Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]/[C:2](/[CH3:9])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].C[O:11][C:12](=O)/[CH:13]=[CH:14]/C(=C(/N)\C)/C(=O)CCC>CN(C=O)C.C(OCC)(=O)C>[OH:11][C:12]1[CH:13]=[CH:14][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([CH3:9])[N:1]=1
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CCCC(=O)C(/C=C/C(=O)OC)=C(/C)N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(O)nc1C

Procedure:
Stoichiometric amounts (0.04 mol) of methyl proplolate and ethyl 3-aminocrotonate were heated to 140° C. for 1 h. 1 g of the crude (2E,4Z)-methyl-4-(1-aminoethylidene)-5-oxooct-2-enoate in 4 mL of DMF was heated to 230° C. in a sealed microwave reactor for 40 min. The reaction mixture was diluted with ethyl acetate, washed with H2O, dried (MgSO4) and evaporated to afford crude ethyl 6-hydroxy-2-methylnicotinate. A mixture of 800 mg of crude ethyl 6-hydroxy-2-methylnicotinate in 4 mL of phosphorus oxychloride was heated to 150° C. in a sealed microwave reactor for 15 min. The reaction mixture was poured into ice/water, extracted with diethyl ether. The combined organic layers were dried (MgSO4) and evaporated. Purified by silica gel chromatograph (0-20% ethyl acetate/hexane) to yield ethyl 6-chloro-2-methylnicotinate. 400 mg of ethyl 6-chloro-2-methylnicotinate was hydrolyzed via Procedure M to give 6-chloro-2-methylnicotinic acid. 300 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-chloro-2-methylnicotinic acid via Procedure G. The reaction mixture was diluted with ethyl acetate, washed with 0.1 N sodium hydroxide and brine, dried (MgSO4) and evaporated to afford 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide. Procedure F was performed using 100 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 128 mg of 2,6-dimethylpiperazine in 1 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)-2-methylnicotinamide. MS (Q1) 436.3 (M)+.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([N:15]2[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[N:17]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[CH:26][CH:25]=3)[C:16]2=[O:34])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])C.Cl.C1(C)C=CC=CC=1>O1CCOCC1>[CH3:21][C:18]1([CH3:22])[C:19](=[O:20])[N:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([CH:8]=2)[O:6][CH2:5][CH:4]=[O:3])[C:16](=[O:34])[N:17]1[CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1
Reactant: CCOC(COc1cc(N2C(=O)N(Cc3ccnc4ccccc34)C(C)(C)C2=O)ccc1OC)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COc1ccc(N2C(=O)N(Cc3ccnc4ccccc34)C(C)(C)C2=O)cc1OCC=O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
410 mg 3-[3-(2,2-Diethoxy-ethoxy)-4-methoxy-phenyl]-5,5-dimethyl-1-quinolin-4-ylmethyl-imidazolidine-2,4-dione were dissolved in 8 ml 1,4-dioxane and 2.05 ml of an aqueous 1 N solution of hydrochloric acid were added. The mixture was stirred for 2 hours at 80° C. Removal of the solvent under reduced pressure yielded a white solid, which was coevaporated twice with toluene. Yield: 340 mg
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:35]=[C:34]3[C:30]([C:31]([NH:44][C:45](=[O:49])[CH2:46][CH2:47][CH3:48])=[N:32][N:33]3COCC[Si](C)(C)C)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)#[N:20]>O1CCCC1.C(OCC)(=O)C>[C:19]([C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:35]=[C:34]3[C:30]([C:31]([NH:44][C:45](=[O:49])[CH2:46][CH2:47][CH3:48])=[N:32][NH:33]3)=[CH:29][CH:28]=2)=[CH:25][CH:26]=1)#[N:20]
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(C#N)cc3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(C#N)cc3)ccc12
Yield: 42.8 %

Procedure:
3.0 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 400 mg of N-[6-(4-cyanophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 10 cm3 of tetrahydrofuran, and the mixture is refluxed for 18 hours. The reaction medium is diluted with 20 cm3 of ethyl acetate and the organic phase is washed successively with 20 cm3 of saturated sodium hydrogen carbonate solution, with 2×20 cm3 of water and with 20 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and then concentrated under reduced pressure (2 kPa; 50° C.). The crude product obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3 cm), eluting with a methylene chloride/methanol gradient (100/0 to 98/2 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); 120 mg of N-[6-(4-cyanophenyl)-1H-indazol-3-yl]butanamide are obtained in the form of a solid melting at 242° C.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].[CH3:28][N:29](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:28]#[N:29])[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccc(Br)cc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccc(C#N)cc12
Temperature: 120 °C
Yield: 76 %

Procedure:
In a microwave vial was degassed with argon for 15 min. a mixture of 6-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (50 mg, 0.118 mmol), zinc cyanide (14 mg, 0.118 mmol) in dimethylformamide (1.5 ml). Tetrakis(triphenylphosphine)palladium (4 ma, 0.003 mmol) was added and the vial was sealed and heated at 120° C. under microwave irradiation for 10 min. The mixture was diluted with ethyl acetate, washed with a 5% aqueous solution of ammonia, brine and dried over sodium sulfate. The solution was concentrated and purified by flash chromatography over silica gel (cyclohexane/ethyl acetate: 0-20%) to yield 6-cyano-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (33 mg, 76%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH:7]=[C:8]1[CH:12]=[C:11]([CH2:13]C)[C:10](=O)[O:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][NH2:18].O.NN>CN1C(=O)CCC1.O>[C:1]([O:5][C:6](=[O:16])[CH2:7][C:8]1[CH:12]=[C:11]([CH3:13])[C:10](=[O:9])[NH:18][N:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC1=CC(=CC(=O)OC(C)(C)C)OC1=O
Reactant: NN
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(CC(=O)OC(C)(C)C)n[nH]c1=O
Temperature: 127.5 °C

Procedure:
To a solution of lactone 18 (2.68 Kg; 12.77 mol) in 7.5 L of NMP cooled to below 0° C. was added 420 mL of anhydrous hydrazine (equivalent quantities of hydrazine hydrate also can be used) while maintaining the internal temperature at less than 20° C. After the addition was completed the reaction mixture was heated to 110-145° C. for one to five h. The reaction mixture was cooled and diluted with H2O (11 L) which resulted in the formation of crystalline pyridazinone 10 which was filtered and washed with water (2×2 L) and dried to afford 2.23 Kg (77.9%) of product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(Cl)c2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc(CN2CCNCC2)c1

Procedure:
To 4-(3-chlorobenzyl)-piperazine-1-carboxylic acid tert-butyl ester (20.24) (8.82 g, 28.4 mmol) is added TFA (45 mL) at ambient temperature over 5 min. After 1 h 50 min, TFA is evaporated, the residue is dissolved in 2N HCl (45 mL) and extracted with ether (2×45 mL). The aqueous layer is basified to pH 13 with 2N NaOH (60 mL) and extracted with CH2Cl2 (6×90 mL). The combined organic extracts are washed with brine (75 mL) and dried over MgSO4. The crude material obtained after filtration and concentration (5.44 g, 25.8 mmol, 91%) is used without further purification. MS (ES): m/z 211.0/213.0 (100/35) [MH+]. tR (method B)=5.1 min.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[C:10]([CH2:11][N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][O:8][C:6]=2[N:7]=1.C1C2NC3C(=CC=CC=3)C=2C=CC=1.[H-].[Na+].NC1N=C(N)C2C(CCl)=COC=2N=1>>[NH2:1][C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[C:10]([CH2:11][N:12]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:18]4[C:13]3=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:9][O:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N)c2c(CN(c3ccccc3)c3ccccc3)coc2n1
Agent: Nc1nc(N)c2c(CCl)coc2n1
Agent: [H-]
Agent: [Na+]
Product: Nc1nc(N)c2c(Cn3c4ccccc4c4ccccc43)coc2n1

Procedure:
N-[(2,4-Diaminofuro[2,3-d]pyrimidin-5-yl)methyl]carbazole (Formula I: Ar=2,4-diaminofuro[2,3-d]pyrimidin-5-yl; W=CH2; X=N; Z=chemical bond; m=n=0) is prepared similarly to N-[(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)methyl]-N,N-diphenylamine as disclosed in Example 11 above by using carbazole (129 mg, 0.8 mmol), NaH (50 mg, 2.1 mmol), and 2,4-diamino-5-chloromethylfuro[2,3-d]pyrimidine (60 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C:11]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[CH:17][C:12]=1[C:13](OC)=[O:14].[OH-].[Li+].Cl.Cl.[CH3:33][C:34]1[C:38]([NH2:39])=[CH:37][O:36][N:35]=1.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.C(Cl)CCl>O1CCCC1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C:11]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[O:22])=[CH:17][C:12]=1[C:13]([NH:39][C:38]1[C:34]([CH3:33])=[N:35][O:36][CH:37]=1)=[O:14]
Reactant: Cc1nocc1N
Reactant: COC(=O)c1cc(C(=O)N2CCOCC2)ccc1OCc1ccc(F)cc1F
Agent: Cl
Agent: On1nnc2cccnc21
Agent: [Li+]
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: O
Product: Cc1nocc1NC(=O)c1cc(C(=O)N2CCOCC2)ccc1OCc1ccc(F)cc1F
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 2-{[(2,4-difluorophenyl)methyl]oxy}-5-(4-morpholinylcarbonyl)benzoate acid (may be prepared as described in Description 110; 100 mg, 0.26 mmol) in tetrahydrofuran (4 ml) was added lithium hydroxide (26 mg, 109 mmol) and water (1 ml). The mixture was heated at 50° C. for one hour, cooled and 2 M hydrochloric acid (0.54 ml, 1.09 mmol) was added. The solvent was removed in vacuo and the residue was redissolved in N,N-dimethylformamide (5 ml). 3-Methyl-4-isoxazolamine hydrochloride (42.8 mg, 0.32 mmol), 1-hydroxy-7-azabenzotriazole (39.7 mg, 0.29 mmol), diisopropylethylamine (0.09 ml, 0.53 mmol) and EDC (76 mg, 0.40 mmol) were added. The solution was stirred for 18 hours. Water (3 ml) was added and a pale brown solid precipitated which was filtered. Recrystallisation with 1:1 methanol/DMSO yielded the title compound as a white solid. 9.5 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[C:11]([C:19]([N:21]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@H:22]2[CH2:27][C@@H:26]([CH2:28][OH:29])[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]2)=[O:20])[N:10]=[N:9]1.[ClH:41].CO>>[ClH:41].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[C:11]([C:19]([N:21]([C@H:22]2[CH2:27][C@@H:26]([CH2:28][OH:29])[CH2:25][NH:24][CH2:23]2)[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:20])[N:10]=[N:9]1
Reactant: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](CO)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1F
Agent: Cl
Solvent: CO
Product: COCCCCc1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](CO)C2)nnn1-c1ccccc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(hydroxymethyl)piperidine-1-carboxylate (400 mg) was dissolved in 10% hydrogen chloride-methanol (4 ml), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated to give the object product (334 mg).
Reaction SMILES: [Cl:1][C:2](Cl)([Cl:12])[CH:3]1[CH:8]2[CH:6]([C:7]2([CH3:10])[CH3:9])[C:5](=[O:11])[O:4]1.O>C(O)(=O)C.CCOCC.[Zn]>[Cl:1][C:2]([Cl:12])=[CH:3][C@@H:8]1[C@H:6]([C:5]([OH:11])=[O:4])[C:7]1([CH3:9])[CH3:10]
Reactant: CC1(C)C2C(=O)OC(C(Cl)(Cl)Cl)C21
Agent: [Zn]
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a suspension of zinc powder (0.52 g, 0.008 mole) in 0.6 ml of acetic acid and 3 ml of ether was added dropwise over a period of 15 minutes a solution of 4-trichloromethyl-6,6-dimethyl-2-oxo-3-oxabicyclo[3.1.0]hexane (0.487 g, 0.002 mole) in 3 ml of ether. The mixture was stirred for two hours at room temperature, 30 ml of ether and 5 ml of water were added, and the mixture was then filtered through Celite filter aid. The organic layer was separated, washed twice with saturated aqueous sodium chloride, dried over magnesium sulfate, and the ether was evaporated to give crystalline cis-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid (0.405 g, 97% yield).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC.N1CCC[C@H]1C(O)=O.Br[C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1>CS(C)=O.O1CCOCC1.[Cu](I)I>[F:43][C:40]1[CH:41]=[CH:42][C:37]([N:1]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=3[CH:3]=[CH:2]2)=[CH:38][CH:39]=1
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: Fc1ccc(Br)cc1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C(O)[C@@H]1CCCN1
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: COC(=O)c1cccc2c1ccn2-c1ccc(F)cc1
Temperature: 110 °C
Yield: 68.3 %

Procedure:
To a solution of methyl 1H-indole-4-carboxylate (3.0 g, 17.1 mmol) in DMSO (25 mL) and 1,4-dioxane (25 mL) in a sealed tube were added potassium phosphate (7.3 g, 34.3 mmol), dimethylethylenediamine (1.0 mL, 9.1 mmol), L-proline (1.1 g, 9.1 mmol), 1-bromo-4-fluorobenzene (1.3 mL, 11.42 mmol), and copper iodide (1.1 g, 5.7 mmol). The mixture was purged with argon gas; the tube was sealed and heated at 110° C. overnight. The reaction mixture was cooled down to rt, washed with water (100 mL) and the aqueous mixture was extracted with dichloromethane (3×150 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification of the resulting residue by column chromatography (0% to 50% dichloromethane in hexanes) afforded methyl 1-(4-fluorophenyl)-1H-indole-4-carboxylate (2.1 g, 68%) as a white solid: 1H NMR (300 MHz, DMSO) δ 7.87-7.82 (m, 2H), 7.75 (d, J=8.4 Hz, 1H), 7.68-7.63 (m, 2H), 7.49-7.42 (m, 2H), 7.32 (t, J=7.8 Hz, 1H), 7.20 (dd, J=3.0, 0.9 Hz, 1H), 3.93 (s, 3H); MS (ESI+) m/z 270 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[C:16]1[C:17]([C:32](OCC)=[O:33])=[CH:18][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:20][CH:21]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:18][C:17]=1[CH2:32][OH:33]
Reactant: CCOC(=O)c1cc(OCc2ccc(OC)cc2)ccc1-c1cc(OC)ccc1F
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(CO)c2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 79.1 %

Procedure:
To a mixture of lithium aluminum hydride (2.58 g) and THF (300 mL) was added ethyl 2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)biphenyl-2-carboxylate (18.6 g) at 0° C., and the mixture was stirred at 0° C. for 20 min. To the reaction mixture was added sodium sulfate decahydrate (22.4 g), and the mixture was filtered. The solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (13.2 g) as a colorless oil.
Reaction SMILES: Cl.[NH2:2][OH:3].O(C)[Na].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:14]#[N:15])[CH:8]=1>>[OH:3]/[N:2]=[C:14](\[NH2:15])/[CH2:13][C:9]1[CH:8]=[N:7][CH:12]=[CH:11][CH:10]=1
Reactant: NO
Reactant: N#CCc1cccnc1
Agent: CO[Na]
Agent: Cl
Product: N/C(Cc1cccnc1)=N\O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Hydroxylamine hydrochloride (0.87 g, 0.0125 mmol) was added to 0.5M NaOCH3 (25 mL, 0.0125 mmol) and stirred at ambient temperature for 30 min. The reaction mixture was filtered and the filtrate was combined with pyridin-3-ylacetonitrile (1.18 g, 0.010 mmol). The resultant mixture was heated at reflux for 2 h, stirred at ambient temperature overnight and concentrated to give crude (1Z)-N′-hydroxy-2-pyridin-3-ylethanimidamide which was used immediately without purification. ES-LCMS m/z 152.18 (M+H).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[CH2:14]([OH:19])[CH:15]([OH:18])[CH:16]=[CH2:17]>>[Si:1]([O:19][CH2:14][CH:15]([OH:18])[CH:16]=[CH2:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=CC(O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: C=CC(O)CO[Si](C)(C)C(C)(C)C
Reaction time: 2 h

Procedure:
t-Butyl dimethylsilylchloride (4.28 g, 28.4 mmol) and imidazole (4.83 g, 70.9 mmol) were added to a flask purged with N2 and dichloromethane (50 mL) was added. 3-Butene-1,2-diol (2.50 g, 28.4 mmol) was then added to the flask and the mixture was stirred for 2 hours. The solvent was removed and the titled product (2.71 g, 47.9%) was purified by column chromatography (5% ethyl acetate in hexanes).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:13][CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[O:12])[N:3]=[N:2]1.Cl>O1CCOCC1>[NH:17]1[CH2:16][CH2:15][CH:14]([NH:13][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:4]2[N:3]=[N:2][NH:1][CH:5]=2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)CCCCCc2c[nH]nn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CCCCCc1c[nH]nn1)NC1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tert-butyl 4-(6-(1H-1,2,3-triazol-4-yl)hexanamido)piperidine-1-carboxylate (135 mg, 0.369 mmol) in 1,4-dioxane (1.2 ml) was treated with 4M HCl in dioxane (1.8 ml, 7.39 mmol). The reaction mixture was allowed to stir at RT for 3 hours. Concentration yielded the title compound as a hydrochloride salt.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[Br:8][C:9]1[CH:10]=[C:11]([NH:12][C:5](=[O:7])[CH3:6])[CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(Br)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
691 mL of acetic anhydride are added to a solution cooled to 10° C. of 1200 g (6.976 mol, 1 eq) of 3-bromoaniline in 6 L of dichloromethane in the presence of 1.07 L (7.67 mol, 1.1 eq) of triethylamine and 25.6 g (0.209 mol, 0.03 eq) of 4-(dimethylamino)pyridine. The reaction medium is stirred at room temperature for 4 hours and then hydrolyzed with 850 mL of 1N hydrochloric acid solution, and the phases are separated by settling. The organic phase is washed with 0.5N hydrochloric acid solution and then with water, and the solvent is evaporated off. After recrystallization from diisopropyl ether/heptane, 1506.1 g of N-(3-bromophenyl)acetamide are obtained in solid form. Yield=100%
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=O)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.C[N:19](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][C:15]([NH2:19])=[O:17])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1
Reactant: O=C(O)CCNc1nc(Cl)cc2nccnc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NC(=O)CCNc1nc(Cl)cc2nccnc12

Procedure:
A solution of 3-(7-chloropyrido[4,3-b]pyrazin-5-ylamino)propanoic acid (2.22 mmol), HATU (2.66 mmol), DIPEA (6.65 mmol) and NH4Cl (4.43 mmol) in THF (10 mL) was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was treated with water. The precipitates were collected by filtration and dried to give the title compound. MS (m/z): 252 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:45])=[C:9]([CH2:11][O:12][C:13]2[CH:42]=[CH:41][C:16]([C:17]([NH:19][C:20]3[C:24](/[CH:25]=[CH:26]/[P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[CH:23][N:22]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:21]=3)=[O:18])=[CH:15][C:14]=2[O:43][CH3:44])[N:10]=1.[H-].[Na+].[CH3:48]N(C)C=O.CI>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:45])=[C:9]([CH2:11][O:12][C:13]2[CH:42]=[CH:41][C:16]([C:17]([N:19]([CH3:48])[C:20]3[C:24](/[CH:25]=[CH:26]/[P:27](=[O:34])([O:28][CH2:29][CH3:30])[O:31][CH2:32][CH3:33])=[CH:23][N:22]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:21]=3)=[O:18])=[CH:15][C:14]=2[O:43][CH3:44])[N:10]=1
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1NC(=O)c1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1N(C)C(=O)c1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Yield: 78 %

Procedure:
To a mixture of diethyl (E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy)-3-methoxybenzoyl)amino]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate (50 mg), sodium hydride (60% in oil, 3.9 mg) and N,N-dimethylformamide (2 mL) was added methyl iodide (14 mg) with stirring, and the mixture was further stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer as washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by reverse phase partition-high performance liquid chromatography (elution with distilled water containing 0.1% trifluoroacetic acid/acetonitrile) to give a colorless oil compound. To remove remaining trifluoroacetic acid, water was added to the oil compound, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated to give diethyl (E)-2-{3-[(4-([2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzoyl)(methyl)amino]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as a colorless oil (39.8 mg, yield 78%).