Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[N:31]3[C:26]([CH:27]=[CH:28][CH:29]=[CH:30]3)=[C:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:24]=2[CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=2[CH3:46])=[O:22])[CH2:17][C@@H:16]1[CH2:47][C:48](=[O:57])[NH:49][CH2:50][C:51]([C:54](=[O:56])[NH2:55])([CH3:53])[CH3:52])=O)(C)(C)C>C(Cl)Cl>[F:45][C:41]1[C:40]([CH3:46])=[C:39]([CH:44]=[CH:43][CH:42]=1)[CH2:38][C:24]1[C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:26]2[N:31]([C:23]=1[C:21]([N:18]1[CH2:19][CH2:20][NH:15][C@@H:16]([CH2:47][C:48]([NH:49][CH2:50][C:51]([CH3:53])([CH3:52])[C:54]([NH2:55])=[O:56])=[O:57])[CH2:17]1)=[O:22])[CH:30]=[CH:29][CH:28]=[CH:27]2
Reactant: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CC(=O)NCC(C)(C)C(N)=O)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN[C@@H](CC(=O)NCC(C)(C)C(N)=O)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 83.1 %

Procedure:
A 4 N solution of hydrogen chloride in dioxane (0.68 ml, 2.71 mmol) was added to a solution of the compound of step 6 (0.185 g, 0.27 mmol) in 2.7 ml of anhydrous DCM and the mixture stirred at room temperature for 2.5 h. After evaporation of the solvents, the obtained solid was triturated with anhydrous diethyl ether/DCM (9:1) and dried in vacuo at 45° C. to give 0.131 g of the title compound in the form of 3-(2-{(S)-4-[2-(3-fluoro-2-methyl-benzyl)-1-phenyl-indolizine-3-carbonyl]-piperazin-2-yl}-acetylamino)-2,2-dimethyl-propionamide hydrochloride as a light green powder with the following characteristics:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C@@H:9]([CH:17]=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([Mg]Br)[CH:21]=[CH2:22].[Cl-].[NH4+]>CCOCC.O>[C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:17]([OH:18])[CH2:22][CH:21]=[CH2:20])[CH3:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](C=O)Cc1ccccc1
Reactant: C=CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: C=CCC(O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Temperature: -78 °C

Procedure:
N-((1R)-1-Formyl-2-phenylethyl)-N-methylcarbamic acid tert-butylester (6.0 g, 20.0 mmol) was dissolved in ether (150 mL). The solution was cooled to -78° C. and allylmagnesium bromide (22 mL of a 1.0 M solution in ether, 22 mmol) was added dropwise. After addition, the solution was warmed to room temp. It was given onto 10% ammonium chloride solution in water (200 mL). The phases were separated. The aqueous phase was extracted with ethyl acetate (3×50 mL). The organic layers were combined and washed with satd. sodium hydrogencarbonate solution (100 mL) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (260 g) with ethyl acetate/heptane 1:1 to give 4.00 g of N-((1R)-1-benzyl-2-hydroxypent-4-enyl)-N-methylcarbamic acid tert-butylester.
Reaction SMILES: C([O:5][C:6](=[O:46])[C:7]([O:10]/[N:11]=[C:12](/[C:33]1[N:34]=[C:35]([NH:38]C(OC(C)(C)C)=O)[S:36][CH:37]=1)\[C:13]([NH:15][C@H:16]1[C@@H:19]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]2=[O:27])[N:18]([S:28]([OH:31])(=[O:30])=[O:29])[C:17]1=[O:32])=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:38][C:35]1[S:36][CH:37]=[C:33](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:46])=[O:5])/[C:13](=[O:14])[NH:15][C@H:16]2[C@@H:19]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])[N:18]([S:28]([OH:31])(=[O:29])=[O:30])[C:17]2=[O:32])[N:34]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2CN2CCCCC2=O)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1CN1CCCCC1=O)c1csc(N)n1)C(=O)O
Yield: 19.9 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (3S,4R)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-oxo-4-((2-oxopiperidin-1-yl)methyl)azetidine-1-sulfonic acid (34 mg, 0.049 mmol), DCM (494 μL) and TFA (228 μl, 2.96 mmol). The crude residue purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (5.2 mg, 17%) as a white powder. LCMS: Rt=0.63 min, m/z=533.1 (M+1) Method 2m_acidic_polar; 1H NMR (400 MHz, D2O) δ 7.02 (s, 1H), 5.27 (d, J=5.5 Hz, 1H), 4.59-4.48 (m, 1H), 3.61 (d, J=4.7 Hz, 2H), 3.48-3.37 (m, 1H), 3.32 (d, J=5.9 Hz, 1H), 2.34-2.13 (m, 2H), 1.78-1.57 (m, 4H), 1.39 (br s, 6H).
Reaction SMILES: C1(C)C=CC=CC=1.[H-].[Br:9][C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[CH2:13][CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16].Cl>CO>[Br:9][C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[CH2:13][CH:14]([CH2:15][OH:16])[CH2:20][OH:21]
Reactant: CCOC(=O)C(Cc1cccc(Br)c1)C(=O)OCC
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: OCC(CO)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
To an ice-cooled 94 ml of 1.0 M diisobutylalminium hydride toluene solution was added dropwise 5.41 g of diethyl (3-bromobenzyl)malonate at 15° C. or less under argon flow. The mixture was stirred for 30 minutes under ice-cooling, warmed to room temperature and stirred for 2 hours. The reaction solution was ice-cooled, and 21 ml of methanol was added dropwise slowly, then 41 ml of 2 N hydrochloric acid was added dropwise. The mixture was stirred for 20 minutes at room temperature. The reaction solution was filtered to remove insolubles, extracted with ethyl acetate, washed with saturated sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, chloroform:methanol=10:1) to provide 1.96 g of the objective compound as white crystals. M.p 61–63° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:15][CH2:14][CH2:13][CH2:12][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1Cc2ccccc2N1CCCCl

Procedure:
Oxindole (2.00 g, 0.0150 mol), 1-bromo-3-chloropropane (2.97 mL, 0.03 mol), and potassium carbonate (4.15 g, 0.03 mol) in acetonitrile (40 mL) were heated at reflux for 20 hours. The mixture was evaporated, diluted with ethyl acetate, washed with 2M aqueous hydrochloric acid and brine, dried (MgSO4), and evaporated. The residue was purified by Biotage flash column chromatography (30% ethyl acetate/hexanes) to give product as an oil which solidified on standing (1.57 g, 50%); MS for C11H12ClNO m/z 210 (M+H)+.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.C([O:19][C:20](=[O:31])[C:21]#[C:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:10]([N:4]1[CH2:3][C:22]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)=[C:21]([C:20]([OH:31])=[O:19])[CH2:5]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)C#Cc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C1=C(c2ccc(Cl)c(Cl)c2)CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At r.t., a solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methyl amine (262.5 g, 1.06 mol) in CH2Cl2 (0.6 l) was added dropwise over 60 min to a solution of (3,4-dichloro-phenyl)-propynoic acid ethyl ester (172.0 g, 0.71 mol) and trifluoroacetic acid (5.4 ml, 0.07 mol) in CH2Cl2 (0.7 l). The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was then evaporated to dryness, and the residue was dissolved in dioxane (1.6 l). An aqueous solution of NaOH (1.0 l, 1.9 mol, 2.8 eq.) was added. The resulting emulsion was stirred at r.t. for 20 h, and the low boiling organic solvent was removed under vacuum. Water (2.0 l) was added, and the aqueous layer was separated and washed with TBME (2 times 1.2 l). The aqueous layer was then acidified to a pH value of 2.5 by addition of 25% HCl. The resulting suspension was then stirred overnight, and the white precipitate was filtered off, washed with water and ethanol and dried under high vacuum to yield 205.0 g (83%) of IIb as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.FC(F)(F)[C:13]([O:15][C:16](=O)C(F)(F)F)=[O:14].O>CN(C=O)C>[CH3:16][O:15][C:13]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][CH:6]=1)=[O:14]
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c[nH]c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A solution of 5-fluoroindole (5 g, 37.0 mmol) in DMF (40 mL) was treated at 0° C. with trifluoroacetic anhydride (6.1 mL, 42.6 mmol). After 30 min, the reaction was poured into water and the resulting precipitate collected by filtration, washed with water, then dried in vacuo. The solid was then dissolved in 10% aqueous NaOH (200 mL) and heated at reflux for 1 h. The reaction mixture was cooled to RT, washed with DCM and acidified with aqueous HCl. The resulting white precipitate was collected by filtration, washed with water, taken up in DCM, washed with water, dried (MgSO4) and evaporated in vacuo. The resulting material (5 g, 75%) was dissolved in methanol (80 mL) and treated with concentrated sulfuric acid (2 mL) then heated at reflux overnight. The reaction was cooled and the resulting precipitate collected, washed with water and concentrated in vacuo to give 5-fluoro-1H-indole-3-carboxylic acid methyl ester as a peach-coloured solid (4.5 g, 83%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:5]([NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:6].C(N(CC)CC)C.[CH3:28][C:29]1([CH3:36])[C:33]([CH3:35])([CH3:34])[O:32][BH:31][O:30]1>O1CCOCC1.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>[CH3:20][C:19]1[CH:18]=[CH:17][C:4]([C:5]([NH:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:6])=[CH:3][C:2]=1[B:31]1[O:32][C:33]([CH3:35])([CH3:34])[C:29]([CH3:36])([CH3:28])[O:30]1
Reactant: Cc1ccc(C(=O)NCCCN2CCOCC2)cc1I
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NCCCN2CCOCC2)cc1B1OC(C)(C)C(C)(C)O1

Procedure:
The procedure used in Example 3: step b was followed using 3-iodo-4-methyl-N-(3-morpholin-4-yl-propyl)-benzamide ((Example 301: step a) 695 mg, 1.79 mmol), PdCl2(PPh3)2 (63 mg, 0.09 mmol), triethylamine (1.25 mL, 9.4 mmol), and 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.91 mL, 6.4 mmol) in dioxane (5 mL). Analogous aqueous workup and purification by SiO2 flash column chromatography (0–10% MeOH in DCM) yielded the title compound contaminated with the product resulting from halide reduction (653 mg, 94%). The material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[O:10][C:11]2[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][C:12]=2[N:13]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:57]1([CH3:66])[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[CH2:63][CH2:64][NH2:65]>CN(C=O)C>[C:57]1([CH3:66])[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[CH2:63][CH2:64][NH:65][C:18]([C:16]1[CH:15]=[CH:14][C:12]2[N:13]=[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[O:10][C:11]=2[CH:17]=1)=[O:20]
Reactant: O=C(O)c1ccc2nc(-c3c(Cl)cccc3Cl)oc2c1
Reactant: Cc1ccccc1CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1CCNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)oc2c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2,6-dichloro-phenyl)-benzooxazole-6-carboxylic acid (8.9 mg) in anhydrous DMF (0.5 mL) was added BOP (17.4 mg), diisopropylethylamine (0.014 mL), and 2-o-tolyl-ethylamine (5.5 mg). The reaction mixture was stirred at 85° C. overnight, quenched with 1N NaOH aqueous solution at 0° C., extracted with EtOAc. The extracts were dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was purified by silica SPE eluting with EtOAc/Hexane to give 2-(2,6-dichlorophenyl)-benzooxazole-6-carboxylic acid (2-o-tolyl-ethyl)-amide: MS (m/z) 425.1 (M+1).
Reaction SMILES: O.O.[F-].[K+].[OH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[C:13]=1[OH:14])[CH:9]=[O:10].Br[CH2:19][CH2:20]Br>CN(C)C=O>[N+:15]([C:12]1[C:13]2[O:14][CH2:19][CH2:20][O:5][C:6]=2[CH:7]=[C:8]([CH:9]=[O:10])[CH:11]=1)([O-:17])=[O:16]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: BrCCBr
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc2c(c([N+](=O)[O-])c1)OCCO2
Temperature: 130 °C
Yield: 61.3 %

Procedure:
To a mixture of potassium fluoride dihydrate (2.573 g, 27.3 mmol), and 3,4-dihydroxy-5-nitrobenzaldehyde (500 mg, 2.73 mmol) in N,N-dimethylformamide (20 mL) was added 1,2-dibromoethane (3.8 mL, 43.7 mmol), and the mixture was heated at 130° C. for 17 h. The reaction mixture was quenched with water followed by a standard aqueous/EtOAc workup and purified by column chromatography on silica gel (petroleum ether/ethyl acetate=15:1) to give Intermediate 45 (350 mg, yield 62.1%).
Reaction SMILES: [H-].[Na+].[C:3]([O:6][C@H:7]([CH3:24])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[NH:19][N:18]=[N:17][C:16]=2[N:15]([CH3:23])[C:13]1=[O:14])(=[O:5])[CH3:4].[CH3:25]I>CS(C)=O>[C:3]([O:6][C@H:7]([CH3:24])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH3:25])[N:18]=[N:17][C:16]=2[N:15]([CH3:23])[C:13]1=[O:14])(=[O:5])[CH3:4]
Reactant: CI
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2[nH]nnc2n(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nnn2C)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.4 %

Procedure:
To a suspension of sodium hydride (22 mg, 0.91 mmol) in anhydrous dimethylsulfoxide (4.0 ml) was added (R)-1-(5-acetoxyhexyl)-3-methyl-8-azaxanthine (225 mg, 0.728 mmol). After stirring at room temperature for 30 min, the mixture was treated with methyl iodide (524 mg, 3.64 mmol). After stirring at room temperature overnight, the reaction was quenched by addition of saturated aqueous sodium chloride solution (20 ml) and then extracted with ethyl acetate (3×15 ml). The combined extracts were washed with water (10 ml), with saturated aqueous sodium chloride solution (10 ml) and dried over magnesium sulfate. TLC showed that there were two products in this mixture. After evaporation of the solvent under reduced pressure, the crude products were purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:1) to provide (R)-1-(5-acetoxyhexyl)-3,7-dimethyl-8-azaxanthine (74 mg, 31% yield) followed by (R)-1-(5-acetoxyhexyl)-3,8-dimethyl-8-azaxanthine (66 mg, 28% yield).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][C:5]1([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)[CH2:7][O:6]1.[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1>CN(C)C=O>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][C:5]([C:8]1([C:11]#[N:12])[CH2:10][CH2:9]1)([OH:6])[CH2:7][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1
Reactant: c1nc[nH]n1
Reactant: N#CC1(C2(Cc3ccccc3F)CO2)CC1
Solvent: CN(C)C=O
Product: N#CC1(C(O)(Cc2ccccc2F)Cn2cncn2)CC1
Reaction time: 4 h
Yield: 46 %

Procedure:
2.26 g (10.4mmol) of 2-(2-fluorobenzyl)-2-(1-cyanocyclo-propyl)-oxirane in 10 ml of dimethylformamide are added dropwise at 80° C. with stirring to a solution of 0.23 g (2.1 mmol) of potassium tert.-butylate and 2.15 g (31.2 mmol) of 1,2,4-triazole in 10 ml of dimethylformamide. When the addition has ended, stirring of the reaction mixture is continued for 4 hours at 80° C. The mixture is subsequently concentrated under reduced pressure, and the residue is taken up in ethyl acetate/water. The aqueous phase is extracted three times using ethyl acetate. The combined organic extracts are dried over sodium sulphate, concentrated under reduced pressure and chromatographed on silica gel using the eluent cyclohexane/ethyl acetate =1:1. 1.37 g (46% of theory) of 1-(2-fluorophenyl)-2-(1-cyanocyclopropyl)-3-(1,2,4-triazol-1-yl)-propan -2-ol are isolated.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH:26]=[C:25]([OH:27])[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:23]1>CN(C=O)C.CCOC(C)=O>[CH2:7]([O:27][C:25]1[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:23][N:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[F:15])[CH:26]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1nn(-c2ccccc2F)cc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(-c2ccccc2F)cc1OCc1ccccc1
Reaction time: 8 h

Procedure:
K2CO3 (2.00 g) and benzylchloride (1.2 mL) were added to a solution of ethyl 1-(2-fluorophenyl)-4-hydroxypyrazole-3-carboxylate (2.47 g) in anhydrous DMF (20 mL) at room temperature, and the mixture was stirred overnight. The mixture was diluted with EtOAc and washed with H2O, sat. NaHCO3 and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc/hexane 1/19, 1/9, 1/4 and 1/2) to yield 3.09 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].CO[CH:15]1[CH2:19][CH2:18][CH:17](OC)O1>C(O)(=O)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([N:1]2[CH:15]=[CH:19][CH:18]=[CH:17]2)=[C:3]([CH:6]=1)[C:4]#[N:5])([O-:12])=[O:11]
Reactant: COC1CCC(OC)O1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Solvent: CC(=O)O
Product: N#Cc1cc([N+](=O)[O-])ccc1-n1cccc1
Yield: 106.8 %

Procedure:
In a manner similar to Example 1, Step A, the reaction of 30.0 g (0.18 mole) of 2-amino-5-nitrobenzonitrile with 28.7 g (0.22 mole) of 2,5-dimethoxytetrahydrofuran in 60 ml of glacial acetic acid produced 41.0 g of 5-nitro-2-(1H-pyrrol-1-yl)benzonitrile.
Reaction SMILES: O.NN.[CH3:4][C:5]1[C:9]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[C:8]([N:15]2C(=O)C3C(=CC=CC=3)C2=O)[S:7][N:6]=1>CCO>[CH3:4][C:5]1[C:9]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[C:8]([NH2:15])[S:7][N:6]=1
Reactant: Cc1nsc(N2C(=O)c3ccccc3C2=O)c1N1CCCC1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1nsc(N)c1N1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Hydrazine hydrate (25.56 mg, 25.03 μL, 0.5106 mmol) was added to a solution of 2-(3-methyl-4-pyrrolidin-1-yl-isothiazol-5-yl)isoindoline-1,3-dione (160 mg, 0.5106 mmol) in EtOH (5 mL) and the mixture was stirred at RT for 10 min. The mixture was heated for 15 min at 120° C. in a microwave, then was concentrated in vacuo. The residue was purified by fractionlynx. The clean fractions were concentrated in vacuo and dried by azeotropic distillation with toluene (×2) to yield 3-methyl-4-(pyrrolidin-1-yl)isothiazol-5-amine as pale yellow solid. (61.7 mg, 59.9% over two steps). MS (ES+) 184.1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=2)=[CH:2]1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.B(F)(F)F.C(Cl)Cl>CCOC(C)=O>[OH:18][C:12]1[CH:17]=[CH:16][C:15]([SH:1]2[CH:5]=[CH:4][C:3]([CH:6]3[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)=[CH:2]2)=[CH:14][CH:13]=1
Reactant: Oc1ccccc1
Reactant: C1=C(c2ccsc2)CCCC1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Oc1ccc([SH]2C=CC(C3CCCCC3)=C2)cc1
Temperature: 70 °C

Procedure:
Thiophene-3-yl cyclohexene (72.3 mg, 0.44 mmol), and phenol (82.8 mg, 0.88 mmol) was mixed and gently heated until uniform and BF3*H3PO4 (4 uL, 0.044 mmol) was added. The mixture was heated at 70° C. overnight and the dark residue was diluted with EtOAc, washed with sat. NaHCO3, dried and concentrated. Column chromatography (silica, 0-20% EtOAc) gave a mixture of isomers and the desired product could be isolated by preparative TLC (DCM eluent). Yield: 3.7 mg, off-white/pale yellow solid. GC-MS: M+=258.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:41][OH:42])[C@@H:21]([OH:40])[C@@H:22]([OH:39])[C@H:23]([OH:38])[C:24]([NH:26][C@H:27]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:28][C:29](O)=[O:30])=[O:25])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:44]1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.N>C(#N)C.CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:41][OH:42])[C@@H:21]([OH:40])[C@@H:22]([OH:39])[C@H:23]([OH:38])[C:24]([NH:26][C@H:27]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:28][C:29]([NH2:44])=[O:30])=[O:25])=[O:18])[CH2:13][CH:14]([CH3:15])[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(N)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
A solution of (S)-3-[(2S,3R,4R,5S)-5-(N-benzyloxycarbonyl-L-leucyl)amino-2,3,4,6-tetrahydroxyhexanoyl]amino-3-phenylpropionic acid (295 mg), N-hydroxysuccinimide (58 mg) and N,N′-dicyclohexylcarbodimide (103 mg) in acetonitrile (10 ml) was stirred at room temperature for 3 hours and the formed insoluble solid was filtrated off. Removal of the organic solvent gave a residue, which was dissolved in dimethylformamide (5 ml), followed by addition of 25% aqueous ammonia solution (1 ml). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was extracted with ethyl acetate and the extract was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine respectively. After drying over anhydrous sodium sulfate, removal of the organic solvent gave a residue, which was recrystallized from methanol-diethylether to give the title compound (97 mg).