Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[F:44][C:45]([F:58])([F:57])[O:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][C:54](O)=[O:55])=[CH:49][CH:48]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:54](=[O:55])[CH2:53][C:50]3[CH:51]=[CH:52][C:47]([O:46][C:45]([F:57])([F:44])[F:58])=[CH:48][CH:49]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(Cc1ccc(OC(F)(F)F)cc1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 4-trifluoromethoxyphenylacetic acid (0.5 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). After stirring at room temperature overnight, the reaction mixture was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL), and the solution was washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2=4:6) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(4-trifluoromethoxy-phenyl)-acetamide (0.7 g, 64%) as a white solid: mp 134-136° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=6.41 min. (98%); 1H NMR (DMSO-d6) δ 2.03-2.08 (m, 1H), 2.52-2.63 (m, 2H), 2.84-2.91 (m, 1H), 3.59 (s, 2H), 4.73 (d, J=5.8 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 7.29-7.32 (d, J=8.6 Hz, 2H), 7.40-7.43 (d, J=8.7 Hz, 2H), 7.63-7.82 (m, 2H), 8.72 (t, J=5.9 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.94, 30.90, 37.85, 41.23, 48.83, 120.81, 118.37 (121.76, 125.15), 121.91, 127.14, 130.91, 131.52, 133.22, 134.65, 135.64, 139.02, 147.02, 166.88, 167.41, 169.78, 170.21, 172.72; Anal. Calcd. for C23H18N3O6F3: C, 56.45; H, 3.71; N, 8.59; F, 11.65. Found: C, 56.20; H, 3.39; N, 8.44; F, 11.87.
Reaction SMILES: [CH2:1]([N:6]1[C:13]([C:14]2[S:15][C:16](Br)=[CH:17][CH:18]=2)=[C:12]2[C:8](=[C:9]([C:26]3[S:27][C:28](Br)=[CH:29][CH:30]=3)[N:10]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:11]2=[O:20])[C:7]1=[O:32])[CH2:2][CH2:3][CH2:4][CH3:5].[Cu][C:34]#[N:35].[CH3:36][N:37](C=O)C>>[CH2:1]([N:6]1[C:13]([C:14]2[S:15][C:16]([C:36]#[N:37])=[CH:17][CH:18]=2)=[C:12]2[C:8](=[C:9]([C:26]3[S:27][C:28]([C:34]#[N:35])=[CH:29][CH:30]=3)[N:10]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:11]2=[O:20])[C:7]1=[O:32])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CN(C)C=O
Reactant: N#C[Cu]
Reactant: CCCCCN1C(=O)C2=C(c3ccc(Br)s3)N(CCCCC)C(=O)C2=C1c1ccc(Br)s1
Product: CCCCCN1C(=O)C2=C(c3ccc(C#N)s3)N(CCCCC)C(=O)C2=C1c1ccc(C#N)s1

Procedure:
The synthesis of 2,5-di-n-pentyl-3,6-bis(5-bromo-thiophen-2-yl)pyrrolo[3,4-c]-pyrrole-1,4-dione is done in analogy to Zhou et al., Macromolecules 43 (2010) 821-826. 2,5-Di-n-pentyl-3,6-bis(5-bromo-thiophen-2-yl)pyrrolo[3,4-c]-pyrrole-1,4-dione (600 mg, 1.00 mmol) and copper(I)-cyanide (1.60 g, 18.0 mmol) in dry DMF (15 mL) are heated under argon at 120° C. for 60 min and at 165° C. for 80 min. The solvent is removed under reduced pressure and the crude product continuously extracted from the reaction mixture with chloroform. The extract is purified by column chromatography (dichloromethane) and washed with hexane affording 64.0 mg (13%) of a dark violet solid.
Reaction SMILES: [OH:1][C@H:2]([C:38]1[C:46]2[S:45][C:44](=[O:47])[NH:43][C:42]=2[C:41]([OH:48])=[CH:40][CH:39]=1)[CH2:3][N:4]([CH2:12][CH2:13][S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:37][CH2:36][C:24]2([O:29][CH2:28][CH2:27][N:26](C(=O)C(F)(F)F)[CH2:25]2)[CH2:23][CH2:22]1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])[O-].[K+].[K+]>CO.O>[O:29]1[C:24]2([CH2:23][CH2:22][N:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][S:14][CH2:13][CH2:12][N:4]([CH2:3][C@H:2]([OH:1])[C:38]3[C:46]4[S:45][C:44](=[O:47])[NH:43][C:42]=4[C:41]([OH:48])=[CH:40][CH:39]=3)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:37][CH2:36]2)[CH2:25][NH:26][CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)N(CCSCCCCCCN1CCC2(CC1)CN(C(=O)C(F)(F)F)CCO2)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N(CCSCCCCCCN1CCC2(CC1)CNCCO2)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirring solution of (R)-tert-butyl 2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl(2-(6-(4-(2,2,2-trifluoroacetyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)hexylthio)ethyl)carbamate (example 101, step f) (0.18 g) in methanol (10 mL) was added a solution of potassium carbonate (0.06 g) in water (10 mL). The mixture was stirred at RT for 17 h then the methanol was removed under a stream of nitrogen. The solution was diluted with brine, extracted with ethyl acetate (×3) and dried over sodium sulfate, filtered and evaporated in vacuo. The residue was dissolved in methanol and evaporated in vacuo to give the subtitled compound as a brown glass. Yield 0.15 g.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[C:20]([CH3:21])=[CH:19][S:18][CH:17]=2)[N:13]([S:22]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])[CH:12]=1)C(=O)OC(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].[Cl:43]CCl>>[ClH:43].[ClH:43].[CH3:1][NH:2][CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[C:20]([CH3:21])=[CH:19][S:18][CH:17]=2)[N:13]([S:22]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)(=[O:23])=[O:24])[CH:12]=1
Reactant: ClCCl
Reactant: Cc1cscc1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cc(-c2cscc2C)n(S(=O)(=O)c2cccnc2)c1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
By a similar operation as in Example 26 and using tert-butyl methyl{[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate (200 mg), the title compound was obtained as colorless crystals (yield 125 mg, 67%). More specifically, tert-butyl methyl{[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate (200 mg) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (1 mL) was added at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction solution was basified by adding dropwise to a 6% aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→1:9) to give a free salt of the title compound as a pale-yellow oil. The obtained free salt was dissolved in ethyl acetate (5 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-ethanol to give the title compound as colorless crystals (yield 125 mg, 67%).
Reaction SMILES: CCCCCC.C([Li:11])CCC.CC(C)([O-])C.[K+].[F:18][C:19]1[C:20]([F:28])=[C:21]([F:27])[C:22]([F:26])=[C:23]([F:25])[CH:24]=1>C(OCC)C>[F:18][C:19]1[C:24]([Li:11])=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[C:20]=1[F:28]
Reactant: [Li]CCCC
Reactant: Fc1cc(F)c(F)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOCC
Product: [Li]c1c(F)c(F)c(F)c(F)c1F
Temperature: -65 °C
Yield: 95.9 %

Procedure:
Inside of a 100 ml volume glass three-neck flask equipped with a 50 ml volume glass dropping funnel, temperature resistor and septum rubber was sufficiently replaced with nitrogen. Into the flask, 15.5 g (29.8 mmol) hexane solution of 15.5 wt. % butyllithium, 3.3 g (29.8 mmol) potassium tertbutoxide and 15 ml diethyl ether were charged, of which solution was cooled to -65° C. Thereafter, 5 g (29.8 mmol) pentafluorobenzene and 15 ml diethyl ether charged into the dropping funnel were added dropwise while making the inner temperature not to exceed -55° C. After the completion of dropwise addition, the reaction mixture was kept at a temperature of -65°~-55° C. with stirring to give pentafluorophenyllithium.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:31]([O:32][CH3:33])=[CH:30][C:6]2[S:7][C:8](/[CH:19]=[C:20](\[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)/[C:21]([O-:23])=[O:22])=[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:5]=2[CH:4]=1.[Na+].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[C:31]([O:32][CH3:33])=[CH:30][C:6]2[S:7][C:8]([CH2:19][CH:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:21]([OH:23])=[O:22])=[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:5]=2[CH:4]=1
Reactant: COc1ccc(Oc2c(/C=C(/C(=O)[O-])c3ccccc3)sc3cc(OC)c(OC)cc23)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Oc2c(CC(C(=O)O)c3ccccc3)sc3cc(OC)c(OC)cc23)cc1

Procedure:
The compound obtained in Example 6 after Step F is used as substrate, which is treated with a stream of hydrogen in the presence of 10% Pd/C in methanol for 24 hours. Filtration, at the end of the reaction, followed by chromatography over silica gel enables the expected product to be isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:19])=[CH:12][C:13]=2[O:15][CH2:16][CH2:17]Cl)[C:8]([S:20]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[N:7]1.[CH3:36][NH2:37].Cl.CCOCC>CS(C)=O.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:19])=[CH:12][C:13]=2[O:15][CH2:16][CH2:17][NH:37][CH3:36])[C:8]([S:20]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)(=[O:21])=[O:22])=[N:7]1
Reactant: CN
Reactant: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2cccc(Cl)c2)c2c(OCCCl)cc(F)cc12
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: CNCCOc1cc(F)cc2c(S(=O)(=O)c3cccc4ccccc34)nn(Cc3cccc(Cl)c3)c12
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 1-(3-chloro-benzyl)-7-(2-chloro-ethoxy)-5-fluoro-3-(naphthalene-1-sulfonyl)-1H-indazole (0.075 g, 0.14 mmoles) and methylamine (0.56 mmoles) in DMSO (1 mL) was stirred under nitrogen at 100° C. for 4 hours. Mixture was cooled to room temperature, diluted with water, extracted with EtOAc, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. Compound was purified by flash chromatography using as eluent 5% CH3OH/EtOAc. The purified compound was dissolved in methanol, 1M HCl in ether (0.1 mL, 0.1 mmoles) was added, and compound was dried to afford the title compound as the HCl salt.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6]([CH3:9])([CH3:8])[N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:4]1[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.[CH3:24][C:25]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])[CH3:26].N1C=CN=C1>>[Si:28]([O:1][CH2:2][C@H:3]1[O:7][C:6]([CH3:8])([CH3:9])[N:5]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[C@H:4]1[CH2:17][C:18]1[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=1)([C:25]([CH3:27])([CH3:26])[CH3:24])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccncc2)[C@@H](CO)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccncc2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C

Procedure:
The title compound was synthesized in manner analogous to that described in Example 472, using (4S,5S)-tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-(pyridin-4-ylmethyl)oxazolidine-3-carboxylate in the presence of TBSCl and imidazole, and was used without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH2:17][C:18]([OH:20])=O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl.CN(C)C=O>[C:18]1(=[O:20])[C:15]2=[C:16]3[C:11](=[CH:12][CH:13]=[CH:14]2)[CH:10]=[CH:9][CH:8]=[C:7]3[CH2:17]1
Reactant: O=C(O)Cc1cccc2ccccc12
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1Cc2cccc3cccc1c23
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a 1 litre three-necked flask, oxalyl chloride (2.87 ml, 3.22.10−2 mol, 1 eq.) is added dropwise, under argon, to a solution of (naphth-1-yl)acetic acid (6 g, 3.22.10−2 mol) in anhydrous dichloromethane (270 ml) at 0° C. A few drops of anhydrous dimethylformamide are then added. After 1 hour at 0° C., slight evolution of gas is still observed and the three-necked flask is left at ambient temperature for 40 minutes. After return to 0° C., aluminium chloride (11.2 g, 8.38.10−2 mol, 2.6 eq.) is added gradually with a spatula. The solution is stirred for twenty minutes and becomes green-black in colour. The mixture is poured into an ice/1N HCl mixture. After separation of the phases and washings of the acidic aqueous phase with dichloromethane, the combined organic phases are washed with water, then treated with a saturated NaHCO3 solution and finally washed with a saturated NaCl solution. After drying over MgSO4 and evaporation under reduced pressure, the title product is obtained in the form of a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([CH2:17][CH2:18][C:19]([OH:21])=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[C:1]1([C:7]2[CH:16]=[C:15]([CH2:17][CH2:18][C:19]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:21])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCc1cc(-c2ccccc2)nc2ccccc12
Reactant: C1CCNC1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(CCc1cc(-c2ccccc2)nc2ccccc12)N1CCCC1

Procedure:
The procedure is as in Example 16, starting with 2-phenyl-4-quinolinepropanoic acid (3 g), thionyl chloride (2.3 cc) in chloroform (150 cc) and pyrrolidine (2.7 cc). The residue is stirred for two hours with silica gel (36 g) in ethyl acetate (80 cc). The silica is removed by filtration and washed with ethyl acetate (7×10 cc). The organic phases are combined and concentrated under reduced pressure. After recrystallization of the residue in ethyl acetate, 1-[3-(2-phenyl-4-quinolyl)propionyl]pyrrolidine (2 g), m.p. 116° C., is obtained.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)(=O)[CH2:12][CH3:13].Cl>C(O)C.O1CCOCC1>[ClH:1].[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:11]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[C:12]2[CH3:13]
Reactant: NNc1ccc(Br)cc1
Reactant: CCC(=O)c1cccnc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1c(-c2cccnc2)[nH]c2ccc(Br)cc12

Procedure:
To a suspension of 4-bromophenylhydrazine hydrochloride (10.00 g, 42.95 mmol) in anhydrous ethanol (200 mL) is added 3-propionylpyridine (7.51 g, 42.95 mmol) and the mixture is stirred at reflux for 30 min. 4M HCl in 1,4-dioxane (42.9 mL) is added to the yellow solution and stirring is continued at reflux overnight. The reaction mixture is cooled with an ice-water bath and the yellow precipitate is filtered through a sintered funnel to give 5-bromo-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride as a yellow solid. The product is dissolved in methanol (100 mL) and treated with sodium methoxide to give the free base, which is used in the next step without further purification.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][O:10][C:11](=[O:47])[C:12]([C:37]1[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:38]=1)=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:21]=[C:22]([C:30]([S:33]([CH3:36])(=[O:35])=[O:34])([CH3:32])[CH3:31])[CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)[CH:15]=1>CS(C)=O.O.C(OCC)(=O)C>[CH3:9][O:10][C:11]([C:12]1([C:37]2[CH:38]=[CH:39][C:40]([S:43]([CH3:46])(=[O:44])=[O:45])=[CH:41][CH:42]=2)[CH2:2][CH:13]1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:21]=[C:22]([C:30]([S:33]([CH3:36])(=[O:35])=[O:34])([CH3:32])[CH3:31])[CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)[CH:15]=1)=[O:47]
Reactant: C[S+](C)(C)=O
Reactant: COC(=O)C(=Cc1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1)c1ccc(S(C)(=O)=O)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)C1(c2ccc(S(C)(=O)=O)cc2)CC1c1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1
Temperature: 21 °C
Reaction time: 0.5 h

Procedure:
To a suspension of trimethylsulfoxonium iodide (400 mg, 1.83 mmol) in DMSO (25 mL) at 0° C. was added NaH (60%, 73 mg, 1.83 mmol). After 30 min., 3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-acrylic acid methyl ester from Step 2 (688 mg, 1.22 mmol) was added and the resulting reaction mixture stirred for 18 h at 21° C., then diluted with water and ethyl acetate. The organic extracts were washed (H2O, brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with toluene/acetone, 80:20) provided the 2-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-(4-methanesulfonyl-phenyl)-cyclopropanecarboxylic acid methyl ester compound.
Reaction SMILES: [OH-:1].[Na+].Br[C:4]1(Br)[C:8](=[O:9])NN[CH:5]1[C:10]([CH3:13])([CH3:12])[CH3:11].C(#N)C.Cl>O>[CH3:11][C:10]([CH3:13])([CH3:12])[C:5]#[C:4][C:8]([OH:1])=[O:9]
Reactant: CC(C)(C)C1NNC(=O)C1(Br)Br
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)C#CC(=O)O
Temperature: 5 °C

Procedure:
552 g of sodium hydroxide was dissolved in 3.0 liters of water and ice was added thereto to adjust the temperature to 5° C. or lower. Next, while stirring, dibromo-3-t-butyl-5-pyrazolidone was added thereto little by little while maintaining the temperature at 5° C. or lower. If the temperature would rise, ice was added, and acetonitrile was added in order to prevent foaming. After the completion of the reaction, 6 N hydrochloric acid was added to make the reaction solution acidic, and then the solution was subjected to extraction twice with ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=[CH:10][N:11]=[C:4]2[N:3]=1.[Na+].[I-:13].CC1C=CC(S([N-]Cl)(=O)=O)=CC=1.O.O.O.[Na+]>C(O)(=O)C>[I:13][C:7]1[C:2]([CH3:1])=[N:3][C:4]2[N:5]([N:9]=[CH:10][N:11]=2)[C:6]=1[NH2:8]
Reactant: Cc1cc(N)n2ncnc2n1
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)[N-]Cl)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc2ncnn2c(N)c1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a stirring mixture of 3.05 g (20.4 mmol) of 5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (prepared as described in Kano; Makisumi; Chem. Pharm. Bull.; 6; 1958; 583, 585) in 50 mL of acetic acid at room temperature was added NaI (3.2 g, 21.5 mmol). Chloramine-T trihydrate (6.0 g, 21.5 mmol) was then added portion wise. The resulting mixture was then stirred for 1 h at room temperature. Most of the organic solvent was removed on a rotavap. The mixture was taken tip in 40 mL of CH3CN and filtered. The solid collected was washed with diethyl ether and dried in vacuum oven to give the title compound as a light yellow solid (4.93 g, 88% yield).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([OH:27])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][C:23]([F:26])([F:25])[F:24])[CH2:9]1)C1C=CC=CC=1.[ClH:34].C(O)C.C1(C)C=CC=CC=1>CO.[Pd]>[ClH:34].[NH:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C@:14]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([OH:27])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][C:23]([F:26])([F:25])[F:24])[CH2:9]1
Reactant: OC(Cc1ccccc1OC(F)(F)F)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCO
Product: O[C@@](Cc1ccccc1OC(F)(F)F)(c1ccccc1)[C@H]1CNCCO1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
Alternatively, the following method may be used. A stainless steel Buchi hydrogenation reactor was loaded with 1-(4-Benzyl-morpholin-2-yl)-1-phenyl-2-(2-trifluoromethoxy-phenyl)-ethanol (230 g, 0.503 mole), methanol (1 L), a suspension of Pd/C (10%, 46 g, 20% loading) in methanol (500 ml), and methanol (500 ml) from equipment rinses. A solution of HCl in ethanol (1.6N, 460 ml, 0.736 mole, 1.5 eq.) was added and the reactor was pressurized with H2 (3 Bar). The reaction mixture was heated to 40° C. and stirred for 3 hours. The reaction mixture was cooled to 20° C. and flushed with N2. The catalyst was filtered off and washed with methanol (0.5 L). The filtrates were concentrated under vacuum to a yellow solid. The yield of crude title compound was 198 g (97.5%). A reactor was loaded with crude title compound (190 g, 0.47 mole) and toluene (6.65 L) under N2. The suspension was heated under reflux and toluene (150 ml) was added until all solid dissolved. The solution was stirred for 15 minutes more under reflux and then cooled slowly to 20° C. The suspension was stirred for 1 hour at 20° C. The solid was filtered, washed with toluene (680 ml), and dried at 40° C. under vacuum. The yield of pure anhydrous title compound was 158.5 g (83.4%).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([C:41]2[C:42]([C:47]#[N:48])=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:40])[N:23]([CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[C:24]2[N:25]([N:30]=[C:31]([CH3:33])[N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]2[NH:3][C:4](=[O:7])[O:5][N:48]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:40])[N:23]([CH:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)[C:24]2[N:25]([N:30]=[C:31]([CH3:33])[N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCOCC2)c2nc(C)nn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n(C2CCOCC2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 47.7 %

Procedure:
A mixture of hydroxylammonium chloride (0.92 g), sodium hydrogen carbonate (1.5 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 3′-fluoro-4′-{[2-methyl-5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.43 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.17 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.23 g, 49%).