueous hydrochlorid acid. The precipitate was filtered off, washed with water and dried.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][O:6][C:7](=[O:12])[CH2:8][C:9](=[O:11])[CH3:10]>O>[CH3:5][O:6][C:7](=[O:12])[C:8](=[N:1][OH:3])[C:9](=[O:11])[CH3:10]
Reactant: COC(=O)CC(C)=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C(=NO)C(C)=O
Yield: 110.3 %

Procedure:
Part A: NaNO2 (13.8 gram) was dissolved in water (48 ml) at 4° C. The resulting solution was slowly added to a magnetically stirred solution of 3-oxo-butyric acid methyl ester (17.4 gram, 0.15 mol) while keeping the temperature <5° C. After stirring the mixture for two hours water (120 ml) was added and the resulting mixture was extracted twice with diethyl ether. The combined organic layers were successively washed with water and a 5% aqueous NaHCO3 solution. The organic layer was dried over MgSO4, filtered and thoroughly concentrated to give crude 2-hydroxyimino-3-oxo-butyric acid methyl ester (24 gram) as a colorless oil which was not further purified. 1H-NMR (400 MHz, CDCl3): 2.42 (s, 3H), 3.91 (s, 3H), 9.90 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:5][C:4](C(O)=O)([C:6]([OH:8])=[O:7])[CH2:3]1>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1
Reactant: CC1(C)CC(C(=O)O)(C(=O)O)C1
Solvent: c1ccncc1
Product: CC1(C)CC(C(=O)O)C1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
A solution of Intermediate 285C (250 mg, 1.452 mmol) in pyridine (5 mL) was stirred at 120° C. for 16 h. The reaction mixture was then cooled to RT, quenched with a 1.5 N aq. solution of HCl at 0° C., and extracted with diethyl ether (2×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and evaporated to afford Intermediate 285D as a viscous liquid (170 mg, 91% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.90-3.02 (m, 1H), 1.84-1.95 (m, 4H), 1.07-1.14 (m, 3H), 0.99-1.07 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1B(O)O)[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1I.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:23]1[CH:22]=[C:21]([Br:24])[CH:20]=[CH:19][C:18]=1[F:17])[CH3:2]
Reactant: Fc1ccc(Br)cc1I
Reactant: CCOc1ccc2ccccc2c1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOc1ccc2ccccc2c1-c1cc(Br)ccc1F
Temperature: 25 °C
Yield: 70 %

Procedure:
In the atmosphere of argon, 22.7 g of 2-ethoxynaphthalene-1-boronic acid, 30.0 g of 2-fluoro-5-bromoiodobenzene, 2.31 g of tetrakistriphenylphosphine palladium (0), 300 mL of toluene and 150 mL of an aqueous 2M solution of sodium carbonate were placed in a flask, and the resulting mixture was stirred with heating under reflux for 8 hours. After cooling to room temperature, the reaction solution was extracted with toluene. An aqueous phase was removed, and then, an organic phase was washed with saturated saline. The organic phase was dried with magnesium sulfate, and concentrated. Residues were purified by means of silica gel column chromatography, whereby 24.1 g (yield: 70%) of 2-ethoxy-1-(2-fluoro-5-bromophenyl)naphthalene was obtained.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[C@@H:15]([C:16]1[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=1)[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Br)cc1)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 17.9 %

Procedure:
To a solution of 76A (380 mg, 1.01 mmol) in THF (5 mL) at −78° C., was added NaHMDS (1.3 mL, 1.0M, 1.3 mmol), dropwise. The solution was stirred at −78° C. for 3 h. A solution of MeI (0.62 mL, 10 mmol) in 2 mL THF was added. The solution was stirred −78° C. for 3 h, and −40° C. for 1 h. The reaction was quenched with sat. NH4Cl and extracted with EtOAc (3×20 mL). The organic layer washed with brine, dried (Na2SO4), and concentrated. Purification via flash chromatography (0-30% EtOAc in hexanes) gives 76B (70 mg, 18%). MS (ESI) m/z 388.3 (M+H)+.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:13]=O>>[C:6]([C:5]1[CH:9]=[C:10]2[C:2](=[CH:3][CH:4]=1)[C:1](=[O:12])[O:11][CH2:13]2)([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: C=O
Product: O=C(O)c1ccc2c(c1)COC2=O

Procedure:
In the method of the invention, the terephthalic acid is condensed with paraformaldehyde liberating water, which reacts with the SO3. When the reaction is complete, 5-carboxyphthalide may be isolated as follows. The reaction mixture is hydrolysed with water. The condensed product, 5-carboxyphthalide inclusive possible diphthalide impurities may then be filtered off, and the 5-carboxyphthalide may be dissolved in aqueous medium by adjusting pH to about 6.7 to 7.3, leaving possible diphthalide impurities in the solid phase The diphthalide present may be filtered off whereupon 5-carboxyphthalide may be precipitated by acidification, filtered off, washed with water and dried.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([N+:18]([O-:20])=[O:19])=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1.O.O.O.O.[C:31]1([CH3:40])[CH:36]=[CH:35][C:34]([S:37]([O-:39])=[O:38])=[CH:33][CH:32]=1.[Na+]>C(O)C>[CH2:11]([O:10][C:8]([C:7]1[C:2]([S:37]([C:34]2[CH:35]=[CH:36][C:31]([CH3:40])=[CH:32][CH:33]=2)(=[O:39])=[O:38])=[N:3][C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:5]([N+:18]([O-:20])=[O:19])[C:6]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])[CH3:12]
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: CCOC(=O)c1c(Cl)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(S(=O)(=O)c2ccc(C)cc2)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Yield: 57.9 %

Procedure:
A mixture of 0.379 g of 2-chloro-3,4- diethoxycarbonyl-5-nitro-6-phenylpyridine, 0.5 g of sodium p-toluenesulfinate tetrahydrate and 15 ml of ethanol was heated under reflux for 3 hours. After concentration, the concentrate was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. After the solvent was distilled off, the residue was subjected to silica gel column chromatography with n-hexane/ethyl acetate (4:1) as the eluent. The eluate was concentrated to give crystals. The obtained crystals were recrystallized from the same solvent, to give 0.289 g of the title compound as colorless needles.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][CH2:7][CH:6]1[N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:18])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:2][CH2:3][CH:5]1[CH2:8][CH2:7][CH:6]1[N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:18]
Reactant: COC(=O)C1CCC1n1cnc2c(N)ncnc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ncnc2c1ncn2C1CCC1CO
Temperature: 0 °C
Yield: 97.1 %

Procedure:
9-(2-methoxycarbonyl-1-cyclobutyl)adenine (500 mg, 2.02 mmol) from Step A was dissolved in 250 mL of THF and the solution was cooled to 0° C. with stirring under a nitrogen atmosphere. Lithium aluminum hydride (115 mg, 3.03 mmol) was added and the reaction mixture was stirred for 30 minutes then quenched with 115 μL of water followed by 115 μL of 15% sodium hydroxide and 345 μL of water. The reaction mixture was filtered through Celite filter aid. The Celite was washed with ethyl acetate and the filtrater concentrated in vacuo to give 430 mg (97% yield) of the title compound; MS DCI-NH3M/Z: 220 (M+H)+ ; 1H NMR (d6-DMSO) δ 1.65 (m, 1H), 1.90 (m, 1H), 2.32 (m, 1H), 2.50 (m, 1H), 3.10 (m, 1H), 3.47 (t, 2H), 4.67-4.77 (m, 2H, H-1'+OH), 7.20 (bs, 2H), 8.12 (s, 1H), 8.27 (s, 1H); Analysis calculated for C10H13N5O: C, 54.78; H, 5.98; N, 31.95. Found: C, 54.79; H, 6.01; N, 31.66.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.[C:19](Cl)(=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>N1C=CC=CC=1.C(Cl)Cl>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][C:19](=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: CCCCCCCC(=O)Cl
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCC(=O)Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12

Procedure:
Analogously to Example 1, 400 mg (1.53 mmol) of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) in 8 ml of pyridine/methylene chloride 1:1 are reacted at 0° C. with 288 μl (1.68 mmol) of octanoic acid chloride to form 4-(3-chlorophenylamino)-3-octanoylamino-1H-pyrazolo[3,4-d]pyrimidine (18 hours RT): HPLC: tRet(grad20-100)=14.5; FAB-MS: (M+H)+=387.
Reaction SMILES: [Na].[H-].COCCO[Al+]OCCOC.[F:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24](O)=[O:25])=[CH:17][CH:16]=1.[OH-].[Na+]>C1C=CC=CC=1>[F:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[CH2:24][OH:25])=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccccc1Sc1ccc(F)cc1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: OCc1ccccc1Sc1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
36.1 ml of 70% sodium-bis-(2-methoxyethoxy)aluminum hydride in benzene are added dropwise over a one hour span to a stirring mixture of 15 g of 2-(4-fluorophenylthio)benzoic acid in 150 ml of benzene under nitrogen at ambient temperature. After total addition, the reaction mixture is stirred for an additional 30 minutes and then permitted to stand for 4 days. Thereafter, the reaction mixture is cooled to 0° C. before 100 mls of 10% sodium hydroxide are added with stirring. Following this addition, the layers separate and the aqueous layer is extracted twice with 100 ml portions of benzene. The combined benzene solutions are successively washed twice with 100 ml portions of water, washed once with a 60 ml portion of a saturated sodium chloride solution and dried, providing 2-(4-fluorophenylthio)benzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10](O)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:28][Si](C)(C)C>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]([NH2:28])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(Cl)c(Cl)c1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)C(OC1CCOCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
A cooled (0° C.) solution of rac-(3,4-dichloro-phenyl)-[(tetrahydro-pyran-4-yloxy)]-acetic acid (Example 4; 441 mg, 1.45 mmol) in dichloromethane (10 mL) and N,N-dimethylformamide (one drop) was treated with oxalyl chloride (2.0 M solution in dichloromethane, 1.01 mL, 2.02 mmol). The reaction was stirred at 0° C. for 1 h, then 1,1,1,3,3,3-hexamethyldisilazane (1.10 mL, 5.06 mmol) was added and the resulting cloudy mixture was sti f fed at 25° C. for 16 h. The reaction was quenched with methanol (10 mL), washed with an aqueous solution of 5% sulfuric acid (2×15 mL) and extracted with dichloromethane (3×10 mL). The combined organic extracts were washed with brine (1×10 mL), then were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) to provide rac-2-(3,4-dichloro-phenyl)-2-(tetrahydro-pyran-4-yloxy)-acetamide (278 mg, 63% yield) as a white solid, mp 81.9-83.6° C.; FAB-HRMS m/e calcd for C13H15NCl2O3 (M+H)+303.0428, found 303.0426.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=S)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.IC.[C:21]1([CH2:27][C:28]([NH:30][NH2:31])=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+].Cl>CC(C)=O.C(OCC)C>[CH2:27]([C:28]1[NH:18][C:16]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:31][N:30]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: NNC(=O)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: CCOCC
Solvent: CC(C)=O
Product: COc1cc(Nc2nnc(Cc3ccccc3)[nH]2)ccc1-n1cnc(C)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 26.7 %

Procedure:
A solution of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (400 mg, 1.52 mmol) in acetone (25 ml) was treated with iodomethane (0.14 ml, 2.29 mmol) and stirred at 20° C. for 16 h. The reaction mixture was concentrated and the crude S-methyl-isothiourea redissolved in ethanol (25 ml). Phenylacetic acid hydrazide (252 mg, 1.52 mmol) was added and the mixture was refluxed for 16 h under argon. After cooling to 20° C., 2 N sodium hydroxide solution (5 ml) was added and the mixture was refluxed for 2 h. After cooling to 20° C., the mixture was brought to pH 7 by careful addition of 1 N aqueous hydrochloric acid and then extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporation under reduced pressure to afford a sticky semisolid which was triturared in diethyl ether (3 mL). Filtration yielded the title compound (146 mg, 27%) as greyish solid.
Reaction SMILES: [CH2:1]([SiH:7]([Cl:9])[Cl:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(O)(C)C>[CH2:1]([Si:7]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10])([Cl:9])[Cl:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC[SiH](Cl)Cl
Reactant: C=CCCCCCCCCCC
Solvent: CC(C)O
Product: CCCCCCCCCCCC[Si](Cl)(Cl)CCCCCC
Temperature: 50 °C
Reaction time: 15 h

Procedure:
The above-mentioned n-hexyldichlorosilane in an amount of 3.33 g (18 millimol), 3.36 g (20 millimol) of 1-dodecene and as a catalyst a solution of H2PtCl6 ·6H2O in isopropanol (0.05 mol % relative to dichlorosilane) were charged in a flask equipped with a cooler and the mixture was reacted with stirring in an oil bath at 50° C. for 15 hours. After reaction, reaction solution was distilled to obtain n-hexyldodecyldichlorosilane. The infrared spectrum of this compound is shown in FIG. 2. The absorption of Si--H band at 2213 cm-1 vanished. The NMR spectra of this compound is shown in FIG. 6. The formula (n--C6H13)(n--C12H25)SiCl2 for this compound was confirmed.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:21]Br)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C)C=O.O.C(OCC)(=O)C>[N:33]([CH2:21][C@@H:20]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:19])[NH:17]2)[O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 25 °C
Yield: 88.3 %

Procedure:
(R)-8-(Benzyloxy)-5-(2-bromo-1-((tert-butyldimethylsilyl)oxy)ethyl)quinolin-2(1H)-one (10.0 g, 20.5 mmol) was dissolved in dimethyl formamide (180 mL) and water (20 mL). Sodium iodide (3.39 g, 22.6 mmol) and sodium azide (1.47 g, 22.6 mmol) were added sequentially. The reaction mixture was stirred at RT until all the solid was in solution. The solution was heated at 80° C. for 40 hours then cooled to RT and diluted with ethyl acetate (300 mL). The mixture was washed with water, brine (×2) and the organic extract was dried (magnesium sulfate), filtered and concentrated under reduced pressure. The crude residue was triturated with iso-hexane to afford the desired compound (8.16 g, 88%). The material was used without further purification in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:24]1[CH2:25][CH2:26][O:27][CH2:28][CH:29]=1)CCC>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:24]3[CH2:29][CH2:28][O:27][CH2:26][CH:25]=3)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(I)cc2C1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCOCC1
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(C3=CCOCC3)cc2C1

Procedure:
Prepared in analogy to Example A49(a) from 5-chloro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) and tributyl-(3,6-dihydro-2H-pyran-4-yl)-stannane. Yellow solid. MS (m/e): 282.3 ({37Cl}[M+H-Me2C═CH2]+, 49%), 280.3 ({35Cl}[M+H-Me2C═CH2]+, 100%).
Reaction SMILES: [NH2:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:6]=2[SH:5](=[O:19])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:4][C:3]1=[NH:20].[H-].[Na+].Cl[C:24](OCC)=[O:25]>O1CCCC1>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]2[N:2]3[NH:1][C:24]([OH:25])=[N:20][C:3]3=[N:4][SH:5](=[O:19])([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:11]=1
Reactant: N=C1N[SH](=O)(c2ccccc2)c2cc(Cl)ccc2N1N
Reactant: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[SH]1(c2ccccc2)N=C2N=C(O)NN2c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7.0 g of 4-amino-7-chloro-3,4-dihydro-3-imino-1-phenyl-1,2,4-benzothiadiazine-1-oxide, prepared according to Example 6, in 250 ml tetrahydrofurane are added 0.68 g of sodium hydride (80%) in portions. After stirring for 30 minutes at room temperature 2.4 ml ethyl chloroformate, dissolved in 10 ml tetrahydrofuran, are added dropwise. The mixture is stirred at room temperature for three hours, then separated from the precipitated sodium chloride and concentrated. The residue is dissolved in 150 ml toluene and boiled for 16 hours under reflux. The precipitated product is sucked off and crystallized from dimethylformamide/methanol as colorless crystals, m. pt. 343°-348° C.
Reaction SMILES: [N: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]([OH:13])=[O:12].OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>C(O)(=O)C.O=[Pt]=O>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: O=[Pt]=O
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CC(=O)O
Product: O=C(O)C1CCc2ccccc2N1

Procedure:
A mixture of PtO2 (25 wt. %) and 2-quinolinecarboxylic acid (Aldrich) in acetic acid was hydrogenated at RT under 60 Psi overnight. The reaction mixture was stripped to dryness to give the title compound.