Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([NH:19][C:20]3[CH:29]=[CH:28][C:23]([C:24](OC)=[O:25])=[CH:22][N:21]=3)[CH2:16][CH2:17][CH3:18])=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[Li+].[OH-].Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:60][CH2:61][CH2:62][C:63]([O:65][CH3:66])=[O:64].C(N(CC)C(C)C)(C)C>C1COCC1.[NH4+].[Cl-]>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([NH:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([NH:60][CH2:61][CH2:62][C:63]([O:65][CH3:66])=[O:64])=[O:25])=[CH:22][N:21]=3)[CH2:16][CH2:17][CH3:18])=[CH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)CCN
Reactant: CCCC(Nc1ccc(C(=O)OC)cn1)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(Nc1ccc(C(=O)NCCC(=O)OC)cn1)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 107.8 %

Procedure:
To a solution of (+/−)-methyl 6-(1-(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-yl)butylamino)nicotinate (796 mg, 1.85 mmol) in THF (10 mL) was added 2N aqueous LiOH (8 mL, 16 mmol). The mixture was stirred at 50° C. overnight. The mixture was neutralized by addition of 1N aqueous HCl and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was dissolved in DMF (5 mL). HATU (1.026 g, 2.7 mmol) was added. The mixture was stirred for 45 min. Methyl 3-aminopropanoate hydrochloride (373 mg, 2.7 mmol) and N,N-diisopropylethylamine (930 mg, 7.2 mmol) were added. The resulting mixture was stirred at room temperature for 2 h. The mixture was diluted with aqueous NH4Cl. The organic layer was washed with water, dried over Na2SO4, and concentrated under reduced pressure to give crude (+/−)-methyl 3-(6-(1-(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-yl)butylamino)nicotinamido)propanoate (1.0 g). Resolution by SFC (Column: OJ 250 mm*20 mm*20 μm, Mobile phase: 75:25 CO2:methanol, Flow rate: 80 mL/min, Modifier: 0.1% diethylamine) to give methyl 3-(6-(1-(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-yl)butylamino)nicotinamido)propanoate, Isomer 1 (Retention time 0.959 min, 390 mg) and methyl 3-(6-(1-(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-yl)butylamino)nicotinamido)propanoate, Isomer 2 (Retention time 1.87 min, 400 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](OC)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].C([Al+]CC(C)C)C(C)C.[O-]S([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][OH:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)c1ccc2[nH]ncc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCc1ccc2[nH]ncc2c1
Reaction time: 3 h
Yield: 50 %

Procedure:
To a solution of methyl 1H-indazole-5-carboxylate (300 mg, 1.69 mmol, prepared according to the procedure described in JP-11-228513) in 8.5 mL of dry toluene was added diisobutylaluminum hydride (1 mol/L in n-hexane, 3.4 mL) under nitrogen at −78° C. After the reaction mixture was stirred at the same temperature for 3 h, saturated Na2SO4 aqueous solution was added carefully at 0° C. After the solution was stirred at room temperature, a sufficient amount of Na2SO4 was added with additional stirring for drying. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (chloroform/methanol=98/2 to 85/15) to obtain (1H-indazol-5-yl)methanol (125 mg, 50%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][C:8](Cl)=[O:9])(=[O:4])[CH:2]=[CH2:3].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(N(CC)CC)C.C1(C=CC(O)=CC=1)O>C1(C)C=CC=CC=1>[C:1]([O:5][CH2:6][CH2:7][C:8](=[O:9])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: Nc1ccccn1
Reactant: C=CC(=O)OCCC(=O)Cl
Agent: Oc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCC(=O)Nc1ccccn1
Reaction time: 18 h

Procedure:
3-Chloro-3-oxopropyl acrylate, 1, (1 eq.), 2-aminopyridine (1 eq.) and triethylamine (3 eq.) are dissolved in toluene at 0° C. A few crystals of hydroquinone is added to inhibit any polymerization side reactions. The solution is allowed to stir approximately 18 hours at a temperature from about 0° C. to room temperature. The solvent is removed under reduced pressure and the crude material purified over silica. For a more detailed account of this procedure See M. A. Diab, A. Z. El-Sonbati, A. A. El-S anabori, F. I. Taha, Polymer Degrad. Stab. 1989, 24, 51, included herein by reference.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:31]CCl.CO.[ClH:36]>C(OCC)C>[ClH:31].[ClH:36].[ClH:31].[N:25]1([CH2:24][CH2:23][CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:16][CH:17]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(OCCCN3CCCCC3)cc2)CC1
Reactant: ClCCl
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: c1cc(OCCCN2CCCCC2)ccc1CN1CCNCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
To a solution of 4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine-1-carboxylic acid tert-butyl ester (D1) (1.576 g, 3.76 mmol) in a (1:1) mixture of dichloromethane and methanol (20 ml) was added a 1M solution of hydrogen chloride in diethyl ether (20 ml) and the reaction stirred for 5 hours at room temperature. The solvent was then evaporated in vacuo and the resulting residue triturated with diethyl ether to afford the title compound (1.5 g, 93%); MS (ES+), m/e 318 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([OH:9])=O.[NH:13]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:6]/[C:7]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:9])[CH:10]=[CH:11][CH:12]=1
Reactant: O=C1CCNCCN1
Reactant: O=C(O)/C=C/c1cccc(Cl)c1
Product: O=C1CCN(C(=O)/C=C/c2cccc(Cl)c2)CCN1

Procedure:
In analogy to the procedure described in intermediate 1A, (E)-3-chlorocinnamic acid and 2,3,6,7-tetrahydro-(1H)-1,4-diazepin-5(4H)-one gave the title compound as a white solid.
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].C([O-])([O-])=O.[K+].[K+].[N+:11]([C:14]1[NH:15][CH:16]=[CH:17][N:18]=1)([O-:13])=[O:12].O>CN(C=O)C>[CH:2]([N:15]1[CH:16]=[CH:17][N:18]=[C:14]1[N+:11]([O-:13])=[O:12])([CH3:4])[CH3:3]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1ccnc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 4 h

Procedure:
2-Bromopropane (7 mmol) and K2CO3 (13 mmol) were added to a solution of 2-nitroimidazole (4 mmol) in DMF (10 mL). The mixture was stirred at 60° C. for 4 h. The contents were cooled to room temperature and water (20 mL) was added and the mixture was extracted with EtOAc (3×10 mL). The combined extracts were dried over MgSO4, filtered and the solvent was removed in vacuo to afford 1-isopropyl-2-nitro-1H-imidazole. The product used for further transformation without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([OH:9])=[C:4]([CH2:10][CH3:11])[N:3]=1.O.[OH-].[Li+].Br[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][C:28]([O:30]C)=[O:29]>CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[C:4]([CH2:10][CH3:11])[N:3]=1
Reactant: COC(=O)CCc1ccccc1OCCCBr
Reactant: CCc1nc(N)nc(N)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc(N)nc(N)c1OCCCOc1ccccc1CCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
2,4-Diamino-6-ethyl-5-hydroxypyrimidine (0.4625 g, 3 mmol) was added to a stirred solution of lithium hydroxide monohydrate (0.4406 g, 10.5 mmol) in DMF (4 mL) and the reaction mixture was stirred at 25° C. for 1 hour. A solution of methyl 3-(2-(3-bromopropoxy)phenyl)propanoate (0.9035 g, 3 mmol) in DMF (1 mL) was added and the reaction mixture was left stirring at 25° C. overnight. DMF was partially removed under reduced pressure to give residue. The residue was diluted with water followed by extraction with dichloromethane. The aqueous layer was neutralized with dil. HCl to give white solid. Recrystallization from acetone afforded the desired diaminopyrimidine as white solid (0.6271 g, 58%, m.p. 155.5-157.5° C.). 1H NMR (400 MHz, DMSO-d6): 1.04 (3H, t, J=7.6 Hz), 2.19 (2H, m), 2.39 (2H, q, J=7.5 Hz), 2.46 (2H, t, J=7.5 Hz), 2.78 (2H, t, J=7.7 Hz), 3.83 (2H, t, J=6.1 Hz), 4.15 (2H, t, J=5.9 Hz), 6.29 (2H, bs), 6.85 (1H, t, J=7.4 Hz), 6.96 (2H, bs), 6.98 (1H, d, J=8.1 Hz), 7.14-7.19 (2H, m).
Reaction SMILES: Cl[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=1)=[O:24].C([O-])(O)=O.[Na+]>O1CCOCC1.O.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>[Cl:10][C:6]1[C:3]([C:4]#[N:5])=[C:2]([C:29]2[CH:28]=[CH:27][C:26]([NH:25][C:23]([NH:22][C:13]3[CH:14]=[C:15]([C:18]([F:19])([F:21])[F:20])[CH:16]=[CH:17][C:12]=3[F:11])=[O:24])=[CH:31][CH:30]=2)[CH:9]=[N:8][CH:7]=1
Reactant: N#Cc1c(Cl)cncc1Cl
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)OC1(C)C
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: O
Solvent: C1COCCO1
Product: N#Cc1c(Cl)cncc1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Reaction time: 8 h
Yield: 33.4 %

Procedure:
To a solution of 346 mg of 3,5-dichloroisonicotinonitrile and 959 mg of 1-(2-fluoro-5-trifluoromethylphenyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea in 24 mL of dioxane are added 462 mg of NaHCO3 in 14.4 mL of water. 462 mg of tetrakis(triphenylphosphine)palladium are then added and the reaction is refluxed for 5 hours and then left overnight at 20° C. 20 mL of water are then added and the mixture is extracted with 2×60 mL of ethyl acetate. The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure. The brown oil is purified on a prepacked Merck cartridge of 30 g of SiO2 15-40 μm (dichloromethane and then 99/1 dichloromethane/methanol). 290 mg of yellow crystals of 1-[4-(5-chloro-4-cyanopyrid-3-yl)phenyl]-3-(2-fluoro-5-trifluoromethylphenyl)urea are obtained.
Reaction SMILES: NC1C2OC=CC=2C=C(F)C=1.[CH2:12]([C:15]1[C:16]([OH:27])=[C:17]([C:23]([Cl:26])=[CH:24][CH:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:13]=C.O=[O+][O-].ClC1C=CC(CC=O)=C(O)C=1C(OCC)=O.P(=O)(O)(O)O>>[Cl:26][C:23]1[CH:24]=[CH:25][C:15]2[CH:12]=[CH:13][O:27][C:16]=2[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: C=CCc1ccc(Cl)c(C(=O)OCC)c1O
Agent: CCOC(=O)c1c(Cl)ccc(CC=O)c1O
Agent: Nc1cc(F)cc2ccoc12
Agent: O=P(O)(O)O
Product: CCOC(=O)c1c(Cl)ccc2ccoc12

Procedure:
Using analogous procedures to those described in the third paragraph of the portion of Note [6] in Example 2 that is concerned with the preparation of 7-amino-5-fluorobenzofuran, ethyl 3-allyl-6-chloro-2-hydroxybenzoate was reacted with ozone and the resultant product, 2-(4-chloro-3-ethoxycarbonyl-2-hydroxyphenyl)acetaldehyde, was treated with 85% phosphoric acid to give ethyl 6-chlorobenzofuran-7-carboxylate (5.9 g); NMR Spectrum: (DMSOd6) 1.35 (t, 3H), 4.45 (q, 2H), 7.10 (d, 1H), 7.45 (d, 1H), 7.85 (d, 1H), 8.15 (d, 1H).
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:21](=[O:37])[N:22]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH2:34][CH2:35][OH:36])[CH3:23])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[OH:36][CH2:35][CH2:34][CH2:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][CH2:24][N:22]([CH3:23])[C:21](=[O:37])[C@H:9]([NH:7][CH3:6])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1
Reactant: CN(CCc1ccccc1OCCCO)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1ccccc1OCCCO
Temperature: 0 °C
Reaction time: 1.75 h
Yield: 69.4 %

Procedure:
A solution of N-[(1R)-1-(N-{2-[2-(3-hydroxypropoxy)phenyl]ethyl}-N-methylcarbamoyl)-2-(2-naphthyl)ethyl]-N-methylcarbamic acid tert-butyl ester (383 mg, 0.74 mmol) in dichloromethane (4 ml) was cooled to 0° C. Trifluoroacetic acid (4 ml) was added. The reaction mixture was stirred for 105 min at 0° C. Dichioromethane (40 ml) was added. A saturated aqueous solution of sodium hydrogen carbonate (40 ml) was added dropwise. Solid sodium hydrogen carbonate was added, until pH 7 was obtained. The phases were separated. The aqueous phase was extracted with dichloromethane (3×60 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (30 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 216 mg of (2R)-N-(2-(2-(3-hydroxypropoxy)phenyl)ethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.Br[C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([CH3:26])[CH:25]=1)[N:22]=[C:21]([O:27][CH3:28])[CH:20]=[CH:19]2>CCCCCC.C1COCC1.[Cl-].[Zn+2].[Cl-].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>[CH3:28][O:27][C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[C:24]([CH3:26])[CH:25]=[C:16]([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=3)[CH:17]=2)[N:22]=1
Reactant: COc1ccc(Br)cc1
Reactant: COc1ccc2cc(Br)cc(C)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(C)c3nc(OC)ccc3c2)cc1
Temperature: 25 °C

Procedure:
n-Butyllithium (33.3 cm3 of a 1.5M solution in n-hexane) was added dropwise at -70° to a stirred solution of 4-bromoanisole (6.26 cm3) in THF (70 cm3) under nitrogen. After ten minutes, a solution of anhydrous zinc chloride (6.814 g) in THF (50 cm3) was added and the mixture was allowed to warm to room temperature over 0.5 hour. A mixture of 6-bromo-2-methoxy-8-methylquinoline (12.8 g) and tetrakis(triphenylphosphine)palladium (0) (0.5 g) was added and the mixture heated under reflux for 2 hours. Volatile material was removed in vacuo and the residue was partitioned between chloroform (150 cm3) and a solution of ethylenediaminetetraacetic acid (40 g) in water (250 cm3). The organic layer was dried (MgSO4) and evaporated to afford an oil which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with hexane:ethyl acetate, 19:1. Combination and evaporation of the appropriate fractions afforded the title compound (5.49 g). A small portion of this was recrystallised from methanol and had m.p. of 104°-106° and the following analysis:
Reaction SMILES: [Li]CCCC.[Si:6]([O:13][CH2:14][C:15]1[N:16]=[N:17][N:18]([CH3:20])[CH:19]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].CN([CH:24]=[O:25])C.[BH4-].[Na+].[NH4+].[Cl-]>C1COCC1.CO>[CH3:10][C:9]([Si:6]([CH3:7])([CH3:8])[O:13][CH2:14][C:15]1[N:16]=[N:17][N:18]([CH3:20])[C:19]=1[CH2:24][OH:25])([CH3:12])[CH3:11]
Reactant: Cn1cc(CO[Si](C)(C)C(C)(C)C)nn1
Reactant: CN(C)C=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nnc(CO[Si](C)(C)C(C)(C)C)c1CO
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 83.3 %

Procedure:
A solution of BuLi (23.6 mmol) in hexanes (1.6 M, 14.7 ml) was added to a stirred solution of 4-(tert-butyldimethylsilanyloxymethyl)-1-methyl-1H-[1,2,3]triazole (3.00 g, 13.2 mmol) in THF (50 ml) at −78° C. under N2. The resulting solution was stirred at −78° C. for 15 min, then warmed to −40° C. and recooled to −78° C. DMF (4.97 ml, 64.2 mmol) was added and the reaction was allowed to warm to room temperature. MeOH (50 ml) was added, followed by sodium borohydride (1.21 g, 32.1 mmol) and the reaction mixture was stirred at room temperature for 30 min. NH4Cl solution (50 ml) was added cautiously. The organic solvents were removed under reduced pressure, then 4N NaOH solution (50 ml) was added and the organics were extracted with CH2Cl2 (3×100 ml). The combined organic extracts were washed with NH4Cl solution (50 ml) and brine (50 ml), then dried and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica using 3% MeOH/CH2Cl2 to yield the desired hydroxymethyltriazole (2.83 g, 83%). 1H NMR (360 MHz, CDCl3) δ 4.77 (2H, s), 4.62 (2H, d, J=5.9 Hz), 3.90 (3H, s), 0.78 (9H, s), 0.00 (6H,s). m/z (ES+) 258 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@:4]([CH3:21])([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>C(O)C.CCOC(C)=O.CCCCCC>[CH3:1][O:2][C:3](=[O:22])[C@:4]([CH3:21])([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:13][CH2:4][CH2:3][OH:2])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@](C)(Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)[C@](C)(Cc1ccc(OCCCO)cc1)NC(=O)OC(C)(C)C

Procedure:
The N-t-butyloxycarbonyl-α-methyltyrosine methylester (1.70 g) from the previous synthesis was dissolved in 25 ml of absolute ethanol and treated with dry sodiun ethoxide (742 mg). 3-Bromopropanol (924 mg, 0.6 ml) was added and the solution was refluxed for 5 hours. The ethanol was then evaporated, 100 ml of dichloromethane added and the solution washed with 100 ml of water. After drying over MgSO4 the solvent was evaporated to yield two spots on a TLC plate developed in EtOAc:Hexane 1:1. The first spot was product and the second was starting material. The product was purified on a silica gel column using EtOAc:Hexane (1:1) A yield of 620 mg (MW 367.2, 31%) was obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:23]>ClCCl>[CH3:27][C:26]([CH3:29])([CH3:28])[CH2:25][O:24][C:22]([N:6]1[CH:7]=[C:2]([F:1])[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]1=[O:8])=[O:23]
Reactant: CN(C)C=Nc1nc(O)ncc1F
Reactant: CC(C)(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C=Nc1nc(=O)n(C(=O)OCC(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 20.5 %

Procedure:
To an 8 mL screw-cap vial was added dichloromethane (CH2Cl2; 3 milliliters (mL)), N′-(5-fluoro-2-hydroxy-pyrimidin-4-yl)-N,N-dimethylformamidine (100 milligrams (mg), 0.54 millimole (mmol)), triethylamine (Et3N; 120 mg, 1.18 mmol), and 2,2-dimethylpropyl chloroformate (90 mg, 0.60 mmol). After shaking for 1.5 hours (h) at room temperature, the mixture was partitioned between ethyl acetate (EtOAc) and water (H2O). The organic phase was dried over magnesium sulfate (MgSO4), filtered, and evaporated. The crude material was purified by reverse phase chromatography to yield 4-(dimethylamino-methyleneamino)-5-fluoro-2-oxo-2H-pyrimidine-1-carboxylic acid 2,2-dimethyl-propyl ester as a white solid (33 mg, 20%): mp 162-164° C.; 1H NMR (300 MHz, CDCl3) δ 8.77 (s, 1H), 7.93 (d, J=6.6 Hz, 1H), 4.08 (s, 2H), 3.27 (s, 3H), 3.20 (s, 3H), 1.05 (s, 9H); ESIMS m/z 299 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=O)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH2:29])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO.C(Cl)Cl>ClC(Cl)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][CH:10]2[CH2:9][CH2:8][C:7]3[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:11]2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(CNC2CCc3ccc([N+](=O)[O-])cc3C2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 7-nitro-3,4-dihydro-1H-naphthalen-2-one (600 mg, 2.98 mmol), prepared as described in J. Med. Chem., 1989, 32(9), 2128-34, and 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (700 mg, 3.3 mmol) in dichloroethane (50 mL) under a nitrogen atmosphere was added sodium triacetoxyborohydride (1.4 g, 6.5 mmol, 2 eq.) in a single portion. The reaction was stirred at room temperature for 24 h. The reaction was concentrated in vacuo and partitioned between EtOAc (100 mL) and 5% aq. KOH (50 mL). The aqueous layer was extracted twice more with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to afford a dark oil. Flash chromatography on silica gel eluting with 5% methanol/methylene chloride afforded 4-[(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester, as an oil (790 mg).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].[Br:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[CH:27][CH:26]=1>CC(CC)=O.CCOCC>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:31][C:28]2[CH:29]=[CH:30][C:25]([CH2:24][Br:23])=[CH:26][CH:27]=2)[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13]
Reactant: BrCc1ccc(CBr)cc1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCOCC
Product: CCCc1c(OCc2ccc(CBr)cc2)ccc(C(C)=O)c1O

Procedure:
To a solution of 1-(2,4-dihydroxy-3-propyl phenyl) ethanone (10.0 g; 0.051 m) in dry methylethyl ketone (100 ml) was added dried anhydrous sodium carbonate (27 g; 5 mol. eq) and sodium iodide (0.5 g). To the stirred suspension was then added α,α'-dibromo-p-xylene (13.5 g; 0.051 m) and the suspension gently heated at reflux for five hours. The cooled suspension was evaporated under reduced pressure, the residue dissolved in water and extracted with dichloromethane (×2). The organic extract was washed with aqueous sodium hydroxide (2N), then water, dried over magnesium sulphate, filtered, and evaporated to dryness under reduced pressure to give a yellow solid. The solid was stirred with ether (200 ml) for 1 hour and filtered to remove any disubstituted impurity. The filtrate was evaporated under reduced pressure to leave a yellow solid. The solid was chromatographed on a U30 Sorbsil solumn using dichloromethane to give a white solid; recrystallised from ethanol, m.p. 98°-99° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[C:10]1[CH:11]=[C:12]([CH:16]2[O:20][CH2:19][CH2:18][O:17]2)[CH:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].N1C=CC=CC=1>ClCCl.[Cu]=O.CCOC(C)=O.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14]2[CH:13]=[C:12]([CH:16]3[O:17][CH2:18][CH2:19][O:20]3)[CH:11]=[CH:10][CH:15]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: Brc1cccc(C2OCCO2)c1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Fc1ccc(Oc2cccc(C3OCCO3)c2)cc1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
Combine 4-fluorophenol (3.0 g, 227.8 mmol), 2-(3-bromophenyl)-1,3-dioxolane (5.0 ml, 33.3 mmol), potassium carbonate (anhydrous, 8.0 g, 55.6 mmol), and dry pyridine (50 ml). Heat to 90° C. and add copper oxide (5.5 g, 69.5 mmol). Heat at reflux. After 24 hours, cool to room temperature, dilute with dichloromethane, and filter. Concentrate the filtrate in vacuum to give a yellow oil. Chromatograph the oil on silica gel eluting with 95:5 hexane:EtOAc to give the title compound.