Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([NH2:30])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[C:31]1([C@H:37]([NH:39][C:40]([NH2:42])=[O:41])[CH3:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].O1CCOCC1>[NH2:30][C:8]1[C:5]2[CH:6]=[N:7][C:2]([NH:42][C:40]([NH:39][C@@H:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH3:38])=[O:41])=[CH:3][C:4]=2[N:10]([C:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:9]=1
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Reactant: Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Agent: Cl[Pd+]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: NCCc1[c-]cccc1
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 50.8 %

Procedure:
6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-amine (500 mg, 1.217 mmol), (R)-1-(1-phenylethyl)urea (400 mg, 2.434 mmol), cesium carbonate (1023 mg, 3.14 mmol) and chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-i-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (58.3 mg, 0.073 mmol) were charge in a 40 mL vial with dioxane (11 ml). System was degassed and stirred at 100° C. for 3 hours. Reaction mixture was evaporated in vacuo and purified by normal phase column chromotography eluting with hexane/EtOAc (0-50%) affording (R)-1-(3-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (333 mg, 0.618 mmol, 50.8% yield) as an off white solid. 1H NMR (500 MHz, dmso) δ 8.82 (s, 1H), 8.51 (s, 1H), 8.32 (bs, 1H), 7.38-7.13 (m, 19H), 6.49 (s, 1H), 5.88 (s, 2H), 4.85-4.75 (m, 1H), 1.35 (d, 3H). MS ESI calc'd. For C34H30N6O[M+H]+ 539. found 539.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.CC1C=CC(C2[O:21]C=CN=2)=CC=1>>[O:10]1[CH:11]=[CH:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH:1]=[O:21])=[CH:7][CH:6]=2)=[N:9]1
Reactant: Cc1ccc(-c2ccon2)cc1
Reactant: Cc1ccc(-c2ncco2)cc1
Product: O=Cc1ccc(-c2ccon2)cc1

Procedure:
The title compound is prepared by a procedure analogous to Step B of Reference Example 73 by substituting 3-(4-methylphenyl)isoxazole (prepared as described in J. Organomet. Chem. 1966, 6, 598) for the 2-(4-methylphenyl)oxazole of Step B of Reference Example 73. MS 174 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:24][C@H:25]([OH:47])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:30]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:29]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[CH2:69]([CH:76]1[CH2:81][CH2:80][NH:79][CH2:78][CH2:77]1)[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1>ClCCl.C(#N)C.C(N(CC)CC)C>[CH2:1]([N:8]([CH:9]1[CH2:10][CH2:11][CH:12]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([N:79]3[CH2:80][CH2:81][CH:76]([CH2:69][C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)[CH2:77][CH2:78]3)=[O:20])=[CH:22][CH:23]=2)[CH2:13][CH2:14]1)[CH2:24][C@H:25]([OH:47])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[C:30]([NH:42][S:43]([CH3:46])(=[O:44])=[O:45])[CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(C(=O)O)cc3)CC2)ccc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN(Cc2ccccc2)C2CCC(c3ccc(C(=O)N4CCC(Cc5ccccc5)CC4)cc3)CC2)ccc1OCc1ccccc1
Reaction time: 24 h

Procedure:
A solution of 2 g (2.88 mmol) of trans-4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}benzoic acid (Preparation 1), 0.78 g (5.76 mmol) of 1-hydroxybenzotriazole, 1.1 g (5.76 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 1.2 ml of triethylamine and 1.01 ml (5.76 mmol) of 4-benzylpiperidine in a mixture of 26 ml of dichloromethane and 5 ml of acetonitrile is stirred for 24 hours. The solvents are evaporated under reduced pressure. Dichloromethane and water are added and the organic phase is washed three times with water. The organic phases are dried over magnesium sulfate and concentrated under reduced pressure. N-[5-({(2S)-3-[benzyl(4-{4-[(4-benzylpiperidin-1-yl)carbonyl]phenyl}-cyclohexyl)amino]-2-hydroxypropyl}oxy)-2-(benzyloxy)phenyl]methanesulfonamide is obtained in the form of a white solid (1.355 g, 57%) after purification on silica gel (eluent: dichloromethane/methanol 90/10). [M+H+]=816.6.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12](=O)[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:6][CH:5]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:22])([F:21])[F:1])=[CH:5][CH:6]=2)[N:11]=1
Reactant: O=c1[nH]c(-c2ccc(OC(F)(F)F)cc2)cc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)Oc1ccc(-c2cc3ccccc3c(Cl)n2)cc1

Procedure:
The resulting 3-(4-trifluoromethoxyphenyl)isoquinolin-1-one (3.01 g) was reacted with phosphorus oxychloride (20 ml) according to the method of Example 10-2, to give 1-chloro-3-(4-trifluoromethoxyphenyl)isoquinoline, which was then reacted as it was with N-ethylpiperazine (40 ml) at 90° C. overnight. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and purified water. The ethyl acetate layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 3.65 g of the free compound of the title compound as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.O/[N:33]=[C:34](\[NH2:44])/[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1>CN(C=O)C.CCOC(C)=O>[CH3:43][O:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][C:34]2[N:33]=[C:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]3)[O:16][N:44]=2)=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: COc1ccc(C/C(N)=N/O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cc2noc(C3CCN(C(=O)OC(C)(C)C)CC3)n2)cc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
1-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid (2.29 g, 10.0 mmoles) in 10 mL DMF was treated with 1,1′-carbonyldiimidazole (1.62 g, 10 mmoles, 1 eq.) at ambient temperature for 30 min until CO2 evolution ceased. (1Z)-N′-hydroxy-2-(4-methoxyphenyl)ethanimidamide [J. Med. Chem., 36(11), 1529 (1993)] (10.0 mmoles, 1 eq.) was dissolved in 5 mL DMF and added to the reaction mixture. The reaction mixture was heated at 70° C. for 6 h then at 120° C. for an additional 6 h. The reaction mixture was diluted with EtOAc and washed successively with water, 1N citric acid, saturated aqueous NaHCO3, and brine. The organic phase was isolated, dried over MgSO4, filtered and concentrated to give the title compound as an amber oil. 1H NMR (300 MHz, CDCl3) δ 7.26 (d, 2H, J=8.5 Hz), 6.88 (d, 2H, J=8.5 Hz), 4.10 (m, 2H), 4.00 (s, 2H), 3.80 (s, 3H), 3.08 (m, 1H), 2.97-2.90 (m, 2H), 2.04 (m, 2H), 1.87-1.73 (m, 2H), 1.47 (s, 9H). ES-LCMS m/z 395.99 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[CH:4]=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(O)(=O)C>[C:7]([C:6]1[C:5]([CH3:9])=[CH:4][N:3]([C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[C:2]=1[NH:1][C:19](=[O:21])[CH3:20])#[N:8]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C)c(-n2cc(C)c(C#N)c2N)c(C)c1
Solvent: CC(=O)O
Product: CC(=O)Nc1c(C#N)c(C)cn1-c1c(C)cc(C)cc1C
Yield: 105.2 %

Procedure:
A mixture of the purified compound of step A (3.000 g, 12.54 mmol) and acetic anhydride (1.410 g, 1.31 ml, 13.82 mmol) in 3 ml of acetic acid was refluxed for 45 minutes, cooled and poured onto crushed ice and extracted with ethyl acetate. The organic layer was neutralized, dried and concentrated to give 3.71 g (105%) of dark-pink glass foam. 1H NMR (CDCl3) □ 1.95(s, 6H), 2.2(s, 3H), 2.32 (s, 3H), 6.2(s, 1H), 6.8(brs, 1H, NH), 6.9(s, 2H) ppm.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[CH:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:17][CH2:18][C@H:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([C:28]([NH2:30])=[O:29])[CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[NH:12]1[C:13]2[C:9](=[CH:8][C:7]([N:1]3[CH2:6][CH2:5][N:4]([CH2:17][CH2:18][C@H:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]([C:28]([NH2:30])=[O:29])[CH2:20]4)[CH2:3][CH2:2]3)=[CH:15][CH:14]=2)[CH:10]=[CH:11]1
Reactant: c1cc2cc(N3CCNCC3)ccc2[nH]1
Reactant: NC(=O)N1C[C@@H](CCBr)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: NC(=O)N1C[C@@H](CCN2CCN(c3ccc4[nH]ccc4c3)CC2)c2ccccc21
Yield: 45.3 %

Procedure:
A mixture of 5-(piperazin-1-yl)-1H-indole (3.37 g, 0.017 mol), (S)-3-(2-bromoethyl)-2,3-dihydro-1H-indole-1-carboxylic acid amide (3.0 g, 0.11 mol), potassium carbonate (2.31 g, 0.017 mol) in butanone (450 mL) was boiled under reflux for 12 h. The mixture was filtered, concentrated in vacuo, and the residue was purified by flash chromatography (ethyl acetate/ethanol/triethylamine 70:25:5). The purified residue was precipitated from ethyl acetate to give the title compound as a white solid (3.0 g). Assignment of the optical rotation was done in dimethyl sulfoxide.
Reaction SMILES: C(OC([N:8]1[C:12]2[C:13]([F:19])=[CH:14][C:15]([NH2:18])=[C:16]([CH3:17])[C:11]=2[N:10]=[CH:9]1)=O)(C)(C)C.[ClH:20]>>[ClH:20].[CH3:17][C:16]1[C:11]2[NH:10][CH:9]=[N:8][C:12]=2[C:13]([F:19])=[CH:14][C:15]=1[NH2:18]
Reactant: Cc1c(N)cc(F)c2c1ncn2C(=O)OC(C)(C)C
Agent: Cl
Product: Cc1c(N)cc(F)c2nc[nH]c12

Procedure:
1-tert-Butoxycarbonyl-4-methyl-5-amino-7-fluorobenzimidazole (1 g) (prepared as described in U.S. Pat. No. 5,478,858 issued to Cupps and Bogdan, Dec. 26, 1995, incorporated herein by reference) and 6N HCl (10 mL) are combined and heated to reflux while stirring. After completion of the t-BOC group deprotection, the reaction mixture is concentrated under reduced pressure and dried to furnish 4methyl-5-amino-7-fluorobenzimidazole hydrochloride.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:9]>C(O)C>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([CH:8]([C:7]2[CH:18]=[C:19]([O:23][CH3:24])[C:20]([O:21][CH3:22])=[C:5]([O:4][CH3:3])[CH:6]=2)[OH:9])=[CH:15][CH:14]=1
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(O)c2cc(OC)c(OC)c(OC)c2)cc1
Yield: 94.3 %

Procedure:
Sodium borohydride (76 mg, 2 mmol) was added in small portions to a well-stirred solution of 3,4,4',5-tetramethoxybenzophenone (27) (302 mg, 1 mmol) in ethanol (15 mL) at 0° C. in 15 min and the resultant mixture was stirred for 3 h at room temperature. The reaction was quenched by careful addition of glacial acetic acid (1 mL), and the solvents were removed at reduced pressure. The residue was poured into water, and the product was extracted with ether (2×50 mL). The combined ether extracts were washed with saturated NaHCO3 solution, followed by water, and dried (Na2SO4). Evaporation of solvents and crystallization of the residue from EtOAc-hexane gave product 28 as a white crystalline solid (287 mg, 94%); mp 104°-105° C.; 1H NMR (CDCl3, 200 MHz) δ7.29 (d, J=8.7 Hz, 2H), 6.88 (d, J=8.7 Hz, 2H), 6.60 (s, 2H), 5.73 (d, J=3.2 Hz, 1H), 3.82 (s, 9H), 3.80 (s, 3H), 2.32 (d, J=3.2 Hz, 1H); CIMS (isobutane) m/e 305 (MH+, 100). Anal. (C17H20O5) C, H.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)C1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@@H](Oc2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Palladium (10 wt. %) on carbon (200 mg) was added in one portion to a solution of ethyl 4-(4-nitrophenoxy)cyclohexanecarboxylate (6.95 g, 23.7 mmol) in EtOH (200 mL) and the reaction mixture was stirred under a hydrogen atmosphere at ambient temperature for 16 h. The reaction mixture was filtered and concentrated in vacuo to leave the title compound as a yellow oil (6.24 g, 100%).
Reaction SMILES: C(O[N:6]([C:10]1[N:15]=[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=[CH:12][CH:11]=1)[C:7](C)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:7][NH:6][C:10]1[N:15]=[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)Cc1cccc(N(OC(C)(C)C)C(C)=O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cc1cccc(NC)n1
Reaction time: 16 h
Yield: 93.6 %

Procedure:
To a solution of ethyl 2-{6-[(tert-butoxy)-N-methylcarbonylamino]-2-pyridyl}acetate (3.56 g, 12.1 mmol) in dichloromethane (15 ml) was added trifluoroacetic acid (8 ml). The reaction was stirred for 16 h. The solvent was removed under vacuum and the crude product was chromatographed over silica gel to yield 2.2 g (100%) of Ethyl 2-[6-(methylamino)-2-pyridyl]acetate.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11]C)=[CH:7][CH:6]=1)=[CH2:4]>C(O)(=O)C.[Pd]>[F:1][C:2]([F:13])([F:14])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:4]
Reactant: C=C(c1ccc(OC)cc1)C(F)(F)F
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(c1ccc(O)cc1)C(F)(F)F

Procedure:
At 60 to 70° C. and under atmospheric pressure, 9.2 g of 4-[1-(trifluoromethyl)vinyl]-1-methoxybenzene in 50 ml of glacial acetic acid were hydrogenated in the presence of 0.26 g of Pd/C (10%) until no further uptake was visible. The catalyst was filtered off, the reaction solution was mixed with 22.7 g of aqueous hydrobromic acid (48%) and heated under reflux for 21 h. The reaction solution was concentrated, taken up in ethyl acetate, washed with aqueous sodium hydrogen carbonate, dried and concentrated to give the title product which was reacted further without any purification.
Reaction SMILES: F[B-](F)(F)F.C([O+:8]([CH2:11][CH3:12])[CH2:9]C)C.[CH3:13][C:14]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)C(=O)[NH:16][CH:15]=1.O.[OH-].[Na+]>C(Cl)Cl>[CH2:11]([O:8][C:9]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)[C:14]([CH3:13])=[CH:15][N:16]=1)[CH3:12]
Reactant: CC[O+](CC)CC
Reactant: Cc1c[nH]c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOc1ncc(C)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.2 %

Procedure:
A solution of triethyloxonium tetrafluoroborate (9.0 g, 47 mmol) in DCM (62 mL) was added to a stirred solution of 5-methyl-1-[3-(trifluoromethyl)phenyl]-1,3-dihydro-2H-imidazol-2-one (9.0 g, 37 mmol) in DCM (124 mL) under a nitrogen atmosphere. The solution was stirred at RT for 2.5 h then treated with water (50 mL) then 1 M sodium hydroxide (50 mL). The phases were partitioned. The aqueous phase was washed with DCM (2×50 mL). The combined organic phase was dried (sodium sulfate). The solution of the crude product was filtered through 2×50 g flash SCX 2 cartridges. Each cartridge was rinsed with 10% methanol in DCM (100 mL) then the product fraction was eluted with 2M methanolic ammonia solution (100 mL). The fractions recovered with methanolic ammonia were combined and concentrated in vacuo to afford the title compound (7.92 g) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7](/[CH:10]=[CH:11]/[C:20]2[CH:23]=[CH:24][C:17]([Br:16])=[CH:18][CH:19]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(Br)cc1
Product: O=S(=O)(/C=C/c1ccc(Br)cc1)Cc1ccc(Br)cc1
Yield: 88 %

Procedure:
A solution of 4-bromobenzyl sulfonylacetic acid (0.01 mol) and 4-bromobenzaldehyde (0.01 mol) was subjected to Procedure 1. The title compound was obtained in 88% yield.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:16]([OH:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[C:51]1[CH:58]=[CH:57][C:54]([CH:55]=[O:56])=[CH:53][CH:52]=1>C1COCC1.O>[CH3:1][C:2]1[C:3]([CH:16]([O:18][C:51]2[CH:58]=[CH:57][C:54]([CH:55]=[O:56])=[CH:53][CH:52]=2)[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1cc2c(cc1C(C)O)C(C)(C)CCC2(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2c(cc1C(C)Oc1ccc(C=O)cc1)C(C)(C)CCC2(C)C

Procedure:
A solution of 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanol (246 mg; 1.0 mmol), triphenylphosphine (262 mg; 1.0 mmol), diethyl azodicarboxylate (0.153 ml; 1.0 mmol) and 4-hydroxybenzaldehyde (183 mg; 1.5 mmol) in THF (20 ml) was stirred at 0° C. for 1.5 hours and for 16 hours at room temperature. Water was added (20 ml) and the mixture was extracted with methylene chloride (3×25 ml). The combined organic phases were dried and evaporated. The residue was purified on column chromatography using ethyl acetate: hexane (1:3) as eluent. Yield 180 mg.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([O:12][CH3:13])[CH:3]=1.[NH2:14][CH2:15][CH2:16][NH2:17].COCC(O)C>>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([NH:14][CH2:15][CH2:16][NH2:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: NCCN
Reactant: COc1cc(Cl)c2ccccc2n1
Solvent: COCC(C)O
Product: COc1cc(NCCN)c2ccccc2n1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
4-Chloro-2-methoxy-quinoline (484 mg, 2.5 mmol) and 1,2-diaminoethan (751 mg, 12.5 mmol) were mixed with 1-methoxy-2-propanol and stirred at 110° C. for 24 hours. The mixture was evaporated to dryness and the residue was purified by column chromatography (pre-packed silica column, gradient of ethyl acetate/methanol each containing 1% triethylamine). 0.324 g were obtained (1.49 mmol; 60%). MS (APCI) m/z=218.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].C[N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=O>>[N:16]1([C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:20][CH:19]=[CH:18][CH2:17]1
Reactant: Brc1ccc(Br)nc1
Reactant: CN1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1ccc(N2CC=CC2)nc1

Procedure:
In 100 ml of 1-methyl-2-pyrrolidone was dissolved 10 g of 2,5-dibromopyridine which was then added with 3.5 ml of 3-pyrrolidine, along with 8.7 g of potassium carbonate at room temperature, followed by reacting them at 100° C. for 24 hours. After completion of the reaction, the same post-treatment was carried out as in Preparation Example 3 to obtain the title compound. 8 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11](=[O:20])(=[O:19])[NH:12][CH2:13][C:14](OCC)=O)=[CH:6][CH:5]=1.C[O-:23].[Na+]>CO>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][C:13](=[O:23])[NH:12][S:11]2(=[O:20])=[O:19])=[CH:6][CH:5]=1
Reactant: C[O-]
Reactant: CCOC(=O)CNS(=O)(=O)Nc1ccc(C(=O)OC)cc1
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(N2CC(=O)NS2(=O)=O)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Compound 102 was dissolved in 5 mL of methanol and cooled to 0° C. A solution of freshly prepared NaOMe in methanol was added, and the solution was warmed to room temperature and stirred overnight. TLC (70:30 hexanes/ethyl acetate) showed no starting material. The reaction was acidified with Dowex resin, filtered, and concentrated to a white solid. The compound 103 was recrystallized from ethyl acetate/hexanes.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[N:25][CH:26]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.[CH2:50]([N:57]1[CH2:61][CH:60]([C:62]2[CH:67]=[CH:66][C:65]([Cl:68])=[C:64]([Cl:69])[CH:63]=2)[CH:59]([CH:70](O)[CH3:71])[CH2:58]1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C1COCC1>[CH2:50]([N:57]1[CH2:61][CH:60]([C:62]2[CH:67]=[CH:66][C:65]([Cl:68])=[C:64]([Cl:69])[CH:63]=2)[CH:59]([CH:70]([O:27][C:24]2[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][N:25]=2)[CH3:71])[CH2:58]1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: CC(O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Reactant: Oc1ccc(Cl)cn1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1ccc(Cl)cn1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
To a suspension of PPh3 (PPh3 polymer bound, 3 mmol PPh3/g resin) (3.14 g, 9.4 mmol) in THF (70 mL) at 0° C. were added 5-chloro-pyridin-2-ol (0.832 g, 6.42 mmol) and then DBAD (1.578 g, 6.85 mmol). After 5 minutes was added (SR)-1-[(3SR,4RS)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (X-B-1) (1.50 g, 4.28 mmol). The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NaOH 1M, followed by column chromatography (SiO2, EtOAc/H, 1:6) yielded 1.71 g (87%) of the title compound as a colorless oil. ES-MS m/e: 461.2 (M+H+).
Reaction SMILES: O=S1(=O)N=CC2C=C(C(C)(C)C)C=C(I)C=2O1.[O:18]=[S:19]1(=[O:37])[N:24]=[CH:23][C:22]2[CH:25]=[C:26]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:27]=[C:28]([C:29]([F:32])([F:31])[F:30])[C:21]=2[O:20]1>>[O:37]=[S:19]1(=[O:18])[NH:24][CH2:23][C:22]2[CH:25]=[C:26]([C:33]([CH3:35])([CH3:34])[CH3:36])[CH:27]=[C:28]([C:29]([F:32])([F:30])[F:31])[C:21]=2[O:20]1
Reactant: CC(C)(C)c1cc2c(c(C(F)(F)F)c1)OS(=O)(=O)N=C2
Agent: CC(C)(C)c1cc(I)c2c(c1)C=NS(=O)(=O)O2
Product: CC(C)(C)c1cc2c(c(C(F)(F)F)c1)OS(=O)(=O)NC2

Procedure:
This compound is prepared by essentially the same method as described in Example 8 except that the 2,2-dioxo-6-(1,1-dimethylethyl)-8-iodo-1,2,3-benzoxathiazine is replaced by 2,2-dioxo-6-(1,1-dimethylethyl)-8-trifluoromethyl-1,2,3-benzoxathiazine. Thereby is obtained 2,2-dioxo-3,4-dihydro-6-(1,1-dimethylethyl)-8-trifluoromethyl-1,2,3-benzoxathiazine.