Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:23])[CH2:15][O:14][CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].[CH3:26]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([O:23][CH3:26])[CH2:15][O:14][CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCOCC(O)(c2ccc(Cl)c(Cl)c2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2ccc(Cl)c(Cl)c2)COCCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (6RS)-6-(3,4-dichlorophenyl)-6-hydroxy-1,4-oxazepane-4-carboxylate (130 mg) in DMF (3.0 mL) were added 60% sodium hydride (44 mg) and methyl iodide (0.068 ml) at room temperature, and the mixture was stirred for 30 min. To the reaction mixture was added ice water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (186 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH3:10])[N:7]([C:11]3[N:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=3)[C:6]=2[CH:18]=1.[C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])#[CH:20]>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.[Cu]I.C(N(CC)CC)C>[CH3:10][C:8]1[N:7]([C:11]2[N:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)[C:6]2[CH:18]=[C:2]([C:20]#[C:19][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=[CH:4][C:5]=2[N:9]=1
Reactant: Cc1nc2ccc(Br)cc2n1-c1ncnc(N)n1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Cc1nc2ccc(C#C[Si](C)(C)C)cc2n1-c1ncnc(N)n1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 4-(6-bromo-2-methyl-1,3-benzodiazol-1-yl)-1,3,5-triazin-2-amine (250 mg, 0.74 mmol), tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.06 mmol), copper(I) iodide (11 mg, 0.06 mmol) and ethynyl(trimethyl)silane 0.230 ml, 1.51 mmol) was added triethylamine (2.6 mL). The mixture was purged with nitrogen for 2 minutes and was stirred at 80° C. for 15 min in the microwave. LC-MS shows 50% conversion. The mixture was retreated with another equivalent of tetrakis(triphenylphosphine)palladium (70 mg) copper(I) iodide (11 mg) and ethynyl(trimethyl)silane (0.230 ml). Heating in the microwave at 90° C. was continued for another
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[C:5]([CH2:14][CH:15]=[CH2:16])[CH:4]=1.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.Cl.[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][O:17]2)=[C:5]([CH2:14][CH:15]=[CH2:16])[CH:4]=1
Reactant: C=CCc1cc(OC)c2ccccc2c1O
Reactant: C1=COCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCc1cc(OC)c2ccccc2c1OC1CCCCO1

Procedure:
A solution of 4-methoxy-2-(2-propenyl)-1-naphthalenol (0.28 g), dihydropyran (0.60 ml) and pyridinium hydrochloride (32 mg) all in 5 ml of methylene chloride is stirred under a nitrogen atmosphere for 16 hrs at which time TLC analysis indicates the reaction is complete. The solution is poured into 25 ml of saturated aqueous sodium bicarbonate and extracted with ether. The organic phase is washed two times with brine, dried with magnesium sulfate, filtered and concentrated to give 0.42 g of crude product as a yellow oil.
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[O:4].[CH:6]1([CH:11]([C:17](OCC)=[O:18])[C:12](OCC)=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7]1>C(O)C>[CH:6]1([CH:11]2[C:12](=[O:13])[NH:5][C:3](=[O:4])[NH:2][C:17]2=[O:18])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: NC(N)=O
Reactant: CCOC(=O)C(C(=O)OCC)C1CCCC1
Agent: [Na]
Solvent: CCO
Product: O=C1NC(=O)C(C2CCCC2)C(=O)N1

Procedure:
To a solution of 3.48 g (151 mmol) of sodium in 50 mL absolute ethanol was added 3.02 g (50 mmol) urea and 10 g (44 mmol) of the diethyl cyclopentylmalonate prepared above. The thick white slurry which formed was refluxed for 12 hours. Most of the ethanol was removed via rotary evaporation, and the residue was diluted with 100 mL of water and acidified with 10 mL of 98% H2SO4. The resulting white solid which formed was collected by filtration and dried on a pump. The solid was recrystallized from water, and recrystallized a second time from 5% water/ethanol to obtain 7.006 g of colorless platelike crystals with a melting point of 222-223° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2 g of 4-(tert-butoxycarbonyl)aminopiperidine was dissolved in 50 ml of dichloromethane. After adding 1.6 ml of triethylamine and 1.2 ml of ethyl bromoacetate, the resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 3.0 g of the title compound as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[CH2:19]([NH:21][CH2:22][CH:23]1[CH2:27][CH2:26][NH:25][CH2:24]1)[CH3:20]>C(#N)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([N:25]3[CH2:26][CH2:27][CH:23]([CH2:22][NH:21][CH2:19][CH3:20])[CH2:24]3)[N:11]=2)[C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: CCNCC1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Solvent: CC#N
Product: CCNCC1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3CC)C1
Yield: 53.5 %

Procedure:
1.00 g (3.69 mmole) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-napthyridine-3-carboxylic acid, 100 ml acetonitrile and 1.42 g (11.08 mmole) of N-ethyl-3-pyrrolidinemethanamine were stirred for three days at room temperature. The reaction mixture was then filtered, and the precipitate washed with water, ethanol/ether (1:3), and finally with ether until dry to give 0.715 g of 1-ethyl-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-1,8-napthyridine-3-carboxylic acid, mp 229.5°-231.5° C.
Reaction SMILES: [O:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=[CH:2]1.Cl.[NH2:10][C@H:11]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[O:32][CH3:33])=[CH:21][CH:20]=1)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[F:31][C:29]1[CH:28]=[CH:27][C:26]([O:32][CH3:33])=[C:25]([C:22]2[CH:21]=[CH:20][C:19]([CH2:18][C@@H:11]([NH:10][C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)=[O:8])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:24][CH:23]=2)[CH:30]=1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cc(F)ccc2OC)cc1
Reactant: O=C(O)c1cnco1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(F)ccc2OC)cc1)NC(=O)c1cnco1
Reaction time: 2 h

Procedure:
To a solution of oxazole-5-carboxylic acid (70 mg, 0.61 mmol) in DMF (1.5 mL) and DCM (1.5 mL) is added (R)-ethyl 3-amino-4-(5′-fluoro-2′-methoxybiphenyl-4-yl)butanoate hydrochloride, intermediate 10, (150 mg, 0.41 mmol), HATU (233 mg, 0.61 mmol), and TEA (284 μL, 2.04 mmol). After stirring for 2 hours, the reaction is quenched with H2O, and the crude is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN), and then lyophilized to give (R)-ethyl 4-(5′-fluoro-2′-methoxybiphenyl-4-yl)-3-(oxazole-5-carboxamido)butanoate (157 mg). HPLC retention time=1.50 minutes (condition A); MS (m+1)=427.4; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19 (t, J=7.2 Hz, 3 H) 2.46-2.62 (m, 2 H) 2.86 (dd, J=13.6, 8.1 Hz, 1 H) 3.02 (dd, J=13.6, 6.1 Hz, 1 H) 3.67 (s, 3 H) 4.05-4.15 (m, 2 H) 4.52-4.69 (m, 1 H) 6.76-6.82 (m, 1 H) 6.83-6.96 (m, 2 H) 7.11-7.21 (m, 3 H) 7.37 (d, J=8.1 Hz, 2 H) 7.61 (s, 1 H) 7.80 (s, 1 H)
Reaction SMILES: [I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH2:13]([O:15][C:16]([C:18]1([NH2:29])[CH2:26][C:25]2[C:20](=[C:21]([F:28])[CH:22]=[CH:23][C:24]=2[F:27])[CH2:19]1)=[O:17])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH2:13]([O:15][C:16]([C:18]1([NH:29][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=2[I:1])[CH2:26][C:25]2[C:20](=[C:21]([F:28])[CH:22]=[CH:23][C:24]=2[F:27])[CH2:19]1)=[O:17])[CH3:14]
Reactant: Cc1cccc(C(=O)O)c1I
Reactant: CCOC(=O)C1(N)Cc2c(F)ccc(F)c2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2c(F)ccc(F)c2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.4 %

Procedure:
To a solution of 2-iodo-3-methyl-benzoic acid (1.31 g, 5 mmol), 2-amino-4,7-difluoro-indan-2-carboxylic acid ethyl ester HCl salt (1.38 g, 5 mmol), HATU [O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium PF6, 3.80 g, 10 mmol) in anhydrous DMF (20 mL) is added DIPEA (N,N-diisopropylethylamine, 3.3 mL, 15 mmol). The resulting solution is stirred at RT for two days. After the removal of DMF in vacuo, the residue obtained is dissolved in EtOAc (200 mL) and washed with saturated NaHCO3 (1×100 mL) and brine (2×100 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The obtained residue is purified by flash column chromatography (40 g silica gel, gradient elution: 0%-50% EtOAc in heptane) to give a pure product (390) as white solid (1.83 g, 75%).
Reaction SMILES: [N:1]([C:4]1[C:21](=[O:22])[CH2:20][CH2:19][C@@:18]2([CH3:23])[C:5]=1[CH2:6][CH2:7][C@@H:8]1[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]1[CH2:10][CH2:11][C@@H:12]2[O:24][CH:25]1[CH2:27][CH2:26]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>O>[NH2:1][C:4]1[C:21](=[O:22])[CH2:20][CH2:19][C@@:18]2([CH3:23])[C:5]=1[CH2:6][CH2:7][C@@H:8]1[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]1[CH2:10][CH2:11][C@@H:12]2[O:24][CH:25]1[CH2:26][CH2:27]1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=C(N=[N+]=[N-])C(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=C(N)C(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1
Yield: 43.1 %

Procedure:
A stirred solution of 4-azido-17β-(cyclopropyloxy)androst-4-en-3-one (1.32 q, 3.57 mM), triphenylphosphine (1.14 g, 4.97 mM), tetrahydrofuran (25 ml) and water (8 ml) was heated to reflux for 15 hours. The reaction was cooled and most of the solvent was evaporated. The residue was dissolved in dichloromethane, loaded onto a column of SiO2 and flash chromatographed (toluene--10% ethyl acetate) to give 4-amino-17β-(cyclopropyloxy)androst-4-en-3-one (0.53 g 43.1%), mp 85°-88° C. IR 3446, 3363, 1672, 1584 cm-1 ; MS (CI) m/z 344 (100%, M+ +1), 1H NMR (CDCl3), 0.38-0.61 (4H, m, 2×cyclopropyl (CH2 's), 0.74 (s, C18 -Me), 1.15 (s, C19 -Me), 3.25-3.33 (m, OCH), 3.44 (t+br s, C17 α-H+NH 2), 13C NMR (CDCl3), 88.95, 132.87, 138.90, 194.33. This compound has the following structure:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[F:37])[CH2:5][C:6]1([C:29](OCC)=[O:30])[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][C:24]([CH3:26])=[N:23][CH:22]=4)=[C:17]([O:27][CH3:28])[CH:16]=3)=[N:13][N:14]=[C:7]12.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[F:37])[CH2:5][C:6]1([CH2:29][OH:30])[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][C:24]([CH3:26])=[N:23][CH:22]=4)=[C:17]([O:27][CH3:28])[CH:16]=3)=[N:13][N:14]=[C:7]12
Reactant: CCOC(=O)C1(Cc2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-c2nnc3n2CCCC3(CO)Cc2ccc(F)c(F)c2)ccc1-c1cnc(C)o1
Reaction time: 0.17 h
Yield: 73.3 %

Procedure:
A mixture of ethyl 8-(3,4-difluorobenzyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (180 mg) in THF (2 mL) was added to a suspension of lithium aluminum hydride (53.7 mg) in THF (2 mL) under ice-cooling. The reaction mixture was stirred for 10 min under ice-cooling, and sodium sulfate decahydrate (500 mg) was added under ice-cooling. The reaction mixture was filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (121 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][OH:26])[C:22]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[N:21]2)=[CH:17][CH:16]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH:25]=[O:26])[C:22]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[N:21]2)=[CH:32][CH:33]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CO)c(-c3cccs3)n2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(C=O)c(-c3cccs3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
A mixture of [1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]methanol (12.15 g), activated manganese dioxide (37.03 g), and tetrahydrofuran (200 ml) was stirred at room temperature overnight. After the manganese dioxide was removed by filtration, the filtrate was concentrated to obtain 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carbaldehyde (11.68 g, yield: 96%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 136˜137° C.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([N:23](C)[C:24](=O)OC(C)(C)C)[CH2:19][CH2:18]2)=[CH:13][C:12]([C:32]2[CH:37]=[C:36]([Cl:38])[C:35]([OH:39])=[C:34]([Cl:40])[CH:33]=2)=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>>[CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[NH:16][C@H:17]2[CH2:18][CH2:19][C@H:20]([NH:23][CH3:24])[CH2:21][CH2:22]2)=[CH:13][C:12]([C:32]2[CH:37]=[C:36]([Cl:38])[C:35]([OH:39])=[C:34]([Cl:40])[CH:33]=2)=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)CC1

Procedure:
Following general procedure A-2, tert-butyl trans-4-[3-(cyclopropanecarbonyl)-6-(3,5-dichloro-4-hydroxyphenyl)quinolin-4-ylamino]cyclohexyl(methyl)carbamate (0.120 mmol) was reacted with TFA (2 mL) to afford the desired product (30 mg, 51% over two steps) as a yellow solid: 1H NMR (300 MHz, CD3OD+TFA-d) δ 9.35 (s, 1H), 8.48 (s, 1H), 8.28 (d, J=8.7 Hz, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.75 (s, 2H), 4.52 (s, 1H), 2.84 (s, 1H), 2.73 (s, 2H), 2.53-2.46 (m, 2H), 2.38-2.28 (m, 2H), 1.88-1.77 (m, 2H), 1.65-1.58 (m, 2H), 1.33-1.20 (m, 4H); ESI MS m/z 484 [C26H27Cl2N3O2+H]+; HPLC>99% (AUC), tR=9.66 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[N-:12]=[N+]=[N-].[Na+]>CN(C)C=O>[NH2:12][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1
Reactant: COC(=O)c1cc(Cl)ccn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N)ccn1
Reaction time: 8 h

Procedure:
A mixture of 2.0 g of methyl 4-chloropicolinate and 2 g of sodium azide in 20 ml of dimethylformamide is stirred at 100° for 8 hours. The solvent is removed in vacuo, the reaction is diluted with water and the product extracted into ethyl acetate. After drying over magnesium sulfate, the solvent is removed in vacuo. The residue is hydrogenated in 30 ml of ethanol at atmospheric pressure over 500 mg of 10% palladium on carbon catalyst for 3 hours. After filtration through filter-cel the solvent is removed in vacuo and the residue crystallized from ether to afford methyl 4-aminopicolinate.
Reaction SMILES: C=O.[C:3](O)(=O)C.[H-].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)=[CH:24][CH:23]=1>C(Cl)(Cl)Cl.C(O)C.C(OCC)(=O)C>[Br:21][C:22]1[CH:23]=[CH:24][C:25]([CH:28]2[CH2:32][CH2:31][N:30]([CH3:3])[CH2:29]2)=[CH:26][CH:27]=1
Reactant: Brc1ccc(C2CCNC2)cc1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [H-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN1CCC(c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 96.3 %

Procedure:
Formalin (0.0452 ml, 0.557 mmol), 0.0319 ml (0.557 mmol) of acetic acid, and 118 mg (0.557 mmol) of triacetoxy borohydride hydride were added to a solution of 42 mg (0.186 mmol) of 3-(4-bromophenyl)pyrrolidine, synthesized in the same manner as in Reference Example 1, in chloroform-ethanol 3:1 (2 ml), and the mixture was stirred at room temperature for 40 min. The reaction solution was diluted with ethyl acetate, and the diluted solution was washed with a 10% aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous sodium sulfate, was filtered, and was then concentrated under the reduced pressure to give 43 mg (yield 97%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:23]C)[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N>Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:23])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COCCNc1nc(N)c2nc(OC)n(Cc3ccccc3)c2n1
Agent: Cl
Agent: N
Product: COCCNc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Yield: 72.5 %

Procedure:
6-Amino-9-benzyl-8-methoxy-2-(2-methoxyethyl)aminopurine (26 mg, 0.079 mmol) in concentrated hydrochloric acid (20 ml) was stirred at room temperature for 7 hours. The reaction mixture was made basic with 28% aqueous ammonia. The resulting crystals were filtered to give the subject compound (18 mg, yield 73%).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[N:24]=[N+]=[N-])(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[NH2:24])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@H]1N=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CC(=O)N[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@H]1N
Yield: 88.8 %

Procedure:
2-Acetamido-2-deoxy-3,4,6-tri-O-acetyl-β-D-glucopyranosyl azide (100 mg, 0.26 mmol) was dissolved in MeOH (5 ml) and hydrogenated over Pd/C (10%) (10 mg) for 5 h. The suspension was filtered, and the filtrate was evaporated to give 2-Acetamido-2-deoxy-3,4,6-tri-O-acetyl-β-D-glucopyranosyl amine (18) (80 mg, 86%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH2:4]Cl.[N-:12]=[N+]=[N-].[Na+].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CS(C)=O>[CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH2:4][NH2:12]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(C)c(CCl)c(C)c1
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C)c(CN)c(C)c1
Temperature: 60 °C
Yield: 60.9 %

Procedure:
To a solution of 2,4,6-trimethylbenzyl chloride (5 g, 29.7 mmol) in DMSO (20 mL) was added sodium azide (2.9 g, 44.6 mmol). The mixture was heated at 60° C. for 3 h before it was allowed to cool to rt and poured to water (200 mL). The resulted precipitate was filtered dissolved in wet THF (50 mL) followed by the addition of triphenylphosphine (15.6, 59.4 mmol). The mixture was heated under reflux for 3 h and the volatiles were evaporated. The residue was added to 1 N HCl (200 mL) and the solids were filtered off. The filtrate was basified and the resulted precipitate was filtered, dried under vacuum to give 2,4,6-trimethylbenzylamine (2.7 g, 61% yleld).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:19][C:20]([C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=3)=[O:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:19][C:20]([C:22]3[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=3)=[O:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2nc(-c3cccc(C)c3)c(-c3ccncn3)s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(-c2nc(NC(=O)c3ccc(C(=O)O)cc3)sc2-c2ccncn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a suspension of methyl 4-[[[4-(3-methylphenyl)-5-(4-pyrimidinyl)-1,3-thiazol-2-yl]amino]carbonyl]benzoate (0.50 g, 1.2 mmol) in ethanol (10 mL) was added 2N aqueous sodium hydroxide solution (1.2 mL), and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was acidified with 2N hydrochloric acid and the precipitated solids were collected by filtration. Crude crystals were washed with water and dried to give the title compound (0.40 g, yield 0.82%).
Reaction SMILES: CN([CH:4]=[N:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)C.C([O:19][C:20](=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[NH:29])[NH2:28])[CH:22]=1)(C)(C)C>C(O)(=O)C>[C:10]1([CH3:13])[CH:11]=[CH:12][C:7]([C:6]2[N:5]=[CH:4][N:28]=[C:27]([C:23]3[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=3)[C:20]([OH:19])=[O:30])[N:29]=2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)c1cccc(C(=N)N)c1
Reactant: Cc1ccc(C(=O)N=CN(C)C)cc1
Solvent: CC(=O)O
Product: Cc1ccc(-c2ncnc(-c3cccc(C(=O)O)c3)n2)cc1
Temperature: 115 °C
Yield: 8.9 %

Procedure:
Part D. A mixture of N-dimethylaminomethylene-4-methyl-benzamide (221.9 mg, 1.15 mmol) and 3-carbamimidoyl-benzoic acid tert-butyl ester (196.0 mg, 0.89 mmol) in anhydrous acetic acid (8 mL) is heated to 115° C. at 150 W, 250 psi in a microwave reactor for 30 min. until complete consumption of the starting material is determined by TLC. A white solid is precipitated by addition of 1 N HCl, and collected by filtration, followed by washing with water and hexanes. The obtained solid is further purified by flash column chromatography, eluting with methanol/methylene chloride (1:20) to afford the title product (23.1 mg, 5.3% yield), m.p. 298-300° C. 1H NMR (300 MHz, DMSO-d6): δ 9.40 (1H, s), 8.63 (2H, d, J=8.3 Hz), 8.48 (2H, d, J=8.0 Hz), 8.13 (2H, d, J=8.0 Hz), 7.41 (2H, m), 2.41 (3H, s). MS (ES+): m/e 292.30.