Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([CH:34]=[CH:35][CH:36]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([CH2:16][O:17][C:18]3[CH:31]=[CH:30][C:21]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[NH:25][C:24]4=[O:29])=[CH:20][CH:19]=3)[N:13]([CH3:32])[C:12]=2[CH:33]=1.[C:37]([C:39]1[CH:40]=[C:41]([N:45]=[C:46]=[O:47])[CH:42]=[CH:43][CH:44]=1)#[N:38].C(N(CC)CC)C>CN(C)C=O>[C:37]([C:39]1[CH:40]=[C:41]([NH:45][C:46]([NH:3][C:4]2[CH:36]=[CH:35][CH:34]=[C:6]([O:7][C:8]3[CH:9]=[CH:10][C:11]4[N:15]=[C:14]([CH2:16][O:17][C:18]5[CH:31]=[CH:30][C:21]([CH2:22][CH:23]6[S:27][C:26](=[O:28])[NH:25][C:24]6=[O:29])=[CH:20][CH:19]=5)[N:13]([CH3:32])[C:12]=4[CH:33]=3)[CH:5]=2)=[O:47])[CH:42]=[CH:43][CH:44]=1)#[N:38]
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3cccc(N)c3)cc21
Reactant: N#Cc1cccc(N=C=O)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3cccc(NC(=O)Nc4cccc(C#N)c4)c3)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
A mixture of 5-[4-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg), 3-cyanophenyl isocyanate (260 mg), triethylamine (153 mg) and anhydrous N,N-dimethylformamide (8 ml) was stirred at room temperature for 4 hours and then at 50° C. for 2.5 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=3:1→ethyl acetate as the eluant. The product was recrystallized from methanol to afford the title compound (260 mg, mp 148.4-154.0° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[Li].CO.C(Cl)(Cl)Cl>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([OH:8])[C:10]2[S:9][CH:13]=[CH:12][CH:11]=2)[CH:2]=1
Reactant: [Li]c1cccs1
Reactant: O=Cc1cccnc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: OC(c1cccnc1)c1cccs1
Temperature: -78 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
To a solution of 3-pyridinecarboxaldehyde (5.0 mL, 53 mmol) in THF at -78° C. was added 2-thienyllithium (1.0M in THF, 64 mL, 64 mmol) and the reaction mixture was stirred for 2 hours at -78° C. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with ether. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. Chromatography on silica gel (5%, then 10% methanol/CHCl3) gave 2-(3-pyridylhydroxymethyl)thiophene (6.30 g, 62% yield).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][S:12][CH2:13][C:14]#[N:15])=[CH:9][C:4]=2[O:3][CH2:2]1.C([Li])CCC.[C:21](=[O:23])=[O:22].O>CCOCC.CCCCCC>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][S:12][CH:13]([C:14]#[N:15])[C:21]([OH:23])=[O:22])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: N#CCSCCc1ccc2c(c1)OCO2
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: N#CC(SCCc1ccc2c(c1)OCO2)C(=O)O
Temperature: -50 °C
Reaction time: 2 h
Yield: 11.7 %

Procedure:
5.0 g of [{2-(1,3-benzodioxol-5-yl)ethyl}thio]-acetonitrile was dissolved in 50 ml of anhydrous ether. 22 ml of a 1.6 M solution of n-butyllithium in hexane was added to the solution at -78° C. The mixture was stirred at -50° C. for 2 h. It was cooled again to -78° C. and 10 g of dry ice was added thereto. The temperature of the mixture was elevated to room temperature. Water was added to the reaction mixture. After extraction with chloroform, the extract was dried over magnesium sulfate and concentrated. The residue was purified according to silica gel column chromatography (chloroform) and recrystallized from ethyl acetate/hexane to obtain 0.70 g of the intended compound in the form of colorless needles.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26](Cl)[N:25]=3)[CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1N2CC[N:34](CC2)[CH2:33]1.[C-]#N.[K+].CCOC(C)=O>CS(C)=O.O>[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:33]#[N:34])[N:25]=3)[CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(COc2cccc(Oc3ccnc(Cl)n3)c2)cc1
Reactant: C1CN2CCN1CC2
Agent: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(COc2cccc(Oc3ccnc(C#N)n3)c2)cc1
Reaction time: 0.33 h

Procedure:
{4-[3-(2-Chloro-pyrimidin-4-yloxy)-phenoxymethyl]-benzyl}carbamic acid tert-butyl ester (126 mg; 0.285 mmol; Stage 5.2), DABCO (16 mg; 0.143 mmol) and KCN (38 mg; 0.584 mmol) are dissolved in DMSO/water 4:1 (4 mL) at rt under an atmosphere of argon. After 20 min, more DABCO (16 mg) is added and the reaction is continued for a total of 1 h 50 min. The reaction mixture is poured onto brine, taken up into EtOAc, washed with water and brine and dried (Na2SO4). After filtration, the solvent is removed under reduced pressure and the crude product is purified by flash chromatography over silica gel (eluting with Hexane/EtOAc 80:20) to give the title compound of Stage 5.3 as an oil; ES-MS: [M−H]−; m/z=431; Rf (Hexane/EtOAc 1:1)=0.45; HPLC: AtRet=5.19 min.
Reaction SMILES: [Na].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1)([OH:4])=[O:3].[C:12]([O:15][C@@H:16]1[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:19][O:18][C@@H:17]1Cl)(=[O:14])[CH3:13]>CN(C)C=O>[C:12]([O:15][C@@H:16]1[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:19][O:18][C@H:17]1[S:11][C:8]1[CH:9]=[CH:10][C:5]([C:2]([OH:4])=[O:3])=[CH:6][CH:7]=1)(=[O:14])[CH3:13]
Reactant: O=C(O)c1ccc(S)cc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CO[C@@H]1Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccc(C(=O)O)cc2)OC[C@H]1OC(C)=O
Reaction time: 8 h

Procedure:
To 19.8 g. of sodium salt of paracarboxythiophenol in dimethylformamide solution was added 29.5 g of tri-O-acetyl-α-D-xylosylchloride (4). After the resulting reaction mixture was allowed to stand overnight, the dimethylformamide was distilled away and the resulting residue was extracted with ethyl acetate. The obtained organic layer was washed with water, followed by drying over anhydrous magnesium sulfate. When the solvent was distilled away, white powdery paracarboxyphenyl 2,3,4-tri-O-acetyl-1-thio-β-D-xylopyranoside (10) was obtained. To 144 ml. of anhydrous methanol were added 12.0 g. of the obtained paracarboxyphenyl 2,3,4-tri-O-acetyl-1-thio-β-D-xylopyranoside (10) and 720 mg. of lithium hydroxide, and the mixture was allowed to stand overnight at room temperature. Then, the reaction mixture was diluted with water and was passed through an acidic resin in the usual way. The solution which has thus been passed was adjusted to pH 7.0 by adding sodium hydroxide. The so neutralized solution was concentrated to yield 8 g. of the desired para(sodiumoxycarbonyl)phenyl 1-thio-β-D-xylopyranoside in the state of white powder.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][C:14]=1[CH2:15][N:16]([CH3:18])[CH3:17])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[PH2](O)=O.[ClH:29]>CCOCC>[ClH:29].[ClH:29].[CH2:1]([N:8]([CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:14]=1[CH2:15][N:16]([CH3:18])[CH3:17])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(OCCN(C)Cc2ccccc2)c(CN(C)C)c1
Agent: Br
Agent: Cl
Agent: O=[PH2]O
Solvent: CCOCC
Product: CN(C)Cc1cc(O)ccc1OCCN(C)Cc1ccccc1

Procedure:
A mixture of 2-[2-(N-benzyl-N-methylamino)ethoxy]-5-methoxy-N,N-dimethylbenzylamine (1.0 g), aqueous hydrobromic acid (10 ml, 48%) and hypophosphorous acid (0.05 ml, 50% by weight aqueous solution) was boiled under reflux under nitrogen for 1 hour. The mixture was evaporated to dryness under reduced pressure and the residue was neutralised with saturated sodium bicarbonate solution and then basified to pH 9 with 2M sodium hydroxide solution. The mixture was extracted with dichloromethane to give a gum. The gum was purified by flash column chromatography on silica using ethyl acetate/methanol/triethylamine (18:2:1) as the mobile phase to give an oil which was dissolved in ether and acidified with ethereal hydrogen chloride to give a solid which was collected by filtration and then recrystallised from propan-2-ol to give 4-[2-(N-benzyl-N-methylamino)ethoxy]-3-(dimethylaminomethyl)phenol dihydrochloride, m.p. 199°-200° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:14][Mg]I>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:3]=1[CH:4]([OH:5])[CH3:14]
Reactant: C[Mg]I
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Solvent: C1CCOC1
Product: CC(O)c1cc(C(F)(F)F)ccc1Br
Reaction time: 2 h

Procedure:
To 2-bromo-5-trifluoromethyl-benzaldehyde (1.0 g, 3.95 mmol) in THF (10 mL) at 0° C. under N2 was added methylmagnesium iodide (3M in diethyl ether; 2.6 mL, 7.91 mmol). The reaction was stirred for 2 hours, and then quenched with saturated aqueous NH4Cl and diluted with CH2Cl2. The aqueous layer was separated and extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH3:7])[C:3]([CH3:6])([OH:5])[CH3:4].F[C:10]1[C:11]([C:20]#[C:21][Si](C)(C)C)=[C:12]([C:18]#[N:19])[C:13](=[CH:16][CH:17]=1)[C:14]#[N:15].CCN(C(C)C)C(C)C.[NH4+].[Cl-]>[Cu]I.CN(C=O)C.O.CS(C)=O>[OH:5][C:3]([CH3:6])([CH3:4])[C:2]([N:1]1[C:10]2[C:11](=[C:12]([C:18]#[N:19])[C:13]([C:14]#[N:15])=[CH:16][CH:17]=2)[CH:20]=[CH:21]1)([CH3:8])[CH3:7]
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1C#N
Reactant: CC(C)(N)C(C)(C)O
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CC(C)(O)C(C)(C)n1ccc2c(C#N)c(C#N)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 7.7 %

Procedure:
An oven-dried vial was charged with 3-amino-2,3-dimethylbutan-2-ol (Example 35A) (0.063 g, 0.540 mmol), and 4-fluoro-3-((trimethylsilyl)ethynyl)phthalonitrile (Example 40C) (0.109 g, 0.45 mmol) and sealed with a rubber septum. DIEA (0.157 mL, 0.900 mmol) and anhyd DMSO (2 mL) were added via syringe and the mixture was stirred at rt under N2. After 18 h, the temperature was increased to 60° C. and stirring continued an additional 30 h. Upon cooling the mixture was poured into water and extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo to a dark, oily residue. An oven-dried vial was charged with the residue, followed by CuI (0.043 g, 0.225 mmol) and sealed with a rubber septum. Anhyd DMF (3 mL) was added via syringe and the septum was replaced with a PTFE-faced crimp top. The mixture was subjected to microwave heating (140° C.) for 20 min. The mixture was poured into satd NH4Cl and extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) followed by preparative HPLC (C18 stationary phase, MeCN/water gradient with 0.1% TFA additive) affording 1-(3-hydroxy-2,3-dimethylbutan-2-yl)-1H-indole-4,5-dicarbonitrile (0.0093 g, 8% yield) as a colorless solid: 1H NMR (400 MHz, CDCl3) δ 8.21 (dd, J=9.0, 0.8 Hz, 1H), 7.65 (d, J=3.5 Hz, 1H), 7.42 (d, J=9.0 Hz, 1H), 6.81 (dd, J=3.5, 0.8 Hz, 1H), 1.88 (s, 6H), 1.21 (s, 6H); MS (LCMS ES+) m/z 268 ([M+H]+, 29%), 309 ({[M+H]+MeCN}+, 100%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[O:7]1[C:11]2([CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH2:1]=[C:14]1[CH2:15][CH2:16][C:11]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCC2(CC1)OCCO2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=C1CCC2(CC1)OCCO2
Temperature: 0 °C
Yield: 141.9 %

Procedure:
To a solution of methyl triphenylphosphonium bromide (13.7 g, 38 mmol) in 1,4-dioxane (60 mL) was added potassium tert-butoxide (4.3 g, 38 mmol). The resulting yellow mixture was cooled to 0° C. in an ice-water bath and 1,4-dioxaspiro[4.5]decan-8-one (5 g, 32 mmol) was added slowly over 15 min as a solution in 1,4-dioxane (15 mL) via dropping funnel. The reaction was let stir and warm to rt over 1 h. The resulting brown-yellow reaction mixture was partitioned between methyl tert-butyl ether and saturated aqueous NH4Cl solution. The aqueous phase was extracted with methyl tert-butyl ether. The combined organic phases were washed with a saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated by rotary evaporation in vacuo to ˜20 mL. The resultant beige suspension was diluted with heptane and filtered. The filtrated was concentrated by rotary evaporation in vacuo to afford ˜7 g of crude 8-methylene-1,4-dioxaspiro[4.5]decane as a yellow liquid containing residual heptane.
Reaction SMILES: [CH2:1]([Li:5])[CH2:2][CH2:3][CH3:4].[CH3:6][C:7]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]2CCCC[C:9]=2[N:8]=1.CC1C=C(C2C=CC=CC=2)C2CCCC(C(OC)=O)C=2N=1>>[Li:5][CH:1]1[C:9]2[N:8]=[C:7]([CH3:6])[CH:16]=[C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:14]=2[CH2:4][CH2:3][CH2:2]1
Reactant: [Li]CCCC
Reactant: Cc1cc(-c2ccccc2)c2c(n1)CCCC2
Agent: COC(=O)C1CCCc2c(-c3ccccc3)cc(C)nc21
Product: [Li]C1CCCc2c(-c3ccccc3)cc(C)nc21

Procedure:
By the method described in Example 7 using n-butyl lithium solution (9% w/v, 57 ml, 0.077 mol), and 2-methyl-4-phenyl-5,6,7,8-tetrahydroquinoline, the title compound is prepared and converted in situ to methyl 2-methyl-4-phenyl-5,6,7,8-tetrahydroquinoline-8-carboxylate and then to the corresponding 8-thioamide by the procedure described in U.S. Ser. No. 460,265.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7].[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>ClCCl>[CH3:28][O:27][C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)([CH2:13][CH2:14][O:15][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:9]1)=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)N2CCC(CCO)(c3cccnc3)C2)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3cccnc3)C2)cc(OC)c1OC
Reaction time: 1 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-3-yl)-3-(2-hydroxyethyl)pyrrolidine (0.45 g, 1.16 mmol) in dichloromethane (6 mL). Cool in an ice bath. Add methanesulfonyl chloride (0.015 mL, 1.15 mmol) and triethylamine (0.032 mL, 1.6 mmol). After 1 hour, dilute the reaction mixture with dichloromethane and extract with brine. Separate the layers and extract the aqueous layers twice with dichloromethane. Combine the organic layers. Dry over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[N:6][CH:5]=1.[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35]>>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:16]2[C:15]([C:13]3[N:12]=[CH:11][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([NH:35][CH2:34][C:33]([F:37])([F:36])[F:32])=[O:2])=[CH:5][N:6]=4)[CH:14]=3)=[C:19]([C:20]([F:23])([F:21])[F:22])[O:18][N:17]=2)=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(Cl)cc4)noc3C(F)(F)F)c2)nc1
Reactant: NCC(F)(F)F
Product: O=C(NCC(F)(F)F)c1ccc(-n2cnc(-c3c(-c4ccc(Cl)cc4)noc3C(F)(F)F)c2)nc1
Yield: 96 %

Procedure:
As described for Example 48b, 6-{4-[3-(4-chloro-phenyl)-5-trifluoromethyl-isoxazol-4-yl]-imidazol-1-yl}-nicotinic acid methyl ester (100 mg, 0.23 mmol), was converted, using 2,2,2-trifluoroethylamine instead of cyclopropanemethylamine, to the title compound (110 mg, 96%) which was obtained as a white solid. MS: m/e 516.2 [M+H]+.
Reaction SMILES: O.[OH:2][C@H:3]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:8]([O:9][C@@H:10]2[O:18][C@H:17]([CH2:19][OH:20])[C@H:15]([OH:16])[C@H:13]([OH:14])[C@H:11]2[OH:12])[C@H:6]([OH:7])[C@H:4]1[OH:5].O.C(=O)=O>CO>[OH:2][CH:3]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:8]([O:9][C@@H:10]2[O:18][C@H:17]([CH2:19][OH:20])[C@H:15]([OH:16])[C@H:13]([OH:14])[C@H:11]2[OH:12])[C@H:6]([OH:7])[C@H:4]1[OH:5]
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Agent: O=C=O
Solvent: O
Solvent: CO
Product: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O

Procedure:
0.3 g of alpha-lactose monohydrate was dissolved in 2 ml deionized water, 98 ml of methanol was added to the aqueous solution and the mixture was introduced into the 32 ml particle formation vessel through the three-passage nozzle. The operating conditions were 270 bar and 70° C. inside the vessel, a solution flow rate (in the intermediate nozzle passage) of 0.5 ml/min and a supercritical CO2 flow rate (in the inner and outer passages) of 7.5 ml/min. The product (a fine white powder) was collected at the end of the experiment. An SEM micrograph and XRD pattern for the product are shown in FIGS. 5 and 6 respectively.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:14]1[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[N:15]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:10]([CH3:13])[CH2:11]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P([N:75]=[N+:76]=[N-:77])(C2C=CC=CC=2)=O)=CC=1>C1COCC1>[N:75]([CH2:11][C@H:10]([CH3:13])[C@H:9]([C@H:14]1[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[N:15]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[N+:76]=[N-:77]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C[C@@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of (R)-tert-butyl 4-((1R,2S)-1-(tert-butyldimethylsilyloxy)-3-hydroxy-2-methylpropyl)-2,2-dimethyloxazolidine-3-carboxylate (1.0 equiv.), DIAD (2.0 equiv.), and PPh3 (2.0 equiv.) in THF (0.18 M) was added DPPA (2.0 equiv., 1M solution in THF). The reaction mixture was stirred at room temperature overnight. Upon removal of the volatiles under vacuo, the residue was purified by silica gel column chromatography eluting with ethyl acetate and hexanes (1:6) to give (R)-tert-butyl 4-((1R,2S)-3-azido-1-(tert-butyldimethylsilyloxy)-2-methylpropyl)-2,2-dimethyloxazolidine-3-carboxylate as the major product (5:2) in 86% yield. LC/MS=329.3 (M+H-Boc), Rt=1.40 min (Frac 65%-95% method).
Reaction SMILES: [C:1]1([C:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([OH:27])=O)=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][S:29]([NH2:32])(=[O:31])=[O:30]>>[C:1]1([C:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:32][S:29]([CH3:28])(=[O:31])=[O:30])=[O:27])=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C=Cc1ccc(C2=C(c3ccccc3)CCc3ccccc32)cc1
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)C=Cc1ccc(C2=C(c3ccccc3)CCc3ccccc32)cc1

Procedure:
Prepared by coupling 2m and methylsulfonamide in accordance with Procedure 1, Method A described hereinabove. Yield (57%); ESI m/z: 428 (M−H−, 100%).
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][CH:4]([NH:20][C:21]1[CH:35]=[CH:34][C:24]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[O:26])=[CH:23][N:22]=1)[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[N:12]2)=[CH:7][CH:6]=1.[OH-].[Li+].Cl>O.O1CCCC1>[CH3:1][CH:2]([CH3:36])[CH2:3][CH:4]([NH:20][C:21]1[CH:35]=[CH:34][C:24]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][N:22]=1)[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[N:12]2)=[CH:9][CH:10]=1
Reactant: COC(=O)CCNC(=O)c1ccc(NC(CC(C)C)c2ccc(-n3cc(C(F)(F)F)cn3)cc2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(Nc1ccc(C(=O)NCCC(=O)O)cn1)c1ccc(-n2cc(C(F)(F)F)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
Methyl 3-(6-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)butylamino)nicotinamido)propanoate (50 mg, 0.099 mmol) was dissolved in water (5 mL) and tetrahydrofuran (5 mL). Lithium hydroxide (0.387 mL, 2N in water, 0.774 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was neutralized with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by HPLC (column: Boston Analytics Symmetrix ODS-H 150×30 mm, 5 μm; modifier: formic acid 0.225%; gradient 10 to 80% acetonitrile in water) gave (+/−)-3-(6-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)butylamino)nicotinamido)propanoic acid (25 mg, 52%). 1H NMR (400 MHz, CD3OD, δ): 8.70 (s, 1H), 8.40 (s, 1H), 7.97 (s, 1H), 7.82 (d, 1H), 7.74 (d, 2H), 7.53 (d, 2H), 6.59 (d, 1H), 5.12-5.02 (m, 1H), 3.57 (m, 2H), 2.59 (m, 2H), 1.89-1.69 (m, 2H), 1.68-1.58 (m, 1H), 1.02 (d, 3H), 0.98 (d, 3H). MS (M+1): 490.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[N:10][N:11]3[C:16](O)=[CH:15][CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.O=P(Cl)(Cl)[Cl:36]>C1(C)C=CC=CC=1>[Cl:36][C:16]1[N:11]2[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:12]2[N:13]=[CH:14][CH:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2c(-c3ccccc3Cl)nn3c(Cl)ccnc23)cc1
Temperature: 100 °C

Procedure:
To a slurry of 3-(4-chlorophenyl)-2-(2-chlorophenyl)-pyrazolo[1,5-a]pyrimidin-7-ol (I-12A-1a; 2.00 g, 5.61 mmol) and diisopropylethylamine (4.0 ml, 22 mmol) in toluene (60 ml) at room temperature was added POCl3 (2.1 ml, 22 mmol), dropwise. The mixture was heated at 100° C. for 7 hours, concentrated, in vacuo, and the purified by silica gel chromatography using 10% hexanes in methylene chloride as eluant to afford I-13A-1a (1.72 g, 82%) as a solid: +APcI MS (M+1) 374.1; 1H NMR (400 MHz, CD2Cl2) δ 8.49 (d, J=4.6 Hz, 1H), 7.54–7.38 (m, 6H), 7.28 (d, J=8.7 Hz, 2H), 7.12 (d, J=4.2 Hz, 1H).