Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].O1CCCC1.[C@@H:10]12[O:17][CH2:16][C@@H:14]([O:15]1)[CH:13]=[CH:12][C:11]2=[O:18]>C(OCC)(=O)C>[CH:1]([C@:11]1([OH:18])[CH:12]=[CH:13][C@H:14]2[CH2:16][O:17][C@@H:10]1[O:15]2)=[CH2:2]
Reactant: O=C1C=C[C@H]2CO[C@@H]1O2
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C[C@]1(O)C=C[C@H]2CO[C@@H]1O2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
9.5 ml (1 mol) of vinyl magnesium bromide was gradually added to 50 ml of a dry tetrahydrofuran solution containing 1 g of 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranos-2-ulose under stirring at 0° C. under an inert atmosphere of nitrogen gas. 30 minutes later, the ice bath was removed, and stirring was further continued for 30 minutes at room temperature. Completion of the reaction was confirmed by thin layer chromatography, and then a small amount of water was added to inactivate any excess Grignard reagent. Then, the solvent was distilled off under reduced pressure. The obtained crude product was dissolved in 200 ml of ethyl acetate and washed three times with 200 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained syrup product was purified by silica gel column chromatography (ethyl acetate: hexane=1:2) to obtain 0.9 g of the desired product (Compound No. 27). The NMR analytical data of this product are as follows.
Reaction SMILES: C([Li])CCC.[C:6]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:7][C:8]([OH:10])=O.N1C=CC=CC=1C1C=CC=CN=1.[F:27][C:28]1[C:36]([O:37][CH3:38])=[C:35]([F:39])[C:34]([F:40])=[CH:33][C:29]=1C(Cl)=O>O1CCCC1.C(OCC)(=O)C>[OH:10]/[C:8](/[C:29]1[CH:33]=[C:34]([F:40])[C:35]([F:39])=[C:36]([O:37][CH3:38])[C:28]=1[F:27])=[CH:7]\[C:6]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC(=O)O
Reactant: COc1c(F)c(F)cc(C(=O)Cl)c1F
Agent: [Li]CCCC
Agent: c1ccc(-c2ccccn2)nc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C(\O)c1cc(F)c(F)c(OC)c1F
Temperature: 25 °C

Procedure:
Compound B is prepared using the general method of Wierenga and Skulnick (Wierenga, W.; Skulnick, H. I. J. Org. Chem. (1979) 44: 310-311). n-Butyllithium (1.6 M in hexanes) is added to a cooled (−78° C.) solution of tetrahydrofuran (10 mL) containing ethyl hydrogen malonate (180 μL, 1.50 mmol) and 2,2′-bipyridyl (˜1 mg as indicator). The temperature of the reaction mixture is allowed to rise to ca. −5° C. during the addition of n-butyllithium. Sufficient n-butyllithium (2.8 mL, 4.48 mmol) is added until a pink color persists at −5° C. for 5-10 min. A solution of 2,4,5-trifluoro-3-methoxybenzoyl chloride (0.75 mmol, vide supra) in tetrahydrofuran (˜3 mL) is added in one portion to the reaction mixture that had been recooled to −78° C. The resulting mixture is allowed to warm to room temperature, diluted with ethyl acetate (50 mL), and quenched with a 1 M aqueous solution of hydrochloric acid. The organic layer is washed with a 5% aqueous solution of sodium bicarbonate (2×30 mL), followed by brine (2×50 mL), dried over sodium sulfate, and evaporated under reduced pressure to give the crude product. This material is purified by flash column chromatography (eluting with 20% v/v ethyl acetate in hexanes) to give pure B as a white solid. 1H NMR (300 MHz, CDCl3): (enol, predominant tautomer, ≧90%) 81.32 (t, JH-H=7.0 Hz, 3H, CO2CH2CH3), 4.02 (apparent t, JH-F=1.0 Hz, 3H, OCH3), 4.25 (q, JH-H=7.0 Hz, 2H, CO2CH2CH3), 5.79 (s, 1H, CH3C(OH)═CH—CO2CH2CH3), 7.39 (ddd, JH-F=11.0 Hz, 8.5 Hz, 6.5 Hz, 1H, aromatic), 12.68 (s, 1H, OH). 19F{1H} NMR (282 MHz, CDCl3): δ−146.8 (dd, JF-F=21.5 Hz, 10.5 Hz, 1F), −140.2 (dd, JF-F=21.5 Hz, 13.5 Hz, 1F), −131.3 (dd, JF-F=13.5 Hz, 10.5 Hz, 1F).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[CH2:12]([NH:19][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1cnc(Cl)cc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2,4-dichloro-5-nitropyridine E-2.1″ (10.000 g; 51.817 mmol) and benzylamine (5.552 g; 51.817 mmol) in NMP is added DIPEA (20.053 g; 155.451 mmol) at 0° C. The mixture is stirred at RT for 1 h. Water is added, precipitation of the product occurs. Product is filtered off and dried under vacuum.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][CH:7](Br)[CH:3]([CH2:4]2)[CH2:2]1.[Mg].Cl[C:11]1[C:16]([CH3:17])=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:14]=[CH:13][N:12]=1.[Cl-].[NH4+]>C1COCC1>[CH3:17][C:16]1[C:11]([CH:7]2[CH2:6][CH:5]3[CH2:4][CH:3]2[CH2:2][CH2:1]3)=[N:12][CH:13]=[N:14][C:15]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: BrC1CC2CCC1C2
Reactant: Cc1c(Cl)ncnc1-c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(-c2ccccc2)ncnc1C1CC2CCC1C2
Temperature: -20 °C

Procedure:
Into a reaction container, 4.2 g of exo-2-bromonorbornane, 0.70 g of magnesium, and 12 mL of THF were put, and this reaction container was heated by irradiation with microwaves (2.45 GHz, 100 W) for 10 minutes so that the Grignard reagent was prepared. Then, 2.3 g of 4-chloro-5-methyl-6-phenylpyrimidine obtained in Step 1 and 20 mL of THF were mixed, and while the mixture was being stirred at −20° C., the obtained Grignard reagent was added thereto. Further, 40 mg of Ni(dppe)Cl2 was also added, and the temperature of the mixture was increased to room temperature. An aqueous solution of ammonium chloride was added to this reaction solution, and an organic layer was extracted with ethyl acetate. The obtained organic layer was dried with magnesium sulfate. After the drying, the solution was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by flash column chromatography (silica gel) using a mixed solvent of dichloromethane and ethyl acetate as a developing solvent in a volume ratio of 9:1, to give the objective pyrimidine derivative Hnbmppm (yellow oily substance, 17% in yield). Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). The synthesis scheme of Step 2 is shown by (b-3).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=1)(=[O:23])=[O:22].FC(F)(F)O[C:38]1C=C(S(Cl)(=O)=O)C=C[CH:43]=1>>[CH2:38]([O:14][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[C:3]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:32])([F:33])[F:34])[CH:25]=3)(=[O:23])=[O:22])[CH:4]=2)=[CH:10][CH:11]=1)[CH3:43]
Reactant: O=S(=O)(Cl)c1cccc(OC(F)(F)F)c1
Reactant: O=C(O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3cccc(OC(F)(F)F)c3)c2)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3cccc(OC(F)(F)F)c3)c2)cc1

Procedure:
4-[4-Chloro-3-(3-trifluoromethoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=513.1 (M−H), was prepared in analogy to example 21, steps A to D. Step C was performed using 3-trifluoromethoxy-benzenesulfonyl chloride and yielded 4-[4-chloro-3-(3-trifluoromethoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([O:19][CH2:20][CH2:21][CH3:22])[C:6]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[O:9][C:7]=2[N:8]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[F:18][C:14]1[CH:13]=[C:12]([C:10]2[O:9][C:7]3[N:8]=[C:3]([CH2:2][C:28]4[CH:29]=[CH:30][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:26][CH:27]=4)[N:4]=[C:5]([O:19][CH2:20][CH2:21][CH3:22])[C:6]=3[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CCCOc1nc(CBr)nc2oc(-c3cccc(F)c3)nc12
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCOc1nc(Cc2ccc(C(F)(F)F)cc2)nc2oc(-c3cccc(F)c3)nc12
Yield: 13.3 %

Procedure:
146.5 mg of 5-bromomethyl-2-(3-fluoro-phenyl)-7-propoxy-oxazolo[5,4-d]pyrimidine and 114 mg of 4-trifluoromethyl-benzeneboronic acid were dissolved in 3 ml of toluene. 170 mg of tripotassium phosphate and 11.2 mg of tricyclohexylphosphine were added, and argon was bubbled through the mixture for 10 min. Then 4.5 mg of palladium(II) acetate were added, and the reaction mixture was heated to reflux for 8 h under argon. After cooling, ethyl acetate and water were added. The mixture was filtered through a ChemElut cartridge and the cartridge washed with ethyl acetate. The combined filtrates were evaporated in vacuo and the residue purified by preparative HPLC (method HPLC2). 23 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([CH2:21][CH2:22][C:23]([CH3:26])([Cl:25])[CH3:24])[N:5]([S:7]([NH:10]C(OCC1C=CC=CC=1)=O)(=[O:9])=[O:8])[CH3:6]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:27])[CH:4]([CH2:21][CH2:22][C:23]([CH3:24])([Cl:25])[CH3:26])[N:5]([S:7]([NH2:10])(=[O:8])=[O:9])[CH3:6]
Reactant: COC(=O)C(CCC(C)(C)Cl)N(C)S(=O)(=O)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(CCC(C)(C)Cl)N(C)S(N)(=O)=O
Reaction time: 4 h
Yield: 94.9 %

Procedure:
A solution of N-(carbobenzyloxyaminosulfonyl)-2-(3-methyl-3-chlorobutyl)-sarcosine methyl ester (23.61 g, 55.96 mmol) in 200 ml of methanol under nitrogen was cooled to 0° C. and 1.0 g of 10% Pd/C was added. The mixture was placed into a Parr Apparatus and hydrogenated at 50 psi for 4 hours. The catalyst was removed on a pad of CELITE® and the filtrate was concentrated in vacuo to afford 15.23 g (94.9%) of N-(aminosulfonyl)-2-(3-methyl-3-chlorobutyl)-sarcosine methyl ester (Formula VII: R=CH3 ; R1 =H; R2 =(CH2)2C (Cl) (CH3)2 ; R3 =CH3) as an oil.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:23][CH2:24][C:25]([NH:27][CH2:28][CH2:29][O:30][C@H:31]1[O:50][C@H:49]([CH2:51][O:52][C@H:53]2[O:61][C@H:60]([CH2:62][OH:63])[C@@H:58]([OH:59])[C@H:56]([OH:57])[C@@H:54]2[OH:55])[C@@H:47]([OH:48])[C@H:34]([O:35][C@H:36]2[O:44][C@H:43]([CH2:45][OH:46])[C@@H:41]([OH:42])[C@H:39]([OH:40])[C@@H:37]2[OH:38])[C@@H:32]1[OH:33])=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1>O.[Pd]>[NH2:11][C@@H:12]([CH2:23][CH2:24][C:25]([NH:27][CH2:28][CH2:29][O:30][C@H:31]1[O:50][C@H:49]([CH2:51][O:52][C@H:53]2[O:61][C@H:60]([CH2:62][OH:63])[C@@H:58]([OH:59])[C@H:56]([OH:57])[C@@H:54]2[OH:55])[C@@H:47]([OH:48])[C@H:34]([O:35][C@H:36]2[O:44][C@H:43]([CH2:45][OH:46])[C@@H:41]([OH:42])[C@H:39]([OH:40])[C@@H:37]2[OH:38])[C@@H:32]1[OH:33])=[O:26])[C:13]([OH:15])=[O:14]
Reactant: O=C(CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)NCCO[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O
Agent: [Pd]
Solvent: O
Product: N[C@@H](CCC(=O)NCCO[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (S)-benzyl 2-{[(benzyloxy)carbonyl]amino}-5-[(2-{[α-D-mannopyranosyl-(1→3)-[α-D-mannopyranosyl-(1→6)]-α-D-mannopyranosyl]oxy}ethyl)amino]-5-oxopentanoate (1.0 g, 1.11 mmol) and Pd/C (118 mg, 0.111 mmol) in water (10 mL) was allowed to stir under a balloon of H2 at room temperature for 16 hours. The catalyst was filtered off and washed with H2O (3×10 mL). The filtrate was concentrated to give the title compound. UPLC Method B: calculated for C25H44N2O19 676.25, observed m/e: 677.21 [M+1]; Rt=0.86 min.
Reaction SMILES: [S:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][NH:3]1.[H-].[Na+].[F:11][C:12]([F:16])([F:15])[CH2:13]I>CN(C)C=O>[F:11][C:12]([F:16])([F:15])[CH2:13][S:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]=1
Reactant: O=c1cc[nH]c(=S)[nH]1
Reactant: FC(F)(F)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccnc(SCC(F)(F)F)[nH]1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 113.5 %

Procedure:
To solution of 2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (14 g, 0.109 mol) in dimethylformamide (300 mL) was added NaH (13.1 g, 0.327 mol). When the addition was complete, the solution was stirred at 40° C. for 1.5 hours, and 2,2,2-trifluoroethyliodide (27.4 g, 0.131 mol) was added to the solution. The reaction was stirred at 40° C. for 3 hours. The solvent was removed and the residue was poured into water, the mixture was adjusted to pH 3-4 with dilute HCl and extracted with ethyl acetate, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to give 2-(2,2,2-trifluoroethylsulfanyl)-3H-pyrimidin-4-one (26 g, crude) as solid.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([C:16]([O:18]C)=[O:17])=[CH:11][CH:12]=2)[N:7]=[CH:6]1.O[Li].O>C1COCC1.CO.O>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([C:16]([OH:18])=[O:17])=[CH:11][CH:12]=2)[N:7]=[CH:6]1
Reactant: COC(=O)c1ccc2c(=O)n(Cc3ccccc3F)cnc2c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(=O)n(Cc3ccccc3F)cnc2c1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
Methyl 3-(2-flourobenzyl)-4-oxo-3,4-dihydroquinazoline-7-carboylate 300 mg, 0.92 mmol) was dissolved In a mixture of THF-MeOH—H2O (10 mL-3 mL-3 mL) followed by the addition of LiOH—H2O (200 mg). The mixture was stirred at RT over night. The solvent evaporated and the residue was dissolved in 4 mL of water and then acidified with 2N HCl to pH˜3. The solid was filtered off dried to gave 270 mg 3-(2-flourobenzyl)-4-oxo-3,4-dihydroquinazoline-7-carboxylic acid in 75% yield.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]([CH3:18])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)(=O)=O.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.CN1C(=O)CCC1>O>[CH3:18][N:8]([CH2:7][CH2:6][N:23]1[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1
Reactant: CN1CCNCC1
Reactant: CN(CCOS(C)(=O)=O)c1cccc([N+](=O)[O-])c1
Solvent: O
Solvent: CN1CCCC1=O
Product: CN1CCN(CCN(C)c2cccc([N+](=O)[O-])c2)CC1

Procedure:
A mixture of 2-[methyl(3-nitrophenyl)amino]ethyl methanesulfonate (Preparation Example 472) (1.0 g), 1-methylpiperazine (1.61 mL) and NMP (5 mL) was reacted at 130° C. for 30 minutes using a microwave reaction system. The reaction liquid was diluted with water, extracted with a mixed solvent of chloroform and methanol (10:1), and then washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol:saturated aqueous ammonia=10:1:0.1) to give N-methyl-N-[2-(4-methylpiperazin-1-yl)ethyl]-3-nitroaniline (890 mg) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][C:9](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:7][C:6]=1[C:21]([O:23][CH3:24])=[O:22])=[O:4].[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[C:6](=[CH:7][C:8]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([F:25])=[CH:27][CH:28]=2)=[C:9]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([F:25])=[CH:27][CH:28]=2)[CH:10]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)C1=C(C(=O)OC)CC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1
Solvent: CC(=O)O
Product: COC(=O)c1cc(Nc2ccc(F)cc2)c(Nc2ccc(F)cc2)cc1C(=O)OC

Procedure:
A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example 1a) and 2.3 ml (24 mmol) of 4-fluoroaniline in 60 ml of glacial acetic acid is boiled under reflux for 2 hours. The reactionmixture is cooled, the solvent is evaporated off and the dark-brown residueis dissolved in dichloromethane and the solution is washed in succession with 20 ml of 1N HCl, 50 ml of saturated NaHCO3 and twice with 20 ml of water, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with ethyl acetate/hexane 2:1 and the product fractions are concentrated by evaporation and recrystallized from ethyl acetate/hexane, yielding the title compound in the form of yellow crystals, 1H-NMR (CDCl3): δ=7.40 (s, 2H), 7.10-6.80 (m, 8H), 5.70 (br s2H), 3.83 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]=[C:12](SC)[O:13][CH3:14])(=[O:10])=[O:9].S(Cl)([Cl:20])(=O)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]=[C:12]([Cl:20])[O:13][CH3:14])(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=NS(=O)(=O)c1ccccc1C)SC
Solvent: ClCCl
Product: COC(Cl)=NS(=O)(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To 6.8 g of O-methyl S-methyl N-(2-methylphenylsulfonyl)carbonimidothioate in 20 ml of methylene chloride is added 6.8 g of sulfuryl chloride. The reaction mixture is stirred under a nitrogen atmosphere at ambient temperature for 2 hours, and then refluxed for an additional 2 hours. Removal of the solvent under reduced pressure gives 5.0 g of methyl N-(2-methylphenylsulfonyl)carbonimidochloridate as a light yellow oil. This product is used without further purification in the reaction described in Example 3.
Reaction SMILES: [C:1]1([CH:8]([CH3:10])[CH3:9])[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[OH2:11]>>[C:1]1([CH:8]([CH3:10])[CH3:9])[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[CH2:2]([CH:1]([CH2:6][CH2:5][CH2:4][CH3:7])[CH2:8][OH:11])[CH3:3]
Reactant: O
Solvent: Cc1ccc(C(C)C)cc1
Product: CCCCC(CC)CO

Procedure:
Solvent (500 g; 90% para-cymene/10% 2-ethylhexanol) and water (2000 g) was charged to a 5L, 3-necked flask fitted with stirrer, thermometer and distillation head. The mixture was heated to reflux, and oil/water fractions were separated into oil and aqueous layers and the layers weighed to determine the oil:water ratio throughout the distillation. The oil composition was determined by gas/liquid chromatography analysis. Results in Table 4 show that the percent composition relative to the para-cymene and 2-ethylhexanol is substantially unchanged with nearly 95% of solvent recovered.
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[CH:10][C:11]=1[CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1.[Cl-].[NH4+]>C1COCC1>[Si:15]([O:14][CH2:13][CH2:12][C:11]1[CH:10]=[CH:9][S:8][C:7]=1[CH:27]([C:26]1[CH:29]=[CH:30][C:23]([F:22])=[CH:24][CH:25]=1)[OH:28])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccsc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1ccsc1C(O)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
n-Butyllithium in hexanes (12.7 mL, 1.6 M, 20.3 mmol) was added dropwise to a solution of (2-(2-bromothiophen-3-yl)ethoxy)(tert-butyl)dimethylsilane (5.9 g, 18.4 mmol) in anhydrous THF (15 mL) at −78° C. The resulting mixture was stirred at −78° C. for 30 min and 4-fluorobenzaldehyde (2.5 g, 20.3 mmol) in THF was added slowly. The mixture was stirred at −78° C. for 2 h and then warmed up to rt. After cooling again to 0° C. 50 mL of aqueous saturated ammonium chloride was added and the mixture was extracted with ethyl acetate (3×80 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The solvent was evaporated in vacuo and the product was purified by flash chromatography eluting with ethyl acetate/hexane (1:3) to afford the title compound as a solid (3.8 g, 59%).
Reaction SMILES: [CH3:1][N:2]([C:4]1([CH2:10][NH2:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:3].[CH2:12]([O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([NH:11][CH2:10][C:4]2([N:2]([CH3:1])[CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)=[O:22])=[CH:24][CH:25]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Reactant: CN(C)C1(CN)CCCCC1
Product: CCCCOc1ccc(C(=O)NCC2(N(C)C)CCCCC2)cc1

Procedure:
Synthesised from 1-(dimethylaminocyclohexyl)methylamine and 4-butyloxy benzoyl chloride following the procedure of Example 1 (g and purified by LCMS to obtain the product as a trifluoroacetate salt. 1H NMR (CDCl3) δ: 0.97 (t, 3H, J=4 Hz), 1.18 (m, 1H), 1.49 (m, 2H), 1.67 (m, 4H), 1.80 (m, 5H), 2.01 (d, 2H, J=3 Hz), 2.79 (s, 6H), 4.01 (m, 4H), 6.93 (d, 2H, J=4 Hz), 8.18 (d, 2H, J=4 Hz), 8.47 (m, 1H), 11.90 (s, 1H). LCMS m/z 333.2 (MH+; 96.5%). HRMS (FAB) calc. 333.2539, found 333.2536.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][N:17]([CH2:19][O:20][CH3:21])[CH:18]=3)[S:13][C:6]=12.[Cl-].[NH4+]>CCO.O.[Fe]>[F:1][C:2]1[CH:25]=[C:24]([CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][N:17]([CH2:19][O:20][CH3:21])[CH:18]=3)[S:13][C:6]=12)[NH2:26]
Reactant: COCn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a suspension of 94 (132 mg, 0.33 mmol) in EtOH (7 ml) and water (3 ml) was added ammonium chloride (16 mg, 0.9 eq, 0.3 mmol) and Fe (157 mg, 8.5 eq, 0.28 mmol) and the reaction mixture was heated to reflux for 2 hours. The reaction mixture was cooled to RT, filtered through celite then concentrated. The mixture was partitioned between DCM/water and the DCM was collected, dried over anhydrous sodium sulfate, filtered and concentrated. Crude 95 was used directly in the next step (122 mg, 100% yield). MS (m/z): 371.1 (M+H).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:26]([O:28][CH3:29])=[O:27])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[NH:18][CH2:17][CH2:16][CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:31]CCl.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:26]([O:28][CH3:29])=[O:27])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]([CH3:31])[CH2:17][CH2:16][CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCCNc1ccccc1-3
Reactant: ClCCCl
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCCN(C)c1ccccc1-3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 14-cyclohexyl-5,6,7,8-tetrahydroindolo[1,2-e][1,5]benzodiazocine-11-carboxylate in DCE (0.05 M) 1 eq of formaldehyde (37 wt. % sol. in H2O) and 2 eq of NaBH(OAc)3 were added and the solution stirred at RT for 1 h. The reaction mixture was diluted with EtOAc. The organic phase was washed with NaHCO3 (s.s.) and brine. The organic phase was dried over Na2SO4 filtered and concentrated in vacuo. The title compound was used directly in the next step; MS (ES+) m/z 403 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[O:10]1[CH2:15][CH2:14][CH:13](O)[CH2:12][CH2:11]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)=[CH:4][C:3]=1[F:9]
Reactant: OC1CCOCC1
Reactant: Oc1ccc(Br)c(F)c1
Product: Fc1cc(OC2CCOCC2)ccc1Br

Procedure:
The title compound was prepared from 4-bromo-3-fluorophenol and tetrahydro-4H-pyran-4-ol in analogy to Example 9c): MS (EI): 274 and 276 M+.