Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:28])([CH2:25][CH:26]=[CH2:27])[CH2:9][CH2:10][NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:37](Cl)([O:39]C(=O)OC(Cl)(Cl)Cl)Cl.O>C(Cl)Cl>[CH2:25]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[O:28][C:37](=[O:39])[N:11]([C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:13]2)[CH2:10][CH2:9]1)[CH:26]=[CH2:27]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCC(O)(CCN[C@H]1CCCN(C(=O)OC(C)(C)C)C1)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C=CCC1(c2ccc(F)cc2)CCN([C@H]2CCCN(C(=O)OC(C)(C)C)C2)C(=O)O1
Temperature: 25 °C
Yield: 39.8 %

Procedure:
To a solution of (3S)-tert-butyl 3-(3-(4-fluorophenyl)-3-hydroxyhex-5-enylamino)-piperidine-1-carboxylate (500 mg, 1.27 mmol) and triethylamine (515 mg, 5.1 mmol) in dried methylene chloride (13 mL) at 0° C. was added triphosgene (126 mg, 0.42 mmol). The mixture was stirred at room temperature till the reaction was over. Water was added, and the layers were separated. The aqueous layer was extracted with methylene chloride. The combined organic layer was washed with water, dried over Na2SO4, and condensed to give the crude product, which was purified by column chromatography on silica gel to afford (3S)-tert-butyl 3-(6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)piperidine-1-carboxylate (70 mg, 13%). 1H NMR: (CDCl3): 1.37 (d, 9H), 1.43 (m, 1H), 1.64 (m, 1H), 2.22 (m, 2H), 2.64 (m, 5H), 3.11 (m, 1H), 3.91 (broad, 3H), 5.00 (q, 2H), 5.65 (m, 1H), 6.99 (t, 3H), 7.20 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[O:12])[NH:9][C:8]=2[CH:13]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[O:12])[NH:9][C:8]=2[CH:13]=1
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2o1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2oc(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
The mixture of 39-1 (5.1 g, 28.31 mmol), Pd/C (0.5 g) and HCO2NH4 (8.9 g, 141.57 mmol) in MeOH (200 mL) was stirred at room temperature overnight. Filtered with kiselguhr, concentrated in vacuo, the residue was added 5% NaHCO3 solution, collected the solid and washed with water (50 mL), dried in vacuo to get compound 39-2 as a brown solid (4 g, yield 94%).
Reaction SMILES: [OH:1][C@@H:2]1[C:19]2[C:18]3[N:17]([CH3:20])[C:16]4[N:15]=[C:14]5[CH:21]=[CH:22][CH:23]=[CH:24][C:13]5=[CH:12][C:11]=4[C:10](=[O:25])[C:9]=3[C:8]([O:26][CH3:27])=[CH:7][C:6]=2[O:5][C:4]([CH3:29])([CH3:28])[C@@H:3]1[OH:30].C[C:32](=[O:35])CC>C([O-])([O-])=O.[Na+].[Na+]>[CH3:27][O:26][C:8]1[C:9]2[C:10](=[O:25])[C:11]3[CH:12]=[C:13]4[CH:24]=[CH:23][CH:22]=[CH:21][C:14]4=[N:15][C:16]=3[N:17]([CH3:20])[C:18]=2[C:19]2[C@H:2]3[O:1][C:32](=[O:35])[O:30][C@H:3]3[C:4]([CH3:28])([CH3:29])[O:5][C:6]=2[CH:7]=1
Reactant: COc1cc2c(c3c1c(=O)c1cc4ccccc4nc1n3C)[C@@H](O)[C@@H](O)C(C)(C)O2
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cc2c(c3c1c(=O)c1cc4ccccc4nc1n3C)[C@H]1OC(=O)O[C@H]1C(C)(C)O2

Procedure:
635.62 mg of N,N′-carbonyldiimidazole are added to a solution of 200 mg of the compound of Example 3 in 90 ml of 2-butanone. The reaction mixture is refluxed for 4 days under argon and then, after cooling, diluted with an aqueous 5% Na2CO3 solution (15 ml) and extracted with ethyl acetate. The organic solutions are combined, dried over anhydrous sodium sulphate, filtered and then evaporated to dryness under reduced pressure. Chromatography on silica gel (dichloromethane and then a gradient of methanol in dichloromethane of from 0.1 to 1.5%) allow 78 mg of the expected product to be isolated.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([S:9][C:10]2[NH:14][N:13]=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].[CH3:15]S(C)=O.C(=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[N+:1]([C:4]1[S:8][C:7]([S:9][C:10]2[N:14]=[N:13][N:12]([CH3:15])[N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CS(C)=O
Reactant: O=[N+]([O-])c1cnc(Sc2nnn[nH]2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: Cn1nnc(Sc2ncc([N+](=O)[O-])s2)n1
Reaction time: 8 h

Procedure:
5-[(5-Nitrothiazol-2-yl)mercapto]tetrazole (2.44 g) is dissolved in 20 mL of dimethyl formamide, or a mixture of dimethylformamide and dimethylsulfoxide, containing 1.4 g of potassium carbonate and 1.3 g of methyl iodide. After stirring overnight the mixture is diluted with 40 ml of water. The precipitate is collected by vacuum filtration, dried and purified by high performance liquid chromatography on a reversed phased C-18 column using a gradient of acetonitrile in water to give 0.5 g of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25](Cl)=[O:26])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:28]([NH2:31])([CH3:30])[CH3:29].N1C=CC=CC=1>ClCCl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25]([NH:31][CH:28]([CH3:30])[CH3:29])=[O:26])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)N
Reactant: CCCCc1cc(C(=O)Cl)nn1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1cc(C(=O)NC(C)C)nn1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of 5-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]pyrazole-3-carbonyl chloride (550 mg) in dichloromethane (5 ml) were added isopropylamine (0.2 ml) and pyridine (0.2 ml), and the mixture was stirred at room temperature for 0.5 hours. The mixture was then evaporated to dryness under reduced pressure, and the residue was shaken with a mixture of 0.1 N hydrochloric acid (50 ml), dichloromethane (15 ml), and ether (60 ml). The mixture was allowed to separate into layers. The organic layer was washed with an aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate, followed by evaporation of the solvent to give a light yellow syrup (550 mg, 98%).
Reaction SMILES: P([O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]3[O:32][CH2:31][O:30][C:27]=3[CH:28]=2)[N:23]=[C:22]([C:33]2[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[C:35]([O:41][P:42]([O:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:43])[CH:34]=2)[CH:21]=1)(OCC1C=CC=CC=1)(OCC1C=CC=CC=1)=O>CO>[CH2:53]([O:52][P:42]([O:41][C:35]1[CH:34]=[C:33]([C:22]2[CH2:21][C:20](=[O:19])[C:29]3[C:24](=[CH:25][C:26]4[O:32][CH2:31][O:30][C:27]=4[CH:28]=3)[N:23]=2)[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=1)([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: COc1cc(OP(=O)(OCc2ccccc2)OCc2ccccc2)cc(-c2cc(OP(=O)(OCc3ccccc3)OCc3ccccc3)c3cc4c(cc3n2)OCO4)c1
Solvent: CO
Product: COc1cc(OP(=O)(OCc2ccccc2)OCc2ccccc2)cc(C2=Nc3cc4c(cc3C(=O)C2)OCO4)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 45 %

Procedure:
A suspension of 0.92 g (1.11 mmol) of 167 in 100 mL of methanol was stirred at 25° C. for 48 h. The precipitates were collected and purified by column chromatography (SiO2, EtOAc) to give 168.
Reaction SMILES: [OH:1][CH2:2]/[C:3](/[CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:12])=[CH:8]\[C:9]([OH:11])=O.Cl.[CH2:25]([NH2:27])[CH3:26].C(N(CC)CC)C>CN(C)C=O>[CH2:25]([NH:27][C:9](=[O:11])/[CH:8]=[C:7](/[CH3:12])\[CH2:6][CH2:5]/[CH:4]=[C:3](/[CH2:2][OH:1])\[CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH3:26]
Reactant: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C\C(=O)O)CO
Reactant: CCN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)/C=C(/C)CC/C=C(/CO)CC/C=C(\C)CCC=C(C)C

Procedure:
Following the same manner as in Example 9, the reaction and after-treatment were conducted by using 1.1 g of (E,Z,E), (E,E,E), (Z,Z,E) and (Z,E,E)-7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraenoic acid, 350 mg of ethylamine hydrochloride, 0.80 ml of diphenylphosphoric acid azide and 1.0 ml of triethylamine in 6.0 ml of N,N-dimethylformamide to afford 780 mg of the end product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[CH:10]([CH3:23])[N:9]=1.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>Cl>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[NH:12][C:11](=[O:22])[CH:10]([CH3:23])[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:14]=2[CH:15]=1
Reactant: CC1N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2NC1=O
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Product: CC1N=C(c2ccccc2F)c2cc(N)ccc2NC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
62.7 g (0.2 mol) of crude rac-5-(o-fluorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-one in 1 l of concentrated hydrochloric acid is treated portionwise while stirring with a total of 135.5 g (0.6 mol) of tin chloride, stirred at room temperature for 2 hours and the mixture is neutralised in the cold with 10 N sodium hydroxide. The aqueous phase is extracted with a total of 8 l of methylene chloride/ethanol (4:1), the combined organic extracts are washed with saturated sodium chloride solution, dried and evaporated. From ether there is obtained 7-amino-5-(o-fluorophenyl)-1,3-dihydro-3-methyl-2H-1,4-benzodiazepin-2-one of melting point 270°.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][O:28][CH:29]([O:35][CH3:36])[CH2:30][C:31](OC)=[O:32]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:31](=[O:32])[CH2:30][CH:29]([O:35][CH3:36])[O:28][CH3:27])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: COC(=O)CC(OC)OC
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: COC(CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)OC

Procedure:
The title compound, white solid (85 mg, 77%), MS (ISP) m/z=445.3 [(M+H)+], mp 240° C., was prepared in accordance with the general method of example 81 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and methyl 3,3-dimethoxy-propanoate.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12].C(=O)=O.C(Cl)Cl>C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12]
Reactant: COc1ccc(Nc2ccc(Cl)cc2C(=O)O)cc1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Product: O=C(O)c1cc(Cl)ccc1Nc1ccc(O)cc1
Reaction time: 20 h
Yield: 81 %

Procedure:
Boron tribromide (250 ml, 0.8 molar) in methylene dichloride was added dropwise over a period of 70 minutes to a mixture of 25.1 g of 5-chloro-2-(4-methoxyphenylamino)benzoic acid and 125 ml of dry methylene dichloride cooled to -70° C. (Dry Ice/methylene dichloride). The cooling bath was removed and the reaction mixture stirred for about 20 hours. The volatile solvent was stripped off and water (400 ml) was added dropwise to the residue cooled in an ice bath. The mixture was then made basic by addition of potassium carbonate and then acidified with dropwise addition of hydrochloric acid. The solid was collected by filtration and dried to give 19.3 g of 5-chloro-2-(4-hydroxyphenylamino)benzoic acid.
Reaction SMILES: [O-:1][S:2]([C:5]([F:8])([F:7])[F:6])(=O)=[O:3].C1(C)C=C(C)C=C(C)C=1[I+][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24].FC(F)(F)S([O-])=O.[Na+]>[Cu-]=O.CN(C)C=O>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[S:2]([C:5]([F:8])([F:7])[F:6])(=[O:3])=[O:1]
Reactant: Cc1cc(C)c([I+]c2ccccc2F)c(C)c1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: O=[Cu-]
Agent: O=S([O-])C(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1F)C(F)(F)F
Temperature: 25 °C

Procedure:
Mesityl-2-fluorophenyl iodonium triflate (Sanford M et al. JACS, 2005, 127, 7330 and Widdowson, D. et al. Tetrahedron Letters 2000, 41, 5393.) (0.1 g, 0.204 mmol), sodium trifluoromethanesulfinate (0.035 g, 0.224 mmol) and copper(I) oxide (2.92 mg, 0.020 mmol) were weighed into a reactor equipped with a magnetic stir bar. N,N-dimethylformamide (1 mL) was added, the reactor was capped and heated at 25° C. for 24 hours. HPLC analysis of the crude reaction mixture indicated the formation of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[N:15]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:13])=[O:12].[CH:32](O)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:33]1([CH:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:10]([CH2:9][CH2:8][CH2:7][N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[O:1])[S:11]([C:14]2[N:15]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:12])=[O:13])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: O=C1CCCN1CCCNS(=O)(=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Product: O=C1CCCN1CCCN(C(c1ccccc1)c1ccccc1)S(=O)(=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Yield: 35.7 %

Procedure:
Substantially the same procedure as in Reference Example 36 was repeated using N-[3-(2-oxopyrrolidinyl)propyl]-1-benzenesulfonylindole-2-sulfonamide (10.0 g, 21.67 mmol) and benzhydrol (6.00 g, 32.50 mmol) to give 4.85 g (yield: 36%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.Br[CH:12]([C:14](=[O:17])[CH2:15][CH3:16])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([O:8][CH:12]([C:14](=[O:17])[CH2:15][CH3:16])[CH3:13])[CH:7]=1
Reactant: COc1ccc(Br)cc1O
Reactant: CCC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)C(C)Oc1cc(Br)ccc1OC
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 5-bromo-2-methoxyphenol (50.0 g), 2-bromo-3-pentanone (68.1 g), potassium carbonate (52.8 g), and DMF (500 ml) was stirred at 70° C. for 2 hours. After being allowed to stand for cooling, water was added to the mixture followed by extraction with ether. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane:chloroform=1:1) to give Compound IIb-a (86.8 g, 94.0%) as a pale-yellow oily substance.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C@@H:3]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:4]([OH:6])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:45]([O:52][C:53]1[CH:58]=[CH:57][C:56]([CH2:59][C@H:60]([NH2:68])[CH2:61][N:62]2[CH2:67][CH2:66][O:65][CH2:64][CH2:63]2)=[CH:55][CH:54]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C=O)C.C(OCC)C>[CH2:45]([O:52][C:53]1[CH:58]=[CH:57][C:56]([CH2:59][CH:60]([NH:68][C:4](=[O:6])[CH:3]([N:2]([CH3:1])[CH3:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:61][N:62]2[CH2:67][CH2:66][O:65][CH2:64][CH2:63]2)=[CH:55][CH:54]=1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C
Reactant: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)CN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)CC(C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)CN1CCOCC1)N(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
(S)-2-Dimethylamino-4-methyl-pentanoic acid (55.3 mg, 0.347 mmol) was dissolved in dry DMF (3 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added in succession N,N-diisopropylethylamine (0.180 mL, 1.04 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (132 mg, 0.347 mmol, Novabiochem, La Jolla, Calif.). The resulting reaction mixture was stirred at that temperature for 30 minutes, (S)-2-(4-benzyloxy-phenyl)-1-morpholin-4-ylmethyl-ethylamine (153 g, 0.347 mmol, Example 3, Step D) was then added. After an additional 60 minutes stirring at 0° C., the reaction mixture was mixed with 60 mL of diethyl ether, and the resulting mixture was successively washed with saturated aqueous NaHCO3 solution and brine and then dried over Na2SO4. The solution was concentrated in vacuo, an oil was obtained. The crude product was purified by chromatography (silica gel, 10% methanol in chloroform) to give the title compound as a white solid (90 mg, 55%); mp 113-114° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:12]=O)[NH:6]2.[CH2:14]([O:16][C:17]([CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:18])[CH3:15]>C1COCC1>[CH2:14]([O:16][C:17](=[O:18])[CH:19]=[CH:12][C:5]1[NH:6][C:7]2[C:3]([CH:4]=1)=[C:2]([Br:1])[CH:10]=[C:9]([F:11])[CH:8]=2)[CH3:15]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc2c(Br)cc(F)cc2[nH]1
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1cc2c(Br)cc(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
To a solution of 4-bromo-6-fluoro-1H-indole-2-carbaldehyde (1.8 g, 7.4 mmol) in THF (100 mL) at r.t. was added (ethoxycarbonylmethylene)triphenylphosphorane (5 g, 14 mmol). The mixture was stirred for 2 hours at r.t. and the mixture was filtered through a silica gel pad eluted with 40% EtOAc and the filtrate was concentrated. The residue was purified by silica gel chromatography eluted with 20% EtOAc to give 1.6 g of the title compound.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:7]1([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21]C)[CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:8]1=[O:14])[CH3:6]>C(Cl)Cl>[CH2:5]([C:7]1([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:8]1=[O:14])[CH3:6]
Reactant: CCC1(c2cccc(OC)c2)CCCCNC1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC1(c2cccc(O)c2)CCCCNC1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 1M solution of BBr3 (7.1 mL, 7.1 mmol) in CH2Cl2 was added to 3-ethyl-3-(3-methoxy-phenyl)-azepan-2-one (as described in Step A above) (0.800 g, 0.323 mmol) dissolved in anhydrous CH2Cl2 (5 mL) at −78° C. After 48 h of stirring at room temperature, the reaction was quenched with H2O, extracted with CH2Cl2 (3×), dried (MgSO4), concentrated and purified using reverse phase chromatography (95/5-5/95 H2O/CH3CN with 0.1% TFA, flow=65 mL/min) to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[NH:7][CH2:8][CH:9]([C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:31]=1[CH3:45])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[Cl:29])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[C:53]1[C:54]([CH2:59][CH2:60][CH2:61][O:62][CH3:63])=[N:55][CH:56]=[CH:57][CH:58]=1)(=O)=O>>[Cl:27][C:26]1[CH:25]=[C:24]([CH3:28])[CH:23]=[C:22]([Cl:29])[C:21]=1[O:20][CH2:19][CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH:9]([C:30]2[CH:35]=[CH:34][C:33]([C:53]3[C:54]([CH2:59][CH2:60][CH2:61][O:62][CH3:63])=[N:55][CH:56]=[CH:57][CH:58]=3)=[CH:32][C:31]=2[CH3:45])[CH2:8][NH:7][C:6](=[O:46])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:12][CH:13]=1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3C)cc2)c(Cl)c1
Reactant: COCCCc1ncccc1OS(=O)(=O)C(F)(F)F
Product: COCCCc1ncccc1-c1ccc(C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 7, step 2 using tert-butyl{3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl}carbamate from EXAMPLE 9, step 1 and 2-(3-methoxypropyl)pyridin-3-yl trifluoromethanesulfonate (V.16) as starting materials. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (0 to 75%, in 30 min) afforded the desired compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]([CH3:21])([CH3:20])[CH2:3][CH:4]1[CH2:9][CH2:8][N:7](C(OCC2C=CC=CC=2)=O)[CH2:6][CH2:5]1>CO.[C].[Pd]>[CH3:21][C:2]([OH:1])([CH3:20])[CH2:3][CH:4]1[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]1
Reactant: CC(C)(O)CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(O)CC1CCNCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 122.1 %

Procedure:
To a solution of 8.5 g of benzyl 4-(2-hydroxy-2-methylpropyl)piperidine-1-carboxylate in 120 mL of methanol was added 500 mg of 10% palladium-carbon, followed by stirring under a hydrogen atmosphere at room temperature for 1 day. Insoluble material was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure to obtain 5.6 g of 2-methyl-1-(piperidin-4-yl)-2-propanol as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[C:4](C(O)=O)[S:3]1.[C:15](=O)([OH:17])[O-:16].[Na+:19]>O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][SH:3]1[C:15]([O-:17])=[O:16].[Na+:19]
Reactant: O=C([O-])O
Reactant: O=C(O)c1cc2ccccc2c(=O)s1
Agent: [Na+]
Solvent: O
Product: O=C([O-])[SH]1C=Cc2ccccc2C1=O
Reaction time: 2 h

Procedure:
To a stirred suspension of 4.50 g. (21.8 mM) of the carboxylic acid of Example 2 in 200 ml. of distilled water is added 1.833 g. (21.82 mM) of sodium bicarbonate. The mixture is then stirred at 25°-35° for 2 hours, whereupon all the solids dissolve. The solution is frozen and freeze-dried to give sodium 1-oxo-1H-2-benzothiopyran-2-carboxylate as a pale yellow solid, m.p. >350°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=[C:11]([C:19]([NH:21][C@@H:22]3[C@@H:27]([OH:28])[CH2:26]O[CH2:24][CH2:23]3)=[O:20])[CH:10]=2)=[CH:4][CH:3]=1.N[C@H:30]1CCOC[C@@H]1O>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=[C:11]([C:19]([NH:21][C@H:22]3[CH2:23][CH2:24][CH2:30][CH2:26][C@@H:27]3[OH:28])=[O:20])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1CCOC[C@@H]1O)c1cc(Cc2ccc(Cl)nc2)c2c(n1)CCCC2
Reactant: N[C@H]1CCOC[C@@H]1O
Product: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Cc2ccc(Cl)nc2)c2c(n1)CCCC2

Procedure:
4-[(6-Chloropyridin-3-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-5,6,7,8-tetrahydroquinoline-2-carboxamide was prepared by the procedure described for the synthesis of 1,5-anhydro-3-[({4-[(6-chloropyridin-3-yl)methyl]-5,6,7,8-tetrahydroquinolin-2-yl}carbonyl)amino]-2,3-dideoxy-L-threo-pentitol in Example 1, substituting (1S,2S)-2-aminocyclohexanol for (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[NH:7][N:6]=[C:5]([SH:8])[N:4]=1.[F:11][C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])I.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[F:18][C:13]([F:19])([C:12]([F:21])([F:20])[F:11])[C:14]([S:8][C:5]1[N:4]=[C:3]([C:2]([F:10])([F:9])[F:1])[NH:7][N:6]=1)([F:17])[F:16]
Reactant: FC(F)(F)C(F)(F)C(F)(F)I
Reactant: FC(F)(F)c1nc(S)n[nH]1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: FC(F)(F)c1nc(SC(F)(F)C(F)(F)C(F)(F)F)n[nH]1
Temperature: 25 °C
Yield: 17.6 %

Procedure:
5-Trifluoromethyl-1H-(1,2,4)-triazole-3-thiol (11.0 g), heptafluoro-1-iodopropane (3.5 g) and triethylamine (0.90 g) were stirred in DMF (10 ml) at 90° C. for 24 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and saturated aqueous solution of sodium chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure to obtain 3-heptafluoropropylsulfanyl-5-trifluoromethyl-1H-(1,2,4)-triazole (0.70 g).