Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](I)[CH3:17].O>CS(C)=O>[Br:1][C:2]1[O:3][C:4]([C:7]([O:9][CH2:16][CH3:17])=[O:8])=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(Br)o1
Reaction time: 15 h

Procedure:
To absolution of 2-bromo-5-carboxyfuran (10 g) in dimethyl sulfoxide (100 ml), potassium carbonate (7.96 g) was added at 15 to 30° C. and ethyl iodide (16.8 ml) was added dropwise thereto. The mixture was stirred for 15 hours. The reaction solution was then poured into water and extracted with chloroform. The organic layer was washed with water, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=2;l) to obtain 11.34 g of the desired product as an oil.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[CH2:11]O.C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:14][CH2:11][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[I:1])[CH2:8][CH2:7][CH2:6]2
Reactant: OCc1cc2c(cc1I)CCC2
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cc2c(cc1I)CCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (6-iodo-2,3-dihydro-1H-inden-5-yl)methanol (36 mg, 0.131 mmol) and carbon tetrabromide (52 mg, 0.158 mmol) in CH2Cl2 (1 mL) at 0° C. under N2, was added triphenylphosphine (41 mg, 0.158 mmol). The resulting solution was allowed to warm to room temperature and was stirred for 4 h. Another portion of carbon tetrabromide (52 mg, 0.158 mmol) and triphenylphosphine (41 mg, 0.158 mmol) was added to the mixture at 0° C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography (Si, 1% EtOAc in hexanes) to afford 5-(bromomethyl)-6-iodoindane. 1H NMR (500 MHz, CDCl3) δ 7.72 (s, 1H), 7.36 (s, 1H), 4.62 (s, 2H), 2.89 (m, 4H), 2.11-2.07 (m, 2H).
Reaction SMILES: [C:1]([C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1)#[CH:2].[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13].[C-:14]1([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23](I)[CH:22]=2)[CH:18]=[CH:17][CH:16]=[CH:15]1.[CH-:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1.[Fe+2]>>[C-:3]1([C:1]#[C:2][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([C:20]#[C:19][C-:14]3[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH:22]=2)[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13].[CH-:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1.[Fe+2:13]
Reactant: Ic1cccc(C#C[c-]2cccc2)c1
Reactant: C#C[c-]1cccc1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Product: C(#C[c-]1cccc1)c1cccc(C#C[c-]2cccc2)c1

Procedure:
Example 11 describes the procedure for producing 1,3-bis(ferrocenylethynyl) benzene 516. Ethynylferrocene 500 was reacted with 1,3-diiodobenzene 502 to form 1-(ferrocenylethynyl)-3-iodobenzene 504. Sufficient ethynylferrocene 500 was present such that the second step of the reaction immediately proceeded. 1-(Ferrocenylethynyl)-3-iodobenzene 504 reacted with ethynylferrocene 514 to form 1,3-bis(ferrocenylethynyl) benzene 516. The reaction procedure is shown in FIG. 5.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]3[C:20]4[CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][C:16](=[O:23])[C:15]=4[C:14]([CH3:24])=[CH:13]3)=[CH:9][CH:10]=2)[C:5]([C:25]#[N:26])=[CH:4][N:3]=1.[NH2:27][OH:28].C(N(CC)CC)C>CCO>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]3[C:20]4[CH2:19][C:18]([CH3:21])([CH3:22])[CH2:17][C:16](=[O:23])[C:15]=4[C:14]([CH3:24])=[CH:13]3)=[CH:9][CH:10]=2)[C:5]([C:25]([NH:27][OH:28])=[NH:26])=[CH:4][N:3]=1
Reactant: NO
Reactant: Cc1cn(-c2ccc3c(N)ncc(C#N)c3c2)c2c1C(=O)CC(C)(C)C2
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cn(-c2ccc3c(N)ncc(C(=N)NO)c3c2)c2c1C(=O)CC(C)(C)C2
Reaction time: 48 h
Yield: 45 %

Procedure:
A suspension of 1-amino-6-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-isoquinoline-4-carbonitrile (0.035 g, 0.1 mmol), hydroxylamine (7 mg, 0.1 mmol) and triethylamine (0.01 mL, 0.1 mmol) in EtOH (2 mL) is placed in an oil bath at 100° C. and stirred for 2 days. The solvent is evaporated under reduced pressure, and the residue is purified using a Biotage column (0-20% MeOH/CH2Cl2) to afford 0.017 g (48%) of 1-amino-N-hydroxy-6-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-isoquinoline-4-carboxamidine. LC/MS m/z=378 [M+H]+, RT=1.82 min.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:16]([C:26]#[CH:27])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[N:3]=1.[CH3:32][CH:33]([CH3:36])[CH2:34][OH:35].[H-].[Na+].Cl>CN(C=O)C.O>[C:26]([C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([F:20])[C:17]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:7]1[C:2]([O:35][CH2:34][CH:33]([CH3:36])[CH3:32])=[N:3][C:4]([C:28]([F:31])([F:30])[F:29])=[CH:5][CH:6]=1)#[CH:27]
Reactant: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc(F)c1NS(C)(=O)=O
Reactant: CC(C)CO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2OCC(C)C)cc(F)c1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.2 %

Procedure:
A mixture of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (50 mg, 0.11 mmol), 2-methyl-1-propanol (20 μl, 0.22 mmol) and 60% NaH (13 mg, 0.33 mmol) in DMF was stirred at ambient temperature for 4 hrs. The reaction mixture was diluted with water and then acidified with 2N HCl solution. The aqueous phase was extracted with EtOAc and the combined organic phase was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex EtOAc=1/2) to give the title compound (12 mg, 40%).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.N1C=CN=C1.[CH3:12][C:13]([Si:16](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:15])[CH3:14]>C(Cl)Cl.O>[Si:16]([O:6][CH:4]1[CH2:5][NH:2][CH2:3]1)([C:13]([CH3:15])([CH3:14])[CH3:12])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OC1CNC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a solution of azetidin-3-ol hydrochloride (5.11 g, 46.7 mmol, 1.0 equiv) and 1H-imidazole (9.52 g, 140 mmol, 3.0 equiv) in DCM (100 mL) at 0° C. was added TBDPSCl (19.18 g, 70 mmol, 1.5 equiv) dropwise. The resulting mixture was stirred at rt overnight and then diluted with water, and extracted with DCM. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was eluted over a silica gel with DCM/MeOH=100/1 to 10/1 to give 12 g of 3-(tert-butyldiphenylsilyloxy) azetidine as a colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C@@H:9]1[CH2:21][C@@H:22]([OH:24])[CH3:23])=O)(C)(C)C.C(OC(N1CCN(C(OC(C)(C)C)=O)C[C@@H]1C[C@H](O)C)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:24][C@H:22]([CH3:23])[CH2:21][C@H:9]1[CH2:10][NH:11][CH2:12][CH2:13][NH:8]1
Reactant: C[C@H](O)C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: C[C@@H](O)C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](O)C[C@H]1CNCCN1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of 2(S)-(2(S)-hydroxypropyl) piperazine-1,4-dicarboxylic acid di-tert-butyl ester and 2(S)-(2(R)-hydroxypropyl) piperazine-1,4-dicarboxylic acid di-tert-butyl ester (5.11 g, 14.8 mmol) in dichloromethane (100 mL) stirring at 0° C., add trifluoroacetic acid (25 mL). Warm the mixture to room temperature and stir. After 18 hours evaporate to a yellow oil. Dilute the mixture with methanol and apply to a 60 g SCX column. Wash with methanol and elute with 2N ammonia in methanol to obtain the title compound (mixture of diastereoisomers) as an oil (1.932 g, 90%): mass spectrum (APCI): m/z =145.1 (M+1).
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C(N(CC)CC)C.[Cl:12][C:13]1[CH:14]=[C:15]([N:20]=[C:21]=[O:22])[CH:16]=[C:17]([Cl:19])[CH:18]=1>C(Cl)(Cl)Cl>[CH3:2][N:3]([OH:4])[C:21]([NH:20][C:15]1[CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]([Cl:12])[CH:14]=1)=[O:22]
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: CNO
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(O)C(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 20 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
A mixture of 10 g of N-methyl-hydroxylamine hydrochloride in 100 ml of chloroform was stirred while 18 ml of triethylamine were added at 0° C. Then, 20 g of 3,5-dichlorophenyl isocyanate in 30 ml of chloroform were added to the mixture at 10° to 15° C and the mixture was stirred for 5 hours at 20° C and was then distilled to dryness under reduced pressure. The residue was taken up in water and dried to obtain 22 g of N-methyl-N-hydroxy-N'-(3,5-dichlorophenyl)-urea melting at 131°-132° C.
Reaction SMILES: [N:1]1([C:6]2([C:10]#[N:11])[CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12]1([Li])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([CH:10]([NH2:11])[C:6]2([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:7][CH2:8][CH2:9]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [Li]c1ccccc1
Reactant: N#CC1(N2CCCC2)CCC1
Product: NC(c1ccccc1)C1(N2CCCC2)CCC1

Procedure:
The title compound, light yellow liquid, MS: m/e=231.1 [(M+H)+], was prepared in accordance with the general method of intermediate B from 1-pyrrolidin-1-yl-cyclobutanecarbonitrile (intermediate F) and phenyllithium.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.[C:11]([NH:14][CH2:15][C:16]([OH:18])=[O:17])(=O)[CH3:12].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>CC(C)=O>[CH3:12][C:11]1[O:18][C:16](=[O:17])[C:15](=[CH:1][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)[N:14]=1
Reactant: CC(=O)NCC(=O)O
Reactant: N#Cc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC1=NC(=Cc2ccc(C#N)cc2)C(=O)O1
Temperature: 50 °C

Procedure:
Acetone (80.0 l) was introduced into a mixture of 4-formylbenzonitrile (15.0 kg, 114.5 mol), N-acetylglycine (19.2 kg, 162.4 mol) and anhydrous sodium acetate (9.4 kg, 114.5 mol) followed by introduction, with stirring, of acetic anhydride (35.0 l, 370.5 mol). The reaction mixture was stirred under reflux for 1 h. The resulting thin yellow suspension was cooled to 50° C. and ice-water (200 l) was added as quickly as possible, with stirring and cooling. The mixture was stirred at 20° C. for another 1 h. To isolate the product, the yellow suspension was pressed onto a centrifuge and washed with deionized water (75 l), isopropanol (40 l) and methyl-tert-butylether (75 l). The product was dried under reduced pressure at 40° C. Yield 18.17 kg (85.7 mol, 75.2% of theory). M.p.: 192–193° C.; MS (DCl): m/z=213 [M+H+]; 1H-NMR (DMSO-d6): δ=2.42 (s, 3H), 7.30 (s, 1H), 7.96 (d, 2H), 8.33 (d, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[C:20]#[N:21])[CH:5]=[CH:4][N:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])[CH2:35][CH2:34]2)=[CH:28][C:27]=1[CH3:49].Cl.C([O-])(O)=O.[Na+]>C(O)C(F)(F)F.C(Cl)Cl>[C:20]([C:19]1[CH:18]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH:33]4[CH2:34][CH2:35][N:36]([C:39]([O:41][CH2:42][C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)=[O:40])[CH2:37][CH2:38]4)=[CH:28][C:27]=3[CH3:49])[N:7]=2)[CH:24]=[CH:23][CH:22]=1)#[N:21]
Reactant: N#Cc1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: Cc1cc(OC2CCN(C(=O)OCc3ccccc3)CC2)ccc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: OCC(F)(F)F
Product: Cc1cc(OC2CCN(C(=O)OCc3ccccc3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C#N)c3)nc3ccccn23)n1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
3-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzonitrile (Intermediate Example 5) (0.462 g, 1.39 mmol) and phenylmethyl 4-[(4-amino-3-methylphenyl)oxy]-1-piperidinecarboxylate (0.567 g, 1.67 mmol) were dissolved in 16 mL of trifluoroethanol with stirring in a pressure vessel. HCl (4N in dioxane, 0.17 mL, 0.68 mmol) was added via syringe. The vessel was sealed and placed in an 80° C. oil bath. The reaction was stirred at 80° C. for 40 h and cooled to rt. The reaction was poured into half-saturated NaHCO3 solution and DCM. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford 0.700 g (79%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.25 (br. s., 1H), 8.90 (s, 1H), 8.20 (d, J=5.1 Hz, 1H), 8.04 (s, 1H), 7.96-7.86 (m, 2H), 7.72-7.61 (m, 2H), 7.46-7.21 (m, 7H), 6.93-6.79 (m, 3H), 6.41 (d, J=5.3 Hz, 1H), 5.06 (s, 2H), 4.59-4.50 (m, 1H), 3.77-3.65 (m, 2H), 3.36-3.21 (m, 2H), 2.18 (s, 3H), 1.97-1.86 (m, 2H), 1.61-1.49 (m, 2H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([C:34]1[O:38][C:37]([CH2:39][CH2:40][CH2:41][OH:42])=[CH:36][CH:35]=1)[CH3:33].[CH3:43][N:44]1[N:48]=[N:47][C:46]([C:49]2[CH:54]=[C:53]([CH3:55])[C:52](O)=[C:51]([CH3:57])[CH:50]=2)=[N:45]1>O>[CH2:32]([C:34]1[O:38][C:37]([CH2:39][CH2:40][CH2:41][O:42][C:52]2[C:51]([CH3:57])=[CH:50][C:49]([C:46]3[N:47]=[N:48][N:44]([CH3:43])[N:45]=3)=[CH:54][C:53]=2[CH3:55])=[CH:36][CH:35]=1)[CH3:33]
Reactant: CCc1ccc(CCCO)o1
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CCc1ccc(CCCOc2c(C)cc(-c3nnn(C)n3)cc2C)o1
Temperature: 25 °C
Yield: 65.4 %

Procedure:
Diethyl azodicarboxylate (DEAD, 4.84 g; 27.8 mmol) was added under nitrogen to a stirred and cooled (-20° C.) solution of triphenylphosphine (7.37 g; 27.8 mmol), 5-ethyl-2-(3-hydroxypropyl)furan (Intermediate 1c) (3.9 g; 25.3 mmol), and 4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenol (5.69 g; 27.8 mmol). The mixture was stirred at -20° C. for 1/2 h, and then was allowed to warm to room temperature overnight. Water (50 mL) was added to the mixture and the layers were separated. The aqueous layer was extracted with ether (3×50 mL), the organic layer was washed with 10% NaOH solution (3×50 mL), water, and dried over magnesium sulfate. The solvent was concentrated in vacuo to yield a residue and purified by MPLC column chromatography (ethyl acetate/hexane, 3:7) to afford 5.63 g (65%) of 5-ethyl-2-[3-[2,6-dimethyl-4-(2-methyl-tetrazol-5-yl)phenoxy]propyl]furan (Formula II; R3 =5-ethyl, R4 =hydrogen, R1,R2 =3,5-dimethyl, R5 =2-methyltetrazol-5-yl, Y=1,3-propylene).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])=[C:6]([F:18])[C:5]([CH2:19]Br)=[CH:4][CH:3]=1.[NH3:21].CO>O1CCCC1>[NH2:21][CH2:19][C:5]1[C:6]([F:18])=[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])[C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CBr)c2F)c1
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CN)c2F)c1
Reaction time: 16 h
Yield: 21 %

Procedure:
A solution of 3-{[6-bromo-3-(bromomethyl)-2-fluorophenyl]oxy}-5-chlorobenzonitrile (2.5 g, 5.96 mmol) in tetrahydrofuran (THF) (50 mL) was added dropwise to a 7M solution of ammonia in MeOH (42.6 mL, 298 mmol) at RT under nitrogen. The reaction was stirred for 16 h then the reaction mixture was evaporated to dryness. Ethyl acetate and saturated aqueous sodium bicarbonate were added to the residue and the mixture was shaken in a separatory funnel. The organic layer was dried over sodium sulfate and the solvent was evaporated. The residue was purified by chromatography with hexane:ethyl acetate to give the title compound (0.453 g, 21%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.76 (s, 1H), 7.56 (d, 1H), 7.39-7.46 (m, 2H), 7.37 (m, 1H), 3.70 (s, 2H), 1.85 (br. s., 2H).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([CH3:32])[CH:26]=2)[C:13]([N:15]2[C@@H](C(C)C)COC2=O)=[O:14])=[CH:4][C:3]=1[CH3:35].C[OH:37].NO.[C-]#N.[K+]>C1COCC1.O>[F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([CH3:32])[CH:26]=2)[C:13]([NH:15][OH:37])=[O:14])=[CH:4][C:3]=1[CH3:35]
Reactant: Cc1cc(COCCCC[C@@H](Oc2ccc(F)c(C)c2)C(=O)N2C(=O)OC[C@@H]2C(C)C)ccc1F
Reactant: CO
Agent: NO
Agent: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(COCCCC[C@@H](Oc2ccc(F)c(C)c2)C(=O)NO)ccc1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (S)-3-((R)-6-(4-fluoro-3-methylbenzyloxy)-2-(4-fluoro-3-methylphenoxy)hexanoyl)-4-isopropyloxazolidin-2-one (100 mg, 0.20 mmol) dissolved in 2 mL of THF, methanol, and 50 wt % NH2OH in H2O (2:2:1) was added KCN (4.0 mg, 0.06 mmol). The resulting mixture stirred for 3 days at room temperature. The reaction was quenched by the addition of 1M aqueous HCl (10 mL) and the resulting mixture extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (2×5 mL). The product was isolated by flash column chromatography eluting with 0% to 10% methanol/DCM to give the title compound (54.2 mg) as colorless oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=5)[C:19]([C:33](O)=[O:34])=[CH:18][CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN.O1CCCC1.C[CH2:44][N:45](CC)CC>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([N:29]([CH3:30])[CH3:31])=[O:32])=[CH:24][CH:23]=5)[C:19]([C:33]([NH:45][CH3:44])=[O:34])=[CH:18][CH:17]=4)=[O:14])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN(C)C(=O)c1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2C(=O)O)cc1
Reactant: CCN(CC)CC
Agent: CN
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C(=O)N(C)C)cc1
Reaction time: 3 h
Yield: 10.3 %

Procedure:
5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-4′-(dimethylcarbamoyl) biphenyl-2-carboxylic acid (47 mg, 0.10 mmol) and 75 μL of a 2.0 M solution of methylamine in tetrahydrofuran (0.15 mmol) were dissolved in DMF (1.0 mL) containing Et3N (28 μL, 0.20 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and the resulting solution was allowed to stir for 3 hours. The mixture was filtered and purified by reverse phase HPLC to yield 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-N2,N4′,N4′-trimethylbiphenyl-2,4′-dicarboxamide (5.0 mg, 10%). ESI-MS m/z calc. 485.5, found 486.5 (M+1)+; retention time 2.54 minutes.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[O:14][C:13]2=[N:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][N:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl.N>CCO.CO>[N+:18]([C:16]1[N:15]=[C:13]2[N:12]([CH:17]=1)[CH2:11][CH:10]([CH2:9][OH:8])[O:14]2)([O-:20])=[O:19]
Reactant: CC(C)(C)[Si](C)(C)OCC1Cn2cc([N+](=O)[O-])nc2O1
Agent: Cl
Agent: N
Solvent: CCO
Solvent: CO
Product: O=[N+]([O-])c1cn2c(n1)OC(CO)C2
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.1 %

Procedure:
A suspension of silyl ether 89 (503 mg, 1.68 mmol) in a solution of 1% HCl in 95% EtOH (desilylation conditions described by Cunico et al., 1980) (27 mL) was stirred at room temperature for 6 h, and then stored at 4° C. for 2.5 d. The resulting solution was neutralised by dropwise addition of 7M NH3 in MeOH (2 mL) with stirring, and then concentrated to dryness and the residue was chromatographed on silica gel. Elution with 0-2% MeOH/CH2Cl2 firstly gave foreruns, and then further elution with 2-5% MeOH/CH2Cl2 gave (6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazol-2-yl)methanol (90) (reported by Sehgal et al., 1981 via reaction of 2,4-dinitroimidazole and glycidol) (299 mg, 97%) as a white solid (after trituration with CH2Cl2): mp (CH2Cl2) 166-169° C.; 1H NMR [(CD3)2SO] δ 8.10 (s, 1H), 5.40 (m, 1H), 5.27 (t, J=5.6 Hz, 1H), 4.36 (dd, J=10.5, 8.8 Hz, 1H), 4.11 (dd, J=10.5, 6.4 Hz, 1H), 3.80 (ddd, J=12.8, 5.4, 3.0 Hz, 1H), 3.65 (dd, J=12.8, 5.8, 3.9 Hz, 1H). Anal. (C6H7N3O4) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[CH:14]=[N:13][C:12]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(O)(C(F)(F)F)=O.C([SiH](C(C)C)C(C)C)(C)C>O>[NH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[C:11]([C:9]2[S:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[CH:10]=2)=[C:12]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:13]=[CH:14]1
Reactant: CC(C)(C)OC(=O)NCCCCn1cnc(-c2ccccc2)c1-c1cc2c(N)ncnc2s1
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NCCCCn1cnc(-c2ccccc2)c1-c1cc2c(N)ncnc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
tert-Butyl {4-[5-(4-aminothieno[2,3-d]pyrimidin-6-yl)-4-phenyl-1H-imidazol-1-yl]butyl}carbamate (Example 173) (23 mg) was added to a mixture of TFA, water and triisopropyl silane (5:5:1) (5 ml) and stirred at ambient temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue purified by preparative RPHPLC (eluting with a gradient of MeCN and water containing 0.1% TFA) to give the title compound as a colourless solid (18 mg, 90%);
Reaction SMILES: [OH:1]O.[OH:3][C@:4]1([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][CH:25]=3)[CH:16]=2)[O:12][C@H:11]([CH2:13][OH:14])[C@@H:9]([OH:10])[C@H:7]([OH:8])[C@H:5]1[OH:6]>O.C(O)(C(F)(F)F)C(F)(F)F>[OH:3][C@:4]1([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([S:30]([CH3:31])=[O:1])=[CH:28][CH:29]=3)[CH:16]=2)[O:12][C@H:11]([CH2:13][OH:14])[C@@H:9]([OH:10])[C@H:7]([OH:8])[C@H:5]1[OH:6]
Reactant: CSc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2C#N)cc1
Reactant: OO
Solvent: OC(C(F)(F)F)C(F)(F)F
Solvent: O
Product: CS(=O)c1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
35% Hydrogen peroxide in water (48 μL) is added to 4-(β-D-glucopyranos-1-yl)-2-(4-methylsulfanyl-benzyl)-benzonitrile (83 mg) in 1,1,1,3,3,3-hexafluoroisopropanol (2 mL). The resulting solution is stirred at ambient temperature for 1 h and then quenched by the addition of aqueous Na2S2O3 solution and aqueous NaHCO3 solution. The organic phase is separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is removed. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0->5:1).