Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21](Br)=[C:20]([F:25])[CH:19]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:39](/B(O)O)=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21](/[CH:39]=[CH:40]/[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[C:20]([F:25])[CH:19]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC/C=C/B(O)O
Reactant: CCCCCCCCOc1ccc(C#Cc2ccc(Br)c(F)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCC/C=C/c1ccc(C#Cc2ccc(OCCCCCCCC)cc2)cc1F
Yield: 72.4 %

Procedure:
In a four necked flask equipped with a thermometer and a stirrer, 1-(4-octyloxylphenyl)-2-(4-bromo-3-fluorophenyl)acetylene (4.8 g, 0.012 mol), tetrakis(triphenylphosphine)palladium (0.23 g, 0.2 mmol), toluene (50 ml), sodium carbonate (10.6 g, 0.1 mol) and water (90 ml) were charged. Then, to the mixture, E-1-nonenyl-dihydroxyborane (2.5 g, 0.015 mol) was added and reacted at a temperature of 80° to 85° C. for 6 hours. After cooling the reaction mixture, the aqueous layer was separated off, and the organic layer was washed with water. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1-(4-octyloxyphenyl)-2-[4-(1-trans-nonenyl)-3-fluorophenyl]acetylene (3.9 g). Yield: 73%.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[C:16]([C:18]1[C:23]2[N:24]=[C:25]([NH:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[O:26][C:22]=2[C:21](F)=[C:20]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:19]=1[CH3:43])#[N:17]>CS(C)=O>[C:16]([C:18]1[C:23]2[N:24]=[C:25]([NH:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[O:26][C:22]=2[C:21]([N:5]2[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]2)=[C:20]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:19]=1[CH3:43])#[N:17]
Reactant: CCOC(=O)CCCNc1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNc1nc2c(C#N)c(C)c(-c3ccccc3)c(N3CC[C@H](N(C)C)C3)c2o1
Temperature: 150 °C
Reaction time: 5 h
Yield: 48.8 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (139 μl, 1.10 mmol) and triethylamine (153 μl, 1.10 mmol) were added to a dimethyl sulfoxide (5 ml) solution of ethyl 4-[(4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazol-2-yl)amino]butanoate (I-280) (279 mg, 0.732 mmol), followed by stirring in an oil bath at 150° C. for 5 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in chloroform and washed with saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, the residue obtained by concentration was purified by silica gel column chromatography (eluent, chloroform:methanol=10:1, v/v) to obtain the entitled compound (170 mg, 49%) as a brown oily substance.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[CH2:13][CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[N+:21]([O-])([OH:23])=[O:22].O>[N+](C)([O-])=O>[N+:21]([C:5]1[CH:6]=[CH:7][C:2]([CH2:1][CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH2:13][CH2:14][CH3:15])=[CH:3][CH:4]=1)([O-:23])=[O:22]
Reactant: CCCN1CCCC1Cc1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: C[N+](=O)[O-]
Solvent: O
Product: CCCN1CCCC1Cc1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
2-Benzyl-1-propylpyrrolidine (0.90 g, 3.75 mmol) was dissolved in nitromethane (10 mL) and added to a mixture of concentrated H2SO4 (3.7 mL), concentrated nitric acid (0.3 mL) and water (0.6 mL) cooled to 5° C. After stirring for 2 h, the reaction solution was poured into water, extracted with ethyl acetate and the organic phase separated and dried over MgSO4. The filtered solution was concentrated to give a brown oil (0.95 g, 100%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[Na].[CH2:12]([OH:14])[CH3:13]>>[CH2:12]([O:14][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[CH3:13]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCO
Agent: [Na]
Product: CCOc1ccc([N+](=O)[O-])cn1

Procedure:
2-Chloro-5-nitropyridine (30.0 g) was added to a solution of sodium metal (4.4 g) in absolute ethanol (250 ml) under a nitrogen atmosphere. The mixture was boiled under reflux for 4 hours, then cooled slightly and filtered. The filtrate was cooled in ice and filtered to give 2-ethoxy-5-nitropyridine, m.p. 85°-88° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10][N:11]([CH3:13])[CH3:12])[N:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21](=[O:29])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[N:6]=1)=O.[NH3:30]>CO>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]([C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[N:7]1[C:8]([CH2:10][N:11]([CH3:12])[CH3:13])=[N:9][C:5]([C:3]([NH2:30])=[O:2])=[N:6]1)=[O:29]
Reactant: N
Reactant: COC(=O)c1nc(CN(C)C)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Solvent: CO
Product: CN(C)Cc1nc(C(N)=O)nn1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
8.66 g (0.020 mole) of 1-[2-(o-chlorobenzoyl)-4-chlorophenyl)-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-carboxylic acid methyl ester is covered over with 400 ml of methanol and 80 ml of concentrated aqueous ammonia solution. The reaction solution is stirred for 16 hours at room temperature, and thereupon concentrated in vacuo to dryness. Water is added to the residue and extraction is performed twice with methylene chloride. The organic phase is washed twice with ice-cold 1N sodium hydroxide solution and is then extracted twice with 2N hydrochloric acid solution. To the aqueous acidified solutions there are added ice and sufficient 5N sodium hydroxide solution to bring the pH-value to 10. The precipitated base is taken up in methylene chloride. The organic phase is washed twice with water and once with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated by evaporation to dryness. The amorphous residue is triturated with ether, whereupon the reaction product precipitates in crystalline form. It is filtered off with suction and washed with ether. After drying, there is obtained 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-carboxamide, m.p. 177°-180°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH:36]([F:38])[F:37])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](=[O:34])[N:27]3[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]3)[N:9]=2)[CH:7]=1.C(O)(=O)C.[NH2:43][CH2:44][C:45]1([C:48]#[N:49])[CH2:47][CH2:46]1.[Na]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH:36]([F:38])[F:37])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:27]3[CH2:32][CH2:31][CH:30]([NH:49][CH2:48][C:45]4([C:44]#[N:43])[CH2:47][CH2:46]4)[CH2:29][CH2:28]3)=[O:34])[N:9]=2)[CH:7]=1
Reactant: O=C1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Reactant: N#CC1(CN)CC1
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCl
Product: N#CC1(CNC2CCN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 4.3 %

Procedure:
To a solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(4-oxo-1-piperidyl)ethyl]pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (201.7 mg 0.38 mmol) in dichloromethane (1.0 mL) was added acetic acid (0.3 mL, 5.24 mmol). To this was then added 1-(aminomethyl)cyclopropanecarbonitrile (47.2 mg, 0.466 mmol). This was then stirred at room temperature for 5 minutes. The reaction was then cooled to 0° C. and to this was added sodium triacetyoxyborohydride (124.1 mg, 0.56 mmol) and stirred for 3 hours and let warm to room temperature in the process. LC/MS (method 31) shows product as a major peak. The reaction was quenched by adding 2 mL water followed by 10 mL saturated sodium bicarbonate solution. This was the extracted with dichloromethane and the organic layers were dried with solid anhydrous magnesium sulfate powder, filtered and concentrated to give a white solid. 20.6 mg was then purified by reverse phase HPLC purification to afford 10.2 mg of N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-(2-(4-(((1-cyanocyclopropyl)methyl)amino)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LC/MS (method 38) [M+H]+=624.2, RT=2.80 min. 1H NMR (400 MHz, DMSO-d6) 9.75 (s, 1H), 9.34 (dd, J=7.0, 1.7 Hz, 1H), 8.68 (dd, J=4.3, 1.6 Hz, 1H), 8.67 (s, 1H), 8.30 (s, 1H), 7.63 (dd, J=8.8, 2.7 Hz, 1H), 7.56 (d, J=2.7 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.29 (dd, J=7.0, 4.2 Hz, 1H), 7.25 (t, J=73.0 Hz, 1H), 5.23 (d, J=4.7 Hz, 2H), 4.12 (d, J=12.7 Hz, 1H), 3.84 (d, J=13.7 Hz, 1H), 3.14 (t, J=11.9 Hz, 1H), 2.85 (t, J=11.9 Hz, 1H), 2.71-2.65 (m, 3H), 2.02 (s, 1H), 1.83 (t, J=16.2 Hz, 2H), 1.33-1.12 (m, 4H), 0.94 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:24])[CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[ClH:24].[Cl:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH:23]=[CH:22]2
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(Cl)ccc3n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1ccc2nc(N3CCNCC3)ccc2c1

Procedure:
Prepared in analogy to example 1.6(d) from 4-(6-chloro-quinolin-2-yl)-piperazine-1-carboxylic acid tert.-butyl ester and dioxane saturated with gaseous hydrochloric acid.
Reaction SMILES: [CH:1]1([CH:7]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:18]I>O1CCCC1>[CH:1]1([CH:7]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[CH2:8][CH2:9][O:10][CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CI
Reactant: OCCC(C1CCCCC1)n1cccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCC(C1CCCCC1)n1cccn1
Reaction time: 4 h

Procedure:
To a solution of EXAMPLE 184A (0.23 g) in dry tetrahydrofuran (5 mL) was added sodium hydride (0.166 g) at 0° C. The reaction mixture was stirred for 60 minutes when methyl iodide (0.259 mL) was added and stirring was continued for 4 hours at room temperature. The reaction mixture was quenched with ammonium chloride solution (5 mL), and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude material was purified by flash chromatography on silica gel, and was eluted with 10-60% ethyl acetate/hexanes.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19]>CN(C)C=O>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cccc(C=O)c1
Temperature: 0 °C
Yield: 96.7 %

Procedure:
Into 150 ml of N,N-dimethylformamide was dissolved 10 g of 3-hydroxybenzaldehyde; 13.6 g of anhydrous potassium carbonate was added; 13.7 g of methyl 2-bromopropionate was added dropwise at room temperature under stirring and the mixture was stirred overnight at room temperature. The reaction solution was poured into ice water and the mixture was extracted twice with t-butyl methyl ether. The organic layer was washed once with 5N aqueous sodium hydroxide solution, twice with water, once with 0.1N hydrochloric acid and once with saturated aqueous sodium chloride solution in turn, dried over magnesium sulfate and then concentrated under reduced pressure to give 16.48 g of methyl 2-(3-formylphenoxy)propionate.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16](N)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.NC[C:36](N)=[O:37]>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C@H:16]([OH:17])[CH2:36][OH:37])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reactant: NCC(N)=O
Agent: Cl
Product: Cc1ccc(C(=O)NC[C@H](O)CO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting (S)-(−)-3-amino-1,2-propanediol for glycineamide HCl. 1H NMR (CD3OD/400 MHZ) δ8.32 (s, 1H), 7.92 (m, 1H), 7.77 (s, 1H), 7.61 (q, 1H, J=8.4 Hz), 7.53 (d, 1H, J=8.0 Hz), 7.02 (m, 2H), 5.60 (m, 2H), 3.81 (m, 1H), 3.55 (m, 3H), 3.39 (m, 1H), 2.20 (s, 3H). ESHRMS m/z 480.1131 (M+H calculated for C22H21ClF2N3O5 requires 480.1132).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])[CH2:4][CH2:3]1.[H][H]>[Pd].CCOC(C)=O.CO>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:6][CH2:7]1
Reactant: COC(=O)/C=C/c1ccccc1NC1CCN(C)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CCc1ccccc1NC1CCN(C)CC1

Procedure:
A suspension of (E)-methyl 3-(2-(1-methylpiperidin-4-ylamino)phenyl)acrylate (330 mg, 1.20 mmol) and palladium on carbon (10% wt, 128 mg, 0.12 mmol) in 20 mL EtOAc was stirred under a balloon of hydrogen overnight. The suspension was diluted with MeOH (50 mL) and filtered through a pad of celite. The celite pad was rinsed with 10 mL of MeOH. The filtrate was concentrated and the residue was subjected to flash chromatography on silica gel using 5% 2M NH3 in MeOH/CH2Cl2. A light yellow oil was obtained (300 mg, 90.4%). 1H-NMR (CDCl3) δ 7.14-7.08 (m, 1H), 7.04-7.01 (m, 1H), 6.67-6.63 (m, 2H), 3.76-3.74 (m, 1H), 3.69 (s, 3H), 3.35 (brs, 1H), 2.82-2.77 (m, 4H), 2.65-2.60 (m, 2H), 2.31 (s, 3H), 2.19-2.06 (m, 4H), 1.61-1.49 (m, 2H). MS (ESI): 277.2 (M+1, 100%).
Reaction SMILES: CN(C=O)C.[Br:6][C:7]1[CH:8]=[C:9]([Cl:16])[C:10]([Cl:15])=[C:11]([CH2:13][OH:14])[CH:12]=1.Cl[Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>CCOCC>[Br:6][C:7]1[CH:8]=[C:9]([Cl:16])[C:10]([Cl:15])=[C:11]([CH2:13][O:14][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:12]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cc(Br)cc(Cl)c1Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)cc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a DMF (0.34 M) solution of (5-bromo-2,3-dichlorophenyl)methanol (1 eq.) from the previous step was added chloro(1,1-dimethylethyl)dimethylsilane (1.1 eq.) and imidazole (1.5 eq.). The resulting yellow solution was stirred at RT for 16 h. The reaction mixture was then diluted with ether and washed sequentially with 10% aq. HCl, water and brine. The ether extract was dried Na2SO4, filtered and the filtrate concentrated in vacuo to afford the crude title compound as a colorless oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH:7]1[C:9]2([CH2:12][N:11]([C:13]([C:15]3[C:20]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=4[F:29])=[C:19]([F:30])[C:18]([F:31])=[CH:17][CH:16]=3)=[O:14])[CH2:10]2)[O:8]1.[N-:32]=[N+:33]=[N-:34].[Na+].C(OCC)(=O)C>CN(C)C=O>[N:32]([CH:7]([C:9]1([OH:8])[CH2:10][N:11]([C:13]([C:15]2[CH:16]=[CH:17][C:18]([F:31])=[C:19]([F:30])[C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[O:14])[CH2:12]1)[CH2:6][CH:2]1[O:3][CH2:4][CH2:5][O:1]1)=[N+:33]=[N-:34]
Reactant: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC2(C1)OC2CC1OCCO1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(CC1OCCO1)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reaction time: 22 h
Yield: 73.7 %

Procedure:
6-{[2-(1,3-Dioxolan-2-ylmethyl)-1-oxa-5-azaspiro[2.3]hex-5-yl]carbonyl}-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline (31 mg, 0.057 mmol) was dissolved in dimethylformamide (0.5 mL) and sodium azide (20 mg, 0.308 mmol) was added. The mixture was stirred at ambient for 22 h. The mixture was partitioned between ethyl acetate and 5% lithium chloride. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with water, brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 50% ethyl acetate in hexanes) gave 3-[1-azido-2-(1,3-dioxolan-2-yl)ethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (25 mg, 0.042 mmol, 74% yield): MS (EI) for C21H19F3IN5O4: 590 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[N:9]2[C:10](=[O:30])[C:11]([CH:28]=[O:29])=[C:12]([CH2:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)[C:13]([CH:14]3[CH2:16][CH2:15]3)=[C:8]2[S:7][CH2:6]1)=[O:4].[O-:31]Cl=O.[Na+].Cl>CS(C)=O.O>[CH3:1][O:2][C:3]([C@H:5]1[N:9]2[C:10](=[O:30])[C:11]([C:28]([OH:31])=[O:29])=[C:12]([CH2:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)[C:13]([CH:14]3[CH2:16][CH2:15]3)=[C:8]2[S:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CSc2c(C3CC3)c(Cc3cccc4ccccc34)c(C=O)c(=O)n21
Reactant: [O-][Cl+][O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)[C@@H]1CSc2c(C3CC3)c(Cc3cccc4ccccc34)c(C(=O)O)c(=O)n21
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 2 (100 mg, 0.239 mmol) in dimethylsulfoxide (2.40 mL), NaH2PO4 (66.0 mg, 0.478 mmol), dissolved in water (0.960 mL), was added dropwise at room temperature. The mixture was then kept on ice and NaClO2 (86.0 mg, 0.956 mmol) dissolved in water (0.480 mL), was added dropwise during 30 min. A white precipitate formed. The reaction mixture was stirred in room temperature for 1 h and then poured into a separation funnel containing ice-cooled 1M HCl. The aqueous phase was extracted with CH2Cl2 and the combined organic phases concentrated. The residue was dissolved in H2O:MeCN, 8:2 and freeze dried to yield 5 as a white powder (102 mg, yield: 98%). 1H-NMR (400 Mhz, CDCl3) δ 14.60 (s, 1H, CO2H), 8.21 (d, J=8.32 Hz, 1H, ArH), 7.85 (d, J=7.68 Hz 1H, ArH), 7.67 (d, J=8.14 Hz, 1H, ArH) 7.61-7.45 (m, 2H, ArH) 7.30-7.21 (m, 1H, ArH), 6.69 (d, J=6.72 Hz, 1H, ArH), 5.78 (d, J=8.42 Hz, 1H, ArH), 5.51 (d, J=14.55 Hz, 1H, Nph-CH2) 5.37 (d, J=14.55 Hz, 1H, Nph-CH2) 3.87 (s, 3H, CH3) 3.82-3.72 (m, 1H, SCH2) 3.63-3.54 (m, 1H, SCH2) 1.44-1.32 (m, 1H, CH-cyclopropyl) 0.81-0.64 (m, 2H) 0.56 (sd, 2H, CH2-cyclopropyl) 13C-NMR (100 Mhz, CDCl3) δ 167.59, 165.24, 165.09, 163.75, 154.33, 134.92, 133.84, 132.16, 128.83, 126.78, 126.15, 125.76, 125.51, 123.40, 123.23, 118.68, 112.72, 64.10, 53.84, 33.35, 31.58, 12.10, 8.35, 7.67.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](=[O:16])[CH:13]=[N+]=[N-])=[CH:4][CH:3]=1.[BrH:17].C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[Br:17][CH2:13][C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([Br:1])=[CH:3][CH:4]=1)=[O:16]
Reactant: [N-]=[N+]=CC(=O)c1ccc(Br)c2ccccc12
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CBr)c1ccc(Br)c2ccccc12
Reaction time: 0.25 h
Yield: 51 %

Procedure:
1-(4-Bromonaphthalen-1-yl)-2-diazoethanone (13.8 g) was dissolved in ethyl acetate (200 mL), and hydrobromic acid solution (8.4 mL, 5.7 M in acetic acid) was added at 0° C. Reaction mixture was stirred 15 minutes, NaHCO3 solution (100 mL) was added, and mixture was stirred 10 minutes. Ethyl acetate solution was extracted twice with NaHCO3 solution (50 mL), once with brine (50 mL), and evaporated under vacuum. The oil was dissolved in DCM and purified by chromatography (0-20% ethyl acetate:hexane), giving 2-bromo-1-(4-bromo-naphthalen-1-yl)-ethanone (6.67 g, 51%) as a tan solid.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:9][N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH:13]1[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]1
Reactant: CN1CCC(=O)CC1
Reactant: Nc1ccccc1I
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCC(Nc2ccccc2I)CC1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A solution of 2-iodoaniline (1.0 g, 4.57 mmol) in 15 mL 1,2-dichloroethane was treated with 1-methylpiperidin-4-one (530 μL, 4.57 mmol) followed by sodium triacetoxyborohydride (1.55 g, 7.31 mmol) then acetic acid (259 μL). The suspension was stirred at room temperature for 21 hours. After this time, the mixture was cooled to 0° C., quenched with 20 mL 1N NaOH and extracted with 2×100 mL CH2Cl2. The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was subjected to flash chromatography on silica gel using 5% 2M NH3 in MeOH/CH2Cl2. A light yellow oil was obtained (579 mg, 40.2%). 1H-NMR (CDCl3) δ 7.64 (dd, J=1.2, 8.1 Hz, 1H), 7.21-7.15 (m, 1H), 6.57 (d, J=8.1 Hz, 1H), 6.44-6.39 (m, 1H), 4.12-4.10 (m, 1H), 3.37-3.35 (m, 1H), 3.79-2.75 (m, 2H), 2.31 (s, 3H), 2.22-2.03 (m, 4H), 1.65-1.53 (m, 2H). MS (ESI): 317.1 (M+1, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1(N[S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])C=CC=CC=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:24][C:23]([F:26])([F:25])[S:20]([O:1][C:2]1[CH:11]=[C:10]([O:12][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:22])=[O:21]
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reactant: COC(=O)c1ccc(O)cc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1OS(=O)(=O)C(F)(F)F
Yield: 88.8 %

Procedure:
A solution of methyl 2,4-dihydroxybenzoate 46 (0.5 g, 2.97 mmol), N-phenyltrifluoro-methanesulfonamide (2.125 g, 5.95 mmol) and DIPEA (1.039 mL, 5.95 mmol) in DCM (15 mL) was stirred at room temperature for 2 days then washed with saturated NaHCO3, brine, dried over MgSO4, filtered and solvent evaporated to provide methyl 2,4-bis(trifluoromethylsulfonyloxy)benzoate 47 (1.14 g, 89% yield) after purification by Biotage (0 to 10% EtOAc in Hexane). LRMS (ESI): (calc.) 431.94 (found) 455.0 (MNa)+