Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:27])([CH3:26])[CH2:20]/[CH:21]=[CH:22]/[C:23](O)=[O:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN(C)C(=O)[C@H](NC)CC1C=CC=CC=1.[CH3:65][N:66]([CH3:95])[C:67]([C@H:69]([N:77]([CH3:94])[C:78](=[O:93])[CH:79]([NH:91][CH3:92])[CH2:80][C:81]1[CH:90]=[CH:89][C:88]2[C:83](=[CH:84][CH:85]=[CH:86][CH:87]=2)[CH:82]=1)[CH2:70][C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)=[O:68].C(N(C(C)C)CC)(C)C>ClCCl>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][C:19]([CH3:26])([CH3:27])[CH2:20]/[CH:21]=[CH:22]/[C:23](=[O:24])[N:91]([C@@H:79]([C:78](=[O:93])[N:77]([C@@H:69]([C:67](=[O:68])[N:66]([CH3:65])[CH3:95])[CH2:70][C:71]3[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=3)[CH3:94])[CH2:80][C:81]3[CH:90]=[CH:89][C:88]4[C:83](=[CH:84][CH:85]=[CH:86][CH:87]=4)[CH:82]=3)[CH3:92])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CNC(Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN[C@H](Cc1ccccc1)C(=O)N(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
To a solution of (2E)-5-(((9H-flouren-9-yl)methoxy)- carbonylamino)-5-methylhex-2-enoic acid (280 mg, 0.77 mmol) in dichloromethane (5 ml) were added 1-hydroxy-7-azabenzotriazole (126 mg, 0.92 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (207 mg, 1.08 mmol) and the mixture was stirred for 30 min. Then 2R)-N-((1R)-1-dimethylcarbamoyl-2-phenylethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide (386 mg, 0.92 mmol) in dichloromethane (5 ml) and diisopropylethylamine (0.17 ml, 1.00 mmol) were added and the mixture was stirred overnight at room temperature. The mixture was washed with water (20 ml), saturated aqueous sodium bicarbonate (20 ml), water (2×20 ml), brine (20 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (400 g) with ethyl acetate/heptan 1:1 to give 401 mg of ((3E)-4-(N-((1R)-1-(N-((1R)-1-dimethylcarbamoyl-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamic acid 9H-flouren-9-ylmethyl ester. The obtained product was dissolved in 20% piperidine in dimethylformamide (10 ml) and stirred for 30 min. The mixture was chromatographed on silica (20 g) with dichloromethane/methanol/ammonia 89:10:1 to give 228 mg of (2E)-5-amino-5-methylhex-2-enoic acid N-((1R)-1-(N-((1R)-1-(dimethylcarbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide as an oil. The product was redissolved in water (30 ml) and acetic acid (2 ml) was added and the mixture was lyophilized to give 645 mg of the acetate salt of the title compound as an amorphous powder.
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.Cl[CH2:53][CH2:54][O:55][CH:56]1[CH2:58][CH2:57]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:53][CH2:54][O:55][CH:56]3[CH2:58][CH2:57]3)[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: ClCCOC1CC1
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCOC2CC2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]-amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF (0.1 M) was added (2-chloroethoxy)cyclopropane (3 eq.) and cesium carbonate (2 eq.). The reaction was heated to 100° C. and stirred for 3 h. After cooling to rt, the reaction was diluted with ether. The organic extract was washed with water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 35% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=2)[N:3]=1.Cl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:32][CH2:33][N:34]([C:2]3[C:11]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[N:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=4)[N:3]=3)[CH2:35][CH2:36]2)=[CH:27][CH:26]=1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: COC(=O)c1ccc2nc(Cl)c(-c3ccc(F)cc3)nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(N3CCC(c4ccc(Cl)cc4)CC3)c(-c3ccc(F)cc3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed a solution of methyl 2-chloro-3-(4-fluorophenyl)quinoxaline-6-carboxylate (150 mg, 0.47 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), 4-(4-chlorophenyl)piperidine hydrochloride (219 mg, 0.94 mmol, 2.00 equiv), potassium carbonate (326 mg, 2.36 mmol, 5.00 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with dichloromethane/methanol (10:1) and the organic layers were combined. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 200 mg (89%) of methyl 2-(4-(4-chlorophenyl)piperidin-1-yl)-3-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2[CH3:14])([O-])=O.O.NN>CO>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2[CH3:14]
Reactant: Cc1ccnc2c([N+](=O)[O-])cccc12
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1ccnc2c(N)cccc12
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a stirred mixture of 8-nitro-4-methylquinoline (250 mg), ferric chloride hexahydrate (7.18 mg) and activated carbon (38 mg) in methanol was added hydrazine monohydrate (266 mg) at 65° C., and the mixture was stirred for 1 hour at the same temperature. Insoluble material was filtered off, and the filtrate was concentrated in vacuo The mixture was dissolved in ethyl acetate, washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 8-amino-4-methylquinoline (208.8 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]([Br:24])(Br)Br.C(N(CC)CC)C.[C:32]([O:36][C:37](=[O:48])[N:38]([C@H:40]1[CH2:45][CH2:44][C@H:43]([CH:46]=O)[CH2:42][CH2:41]1)[CH3:39])([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl>[C:32]([O:36][C:37](=[O:48])[N:38]([C@H:40]1[CH2:45][CH2:44][C@H:43]([CH:46]=[C:21]([Br:24])[Br:20])[CH2:42][CH2:41]1)[CH3:39])([CH3:35])([CH3:33])[CH3:34]
Reactant: BrC(Br)(Br)Br
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C=O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C=C(Br)Br)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 52.45 g (200 mmol) triphenylphosphine in 200 ml CH2Cl2 was treated with 33.16 g (100 mmol) tetrabromomethane (the reaction heated up to reflux) and after 50 min with 32.06 ml (230 mmol) triethylamine (the reaction heated up to reflux and became dark violet). After cooling (0° C.), 12.83 g (50 mmol) of trans-(4-Formyl-cyclohexyl)-methyl-carbamic acid tert-butyl ester in 125 ml CH2Cl2 were added during 10 min. The solution was stirred for 16 h at RT, evaporated and filtered through silica gel (deactivated with hexane/Et3N) with hexane and then hexane/ether 4:1 to 1:1 as eluent to yield 13.28 g (67%) of trans-[4-(2,2-Dibromo-vinyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester, mp: 93-99° C., dec.; MS: 396 (MH+, 2Br).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[CH2:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]#[CH:13].C(NC(C)C)(C)C.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.O1CCOCC1>C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[N+:8]([C:4]1[CH:3]=[C:2]([C:13]#[C:12][CH2:11][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCC#Cc1cccc([N+](=O)[O-])c1
Temperature: 45 °C

Procedure:
To an oven dried, argon filed, flask was added 1-bromo-3-nitrobenzene (14) (3.09 g, 15.3 mmol), tert-butyl prop-2-ynylcarbamate (15) (2.8 g, 18.0 mmol), diisopropylamine (92.5 ml, 17.8 mmol), CuI (0.054 g, 0.18 mmol), PdCl2(PPh3)2 (0.42 g, 0.6 mmol) and dioxane (17 ml). The resulting mixture was purged with argon three times and then a solution of t-Bu3P-dioxane solution (0.9 ml, 0.9 mmol) was added. The mixture was heated at 45° C. for 15 h, cooled to room temperature, diluted with ethyl acetate, filtered through celite and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (10 to 50% EtOAc-hexanes gradient) gave tert-butyl 3-(3-nitrophenyl)prop-2-ynylcarbamate (16) as colorless oil. Yield (4.98 g, 100%); 1H NMR (400 MHz, CDCl3) δ 8.25 (t, J=1.6 Hz, 1H), 8.15 (ddd, J=8.4, 2.4, 1.2 Hz, 1H), 7.69 (dt, J=7.6, 0.8 Hz, 1H), 4.78 (br s, 1H), 4.16 (d, J=5.6 Hz, 2H), 1.47 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].[S-:11][C:12]#[N:13].[NH4+].BrBr>CC(O)=O>[Br:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[S:11][C:12]([NH2:13])=[N:5][C:4]=2[CH:3]=1
Reactant: COc1ccc(N)cc1Br
Reactant: N#C[S-]
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1cc2sc(N)nc2cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 3-bromo-4-methoxyaniline IV (2.0 g, 9.90 mmol) in AcOH (25.0 mL) was added ammonium thiocyanate (3.80 g, 49.50 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then cooled to 0° C. followed by addition of a solution of Br2 (0.60 mL, 11.0 mmol) in AcOH (10.0 mL). The reaction mixture was then allowed to stir at room temperature for 2 h. After the completion of the reaction (TLC monitoring), AcOH was distilled off, and the residue was cooled to 0° C. followed by basification with aqueous NH3 till pH 12 and extraction with EtOAc (2×250 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the desired product (2.0 g, 78%). 1H NMR (400 MHz, DMSO-d6): δ 3.80 (s, 3H), 7.41 (br s, 2H), 7.49 (s, 1H) and 7.50 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=1)#[N:2].Cl.[H][H]>CO.[Pd]>[NH2:2][CH2:1][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc(-c2cccc(C#N)n2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1ccc(-c2cccc(CN)n2)cc1

Procedure:
16.23 g of 6-cyano-2-(p-ethoxycarbonylphenyl)pyridine is hydrogenated at atmospheric pressure in 254 ml of methanol with 12.9 ml of concentrated hydrochloric acid and 2.63 g of 10% palladium on charcoal until 2 molar equivalents of hydrogen have been consumed. Sodium methoxide (6.9 g) is added and the catalyst is filtered off. The solvent is evaporated. The residue is redissolved in 20 ml of methylene chloride and the salts are removed by filtration. Evaporation of the solvent yields a solid which is recrystallized from chloroform to yield the title compound b), m.p. 141°-143°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].Br[CH2:24][C:25]1[O:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=1.BrCC1CCCCO1>>[F:31][C:30]([F:33])([F:32])[C:27]1[O:26][C:25]([CH2:24][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C@@:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])=[CH:29][CH:28]=1
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using (S)-(2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 2-(bromomethyl)-5-(trifluoromethyl)furan to replace 2-(bromomethyl)tetrahydro-2H-pyran, (S)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (95%) as a colorless solid: mp 53-56° C. (methanol/water); 1H NMR (300 MHz, CDCl3) δ7.30 (dd, J=7.8, 7.8 Hz, 1H), 7.18 (d, J=7.2 Hz, 1H), 7.08 (dd, J=7.5, 7.5 Hz, 1H), 6.99 (d, J=8.1 Hz, 1H), 6.74 (dd, J=2.1, 0.9 Hz, 1H), 6.50 (s, 1H), 6.38 (d, J=3.0 Hz, 1H), 6.19 (s, 1H), 5.06 (d, J=16.2 Hz, 1H), 4.90 (d, J=9.0 Hz, 1H), 4.89 (d, J=16.2 Hz, 1H), 4.64 (d, J=9.0 Hz, 1H), 4.22-4.17 (m, 2H), 4.14-4.09 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.2, 155.3, 152.2, 144.8, 141.8 (q, J=43.0 Hz), 141.5, 138.5, 132.2, 129.1, 124.2, 123.9, 120.9, 118.9 (q, J=267 Hz), 112.8 (q, J=2.8 Hz), 111.6, 109.3, 109.0, 99.5, 80.1, 64.6, 64.0, 58.1, 37.1; MS (ES+) m/z 443.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10](Cl)(=[O:12])=[O:11])=[C:5]([CH3:14])[CH:4]=1.Cl.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=2)[CH2:18][CH2:17]1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=3)[CH2:18][CH2:17]2)(=[O:12])=[O:11])=[C:5]([CH3:14])[CH:4]=1
Reactant: COC(=O)c1ccc2c(c1)NCC2
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1c(C)cc(OC)cc1C)CC2
Temperature: 70 °C
Reaction time: 8 h

Procedure:
4-Methoxy-2,6-dimethylbenzene-1-sulfonyl chloride (1.3 g, 0.0056 mol) was added at 25° C., under argon, to a solution of methyl indoline-6-carboxylate hydrochloride (1.2 g, 0.0056 mol) in dry pyridine (12 ml), and the resulting reaction mixture was stirred overnight at 70° C. The solvent was removed in vacuo, and the residue was taken up in dichloromethane and washed with water (2×), saturated copper sulfate solution (2×) and saturated sodium chloride solution, then dried (Na2SO4) and concentrated in vacuo. The resulting crude product was purified by column chromatography (silica gel, 10-30% ethyl acetate in hexane). Yield: 1.9 g (90%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:10]=1[CH2:11][N:12]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[C:13]1[N:18]=[CH:17][C:16]([OH:19])=[CH:15][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][S:44][CH2:45][CH2:46]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C.O>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:35][C:10]=1[CH2:11][N:12]([CH2:20][C:21]1[CH:22]=[C:23]([C:31]([F:33])([F:32])[F:34])[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1)[C:13]1[N:14]=[CH:15][C:16]([O:19][CH2:46][CH2:45][S:44][CH3:43])=[CH:17][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSCCO
Reactant: Oc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2OCc2ccccc2)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
2-[(2-Benzyloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-amino]-pyrimidin-5-ol (1.33 g) is dissolved in tetrahydrofuran (20 ml), and thereto are added 2-methylsulfanyl-ethanol (290 μl), triphenylphosphine (870 mg) and 40% diethyl azodicarboxylate/toluene solution (1.5 ml) and the mixture is stirred at room temperature for 45 minutes. To the reaction solution are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=99:1→19:1) to give (2-benzyloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-[5-(2-methylsulfanyl-ethoxy)-pyrimidin-2-yl]-amine (1.21 g). MS (m/z): 676 [M+H]+
Reaction SMILES: [C:1]1([CH2:7][C@@H:8]2[CH2:12][O:11][C:10](=[O:13])[NH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:19]1([CH2:24][CH2:25][C:26](Cl)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1>[CH:19]1([CH2:24][CH2:25][C:26]([N:9]2[C@H:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][O:11][C:10]2=[O:13])=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CCC1CCCC1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
A dry round bottom flask was charged with of (R)-4-(phenylmethyl)-2-oxazolidinone (1, 17.7 g, 0.100 mol). Anhydrous tetrahydrofuran (300 mL) was then added, and the solution was cooled to −78° C. A solution of butyllithium (42.0 mL, 0.105 mol, 2.50 M in hexane) was added to the reaction flask over a 10-min period. After a few minutes, 3-Cyclopentylpropionyl chloride (16.8 mL, 0.110 mol) was added. The resulting solution was stirred for 30 min at −78° C., then allowed to warm to ambient temperature over a 30-min period. Excess 3-cyclopentylpropionyl chloride was quenched by the addition of 60 mL of saturated aqueous ammonium chloride. The bulk of the tetrahydrofuran and hexane was removed on a rotary evaporator, and the slurry was extricated with two 80 mL portion of dichloromethane. The combined organic layers were washed with 75 mL of 1 M sodium hydroxide and 75 mL of brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was triturated with hexane to provide 16.5 g of desired product 2 as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.18-7.40 (5 H, m), 4.67 (1 H, m), 4.12-4.22 (2 H, m), 3.30 (1 H, dd, J=13.4, 3.1 Hz), 2.84-3.06 (2 H, m), 2.76 (1 H, dd, J=13.4, 9.6 Hz), 1.42-1.96 (9 H, m), 1.15 (2 H, br, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].C(N1C=CN=C1)(N1C=CN=C1)=O.C([O-])([O-])=O.[K+].[K+].O[C:35]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:36]=1[C:43](=O)[CH2:44][C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13](=[O:15])[O:14][C:37]2[C:36]([C:43]=1[CH2:44][C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=1)=[CH:35][CH:40]=[C:39]([O:41][CH3:42])[CH:38]=2
Reactant: COc1ccc(C(=O)Cc2ccc(O)cc2)c(O)c1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3ccc(O)cc3)c(-c3ccc(C(F)(F)F)cc3Cl)c(=O)oc2c1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2-(chloro-4-trifluoromethylphenyl)-acetic acid (3.2 g, 13.41 mmol) and 1,1′-carbonyldiimidazole (2.72 g, 16.77 mmol) in DMF (15 mL) was heated to 70° C. for 25 min. The reaction mixture was cooled to 10° C. and K2CO3 (2.78 g, 20.1 mmol), 1-(2-hydroxy-4-methoxyphenyl)-2-(4-hydroxyphenyl)-ethan-1-one (1.73 g, 6.7 mmol, prepared as described in Example 4A), DMAP (164 mg, 1.34 mmol) and DMF (10 mL) were added. After stirring the reaction mixture at 115° C. for 1.5 h, the resulting suspension was cooled to r.t., poured onto AcOEt/H2O and the layers were separated. The organic layer was washed with H2O, aq 1N HCl and brine, was dried (MgSO4) and the solvent was removed in vacuo. The resultant red residue was purified using flash chromatography (silica gel, 2:1 to 1:2 hexanes:Et2O) to provide the title compound as a white solid showing: 1H NMR (300 MHz, CDCl3) δ 7.75 (s, 1H), 7.53 (br d, 1H, J=8.0 Hz), 7.47 (d, 1H, J=9.0 Hz), 7.33 (d, 1H, J=8.0 Hz), 6.92-6.85 (m, 3H), 6.80 (d, 1H, J=2.5, 9.0 Hz), 6.70 (d, 2H), J=8.5 Hz), 4.95-4.64 (very br s, 1H), 4.02 (d, 1H, J=15.5 Hz), 3.88 (s, 3H), 3.76 (d, 1H, J=15.5 Hz). MS (ESI) m/z 461 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.I.[NH2:14][NH:15][C:16]([NH:19][NH:20][CH3:21])=[N:17][CH3:18].[OH-].[Na+]>C(O)C.Cl>[CH3:18][NH:17][C:16]1[N:19]([NH:20][CH3:21])[C:9](=[O:11])[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[N:14][N:15]=1
Reactant: CN=C(NN)NNC
Reactant: O=C(O)C(=O)c1cccc(F)c1
Agent: Cl
Agent: I
Agent: [Na+]
Solvent: CCO
Product: CNc1nnc(-c2cccc(F)c2)c(=O)n1NC
Reaction time: 2 h
Yield: 86.3 %

Procedure:
3.8 g (0.02 mole) of 3-fluorophenylglyoxylic acid in 10 ml of ethanol are slowly added dropwise to a solution of 5.4 g (0.022 mole) of 1-amino-2-methyl-3-methylaminoguanidine hydroiodide in 55 ml of 2N hydrochloride acid. The temperature rises from 20° to 30° C. during this addition and a pale yellow precipitate forms. This mixture is stirred for 2 hours to a temperature in the range from 60° to 70° C., whereupon a clear yellow orange solution forms. After cooling, this solution is neutralised with an aqueous solution of sodium hydroxide. The precipitate is then isolated, washed with water and dried at 70° C., affording 4.3 g (76% of theory) of 3,4-bis(methylamino)-6-(3-fluorophenyl)-4H-1,2,4-triazin-5-one with a melting point of 173°-174° C.