Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:14](=[O:17])([O-])[O-].[K+].[K+]>C(#N)C.ClCCl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:1]([N:8]2[CH2:13][CH2:14][O:17][CH2:10][CH2:9]2)=[O:2])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 195 %

Procedure:
Amine preparation: A mixture of 4-morpholinocarbonyl chloride (0.38 ml), 1-BOC-piperazine (552 mg) and potassium carbonate (439 mg) in acetonitrile (7 mL) was stirred at room temperature for 3 hours. The reaction mixture was then diluted with dichloromethane, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 4-(morpholine-4-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (865 mg). Treatment of this compound with HCl in dichloromethane/methanol yielded the title compound, which was isolated as the hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O.[C:16]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[CH2:6]1[C:2]2([NH:1][C:16]3([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[O:8][CH2:7]2)[CH2:3][CH2:4][CH2:5]1
Reactant: NC1(CO)CCCC1
Reactant: O=C1CCCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1CCC2(CC1)NC1(CCCC1)CO2
Temperature: 20 °C
Reaction time: 72 h
Yield: 97.2 %

Procedure:
To a solution of 1-amino-1-(hydroxymethyl)cyclopentane (Method B1c; 1.44 g, 12.54 mmol) in CH2Cl2 (10 mL) at 4° C. was added TFA (0.097 mL, 1.25 mmol), cyclohexanone (1.30 mL, 12.54 mmol) and sodium sulfate (2 g) and the reaction was warmed to 20° C. The reaction was stirred for 72 h and was sequentially washed with water (10 mL) and a saturated NaHCO3 solution (20 mL), dried (MgSO4), and concentrated under reduced pressure to give 14-aza-7-oxadispiro[4.2.5.1]tetradecane (2.38 g, 97%): GC-MS m/z 195 (M+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][F:10].Br[CH2:12]C1CCCCO1.N1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:20]1=[O:40]>>[F:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][CH:12]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:20]1=[O:40]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: FCc1ccccc1CBr
Reactant: BrCC1CCCCO1
Product: O=C1C(Cc2ccccc2CF)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 1-(bromomethyl)-2-(fluoromethyl)benzene (Kirmse, W. et al. J. Org. Chem. (1994), 59(14):3821-3829) to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 3′-[2-(fluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one was obtained (53%) as a colorless solid: mp 188-190° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.50 (d, J=6.6 Hz, 1H), 7.39-7.35 (m, 2H), 7.27-7.15 (m, 3H), 7.04 (dd, J=7.5, 7.5 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 6.54 (s, 1H), 6.23 (s, 1H), 5.69-5.60 (m, 2H), 5.10-4.98 (m, 2H), 4.76 (ABq, 2H), 4.20-4.11 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 177.3, 155.3, 144.7, 142.8, 138.3, 135.3 (d, JC-F=2.8 Hz), 134.2 (d, JC-F=15.5 Hz), 132.1, 130.4 (d, JC-F=7.1 Hz), 130.0 (d, JC-F=3.3 Hz), 129.3, 128.1, 126.9 (d, JC-F=1.8 Hz), 124.2, 123.6, 121.5, 111.7, 109.9, 99.3, 82.9 (d, JC-F=160.6 Hz), 80.1, 64.7, 64.1, 57.8, 55.4; MS (ES+) m/z 439.9 (M+23).
Reaction SMILES: [CH2:1]([I:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][N:8]=1>C(O)C>[I-:6].[CH2:1]([N+:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1)[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: c1ccc2cnccc2c1
Reactant: CC(C)CCI
Solvent: CCO
Product: CC(C)CC[n+]1ccc2ccccc2c1
Product: [I-]
Yield: 91 %

Procedure:
To 15.3 g of isoamyliodide and 10 g of isoquinoline placed in a four-necked flask equipped with a reflux condenser and mechanical stirrer was added 30 ml of ethanol. The mixture was reacted for 3 hours under reflux. When the reaction was completed, ethanol was removed from the reaction mixture under reduced pressure, the residue was washed 2-times with 45 ml of ethyl ether. 23.0 g of N-isoamylisoquinolinium iodide was obtained as yellow crystals. Subsequently, into a four-necked flask equipped with a reflux condenser and mechanical stirrer was placed 8 g of TCNQ and 280 ml of acetonitrile, and the TCNQ was dissolved in the acetonitrile under reflux. To the flask was added a solution of 9.6 g of N-isoamylisoquinolinium iodide in 40 ml of acetonitrile, and the mixture was reacted for 20 minutes under reflux. The reaction mixture was cooled to 5° C., separated black needles were filtered out and washed 2-times with 100 ml of methanol. 10.4 g of charge transfer complex of N-isoamylisoquinolinium TCNQ was obtained. The infra-red spectrum of the complex was shown in FIG. 3. The specific resistance of the complex measured by the same method as that described in Example 1 was 3.6 Ωcm.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH2:10][CH2:11][C@@H:12]1[O:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH2:13]1.Cl[CH:26](Cl)[C:27](=[N:29][NH:30]S(C1C=CC(C)=CC=1)(=O)=O)[CH3:28]>CO>[F:24][C:20]1[CH:19]=[C:18]([N:14]2[CH2:13][C@H:12]([CH2:11][N:10]3[CH:26]=[C:27]([CH3:28])[N:29]=[N:30]3)[O:16][C:15]2=[O:17])[CH:23]=[CH:22][CH:21]=1
Reactant: CC(=NNS(=O)(=O)c1ccc(C)cc1)C(Cl)Cl
Reactant: NC[C@H]1CN(c2cccc(F)c2)C(=O)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1cn(C[C@H]2CN(c3cccc(F)c3)C(=O)O2)nn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
N,N-Diisopropylethylamine (3.20 mL, 18.35 mM) was added to a solution of (5S)-5-(aminomethyl)-3-(3-fluorophenyl)-1,3-oxazolidin-2-one (0.77 g, 3.57 mM; see Dong Pharmaceuticals WO 0194342) in anhydrous methanol (25 mL). The solution was cooled to 0° C., and N′-[2,2-dichloro-1-methylethylidene]-4-methylbenzenesulfonohydrazide (1.28 g, 4.58 mM) was added. The solution was warmed to room temperature and stirred overnight. The reaction mixture was then concentrated under vacuum and chromatographed on silica gel using 2% methanol/dichloromethane to give 0.71 g of the title product.
Reaction SMILES: [CH2:1]([Li:5])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH3:11][C:12]1([CH3:43])[CH2:21][CH:20]=[C:19](OS(C(F)(F)F)(=O)=O)[C:18]2[CH:17]=[C:16]([C:30]#[C:31][C:32]3[CH:42]=[CH:41][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][CH:33]=3)[CH:15]=[CH:14][C:13]1=2>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>[Li:5][C:1]1[S:6][CH:10]=[CH:9][N:8]=1.[CH3:43][C:12]1([CH3:11])[CH2:21][CH:20]=[C:19]([C:7]2[S:6][CH:10]=[CH:9][N:8]=2)[C:18]2[CH:17]=[C:16]([C:30]#[C:31][C:32]3[CH:33]=[CH:34][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:41][CH:42]=3)[CH:15]=[CH:14][C:13]1=2
Reactant: [Li]CCCC
Reactant: c1cscn1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2nccs2)=CCC3(C)C)cc1
Product: [Li]c1nccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-lithiothiazole was prepared by the addition of 41.2 mg (0.42 ml, 0.63 mmol) of n-butyl-lithium (1.5M solution in hexanes) to a cold solution (−78° C.) of 53.4 mg (0.63 mmol) of thiazole in 1.0 ml of THF. The solution was stirred at for 30 minutes and then a solution of 113.9 mg (0.84 mmol) of zinc chloride in 1.5 ml of THF was added. The resulting solution was warmed to room temperature, stirred for 30 minutes and then the organozinc was added via cannula to a solution of 200.0 mg (0.42 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-2-naphthalenyl)ethynyl]benzoate (Compound G) and 12.4 mg (0.01 mmnol) of tetrakis(triphenylphosphine)palladium(0) in 1.5 ml of THF. The resulting solution was heated at 50° C. for 45 minutes, cooled to room temperature and diluted with sat. aqueous NH4CI. The mixture was extracted with EtOAc (40 ml) and the combined organic layers were washed with water and brine. The organic phase was dried over Na2SO4 and concentrated in vacuo to a yellow oil. Purification by column chromatography (silica, 20% EtOAc-hexanes) yielded the title compound as a colorless oil. PMR (CDCl3): δ 1.35 (6H, s), 1.40 (3H, t, J=7.1 Hz), 2.42 (2H, d, J=4.8 Hz), 4.38 (2H, q, J=7.1 Hz), 6.57 (1H, t, J=4.8 Hz), 7.33 (1H, d, J=3.3 Hz), 7.36 (1H, d, J=8.0 Hz), 7.46 (1H, dd, J=1.7 , 8.1 Hz), 7.55 (2H, d, J=8.4 Hz), 7.87 (1H, d, J=1.7 Hz), 7.92 (1H, d, J=3.3 Hz), 8.00 (2H, d, J=8.4 Hz).
Reaction SMILES: [N:1]1([C:6]([C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClCCl.Cl>O1CCOCC1>[NH:10]1[CH2:11][CH2:12][CH2:13][C@@H:8]([C:6]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)N2CCCC2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C([C@@H]1CCCNC1)N1CCCC1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
Into a flask containing (R)-tert-butyl 3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate was added dichloromethane (24 mL) followed by a solution of hydrogen chloride in 1,4-dioxane (4M, 8 mL). The reaction mixture was stirred at 30° C. for 2 h. The solvent was evaporated under reduced pressure to afford (R)-piperidin-3-yl(pyrrolidin-1-yl)methanone which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[C:11]([CH2:13][C:14]([NH2:16])=[S:15])#[N:12]>C(O)C.N1CCCCC1>[C:11]([C:13](=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([OH:10])=[C:2]([OH:1])[CH:3]=1)[C:14](=[S:15])[NH2:16])#[N:12]
Reactant: N#CCC(N)=S
Reactant: O=Cc1ccc(O)c(O)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CC(=Cc1ccc(O)c(O)c1)C(N)=S
Temperature: 0 °C
Yield: 40.9 %

Procedure:
To 0.83 g (6mmol) 3,4-dihydroxybenzaldehyde and 0.7 g (7 mmol) cyanothioacetamide in 30 ml ethanol was added 4 drops of piperidine. The mixture was refluxed for 1 hour, poured into ice water, filtered and dried, giving 0.54 g (41% yield) of an orange solid, m.p. 213° C. Calculated analysis for C10H8N2O2S: C=54.54, H=3.64, N=12.73; found: C=54.44, H=3.87, N=12.91.
Reaction SMILES: Cl.[CH2:2]([NH:10][NH2:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]([O:17][CH3:18])(=[O:16])[C:13]([CH3:15])=O.CO>O>[CH2:2]([NH:10][N:11]=[C:13]([CH3:15])[C:12]([O:17][CH3:18])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NNCCc1ccccc1
Reactant: COC(=O)C(C)=O
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)C(C)=NNCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3.6 g. Phenethylhydrazine hydrochloride and 2.0 g. methyl pyruvate are dissolved in 20 ml. methanol and left to stand at ambient temperature for 30 minutes, followed by cooling to 0° C., whereafter 30 ml. water are added thereto. 2.8 g. (61% of theory) methyl 2-(phenethylhydrazono)-propionate crystallizes out; m.p. 59°-60° C. (decomp.).
Reaction SMILES: C(C1C=C(C(C2N(C)N=C(C3C=CC=CC=3)N=2)O)C=CC=1)C.[CH3:23][N:24]1[CH:28]=[N:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:25]1.[Cl:35][C:36]1[C:43]([CH2:44][CH3:45])=[CH:42][C:39]([CH:40]=[O:41])=[C:38]([F:46])[CH:37]=1>>[Cl:35][C:36]1[C:43]([CH2:44][CH3:45])=[CH:42][C:39]([CH:40]([C:28]2[N:24]([CH3:23])[N:25]=[C:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:27]=2)[OH:41])=[C:38]([F:46])[CH:37]=1
Reactant: CCc1cc(C=O)c(F)cc1Cl
Reactant: Cn1cnc(-c2ccccc2)n1
Agent: CCc1cccc(C(O)c2nc(-c3ccccc3)nn2C)c1
Product: CCc1cc(C(O)c2nc(-c3ccccc3)nn2C)c(F)cc1Cl
Yield: 90.2 %

Procedure:
According to the procedure for Intermediate 370.2, 1-methyl-3-phenyl-1H-1,2,4-triazole (80 mg, 0.50 mmol) and Intermediate 390.2 (105 mg, 0.55 mmol) afforded 156 mg of Intermediate 390.3 as a white solid. LCMS 346.26 (M+H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:10])[CH2:8][NH2:9])=[CH:3][CH:2]=1.CS[C:13](SC)=[CH:14][N+:15]([O-:17])=[O:16]>C(O)C.C1(C)C(C)=CC=CC=1>[N+:15]([CH:14]=[C:13]1[NH:9][CH2:8][CH:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[O:10]1)([O-:17])=[O:16]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCC(O)c1ccccc1
Solvent: Cc1ccccc1C
Solvent: CCO
Product: O=[N+]([O-])C=C1NCC(c2ccccc2)O1
Yield: 56.5 %

Procedure:
In a mixture of 60 ml of ethanol and 200 ml of xylene was dissolved 40 g of DL-β-hydroxyphenethylamine, and the resulting solution was added dropwise to a solution of 57.8 g of 1,1-bis(methylthio)-2-nitroethene in 600 ml of xylene under reflux over a period of 1.5 hours to effect reaction. During the reaction, the low-boiling fractions were gradually removed by distillation and the reaction temperature was maintained at 130° C. to 140° C. After completion of the reaction, crystals were deposited with stirring under ice-cooling. The crystals deposited were collected by filtration, dried, and then mixed with 200 ml of a 5% (by weight) aqueous sodium hydroxide solution. After a slight amount of insolubles were removed by filtration, the filtrate was adjusted to pH 6 with a 10% (by weight) aqueous acetic acid solution, and the crystals deposited were collected by filtration and dried to obtain 34 g of 2-nitromethylene-5-phenyloxazolidine having a melting point of 139°-141° C.
Reaction SMILES: [CH:1]([N-:4][CH:5](C)C)(C)[CH3:2].[Li+].C([Li])CCC.C(NC(C)C)(C)C.[Br:21][C:22]1[C:23](=O)[CH2:24][CH2:25][CH2:26][C:27]=1[O:28]C.Cl.[CH2:32]1[CH2:36][O:35][CH2:34][CH2:33]1>CCOCC.O>[Br:21][C:22]1[C:27](=[O:28])[CH2:26][CH2:25][CH2:24][C:23]=1[CH:33]1[CH2:32][CH2:36][CH2:2][CH2:1][N:4]([CH3:5])[C:34]1=[O:35]
Reactant: COC1=C(Br)C(=O)CCC1
Reactant: CC(C)[N-]C(C)C
Reactant: C1CCOC1
Agent: Cl
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: CCOCC
Product: CN1CCCCC(C2=C(Br)C(=O)CCC2)C1=O

Procedure:
Lithium diisopropylamide was made from n-butyl lithium (1.55M in hexane, 12.9 ml) and diisopropylamine (2.8 ml) in THF (13 ml). The mixture was treated with 1-methyl-caprolactam (2.54 g) and then with 2-bromo-3-methoxycyclohexenone (4.1 g) in THF (15 ml). After 1 min. the reaction mixture was poured onto 5N HCl (8 ml) and cold water (100 ml). After 0.5 h ether was added and the organic phase separated, dried and evaporated. Recrystallisation of the residue from ethyl acetate gave the title compound (4.9 g), m.p. 112°-115° C. (d). (Found: C, 51.7; H, 6.2; N, 4.7%. C13H18BrNO2 requires: C, 52.0; H, 6.0; 4.7%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[N:3]=1.[Br:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([Cl:25])=[O:24]>O1CCOCC1>[ClH:25].[Br:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[N:3]=1)=[O:24]
Reactant: CN1CCC(C(=O)c2cccc(N)n2)CC1
Reactant: O=C(Cl)c1sccc1Br
Solvent: C1COCCO1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3sccc3Br)n2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
Combine 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (0.104 g, 0.48 mmol), 3-Bromo-thiophene-2-carbonyl chloride (0.215 g, 0.95 mmol), and 1,4-Dioxane (10 mL). Stir and heat the mixture at reflux. After 2 hr., cool the reaction mixture to ambient temperature and concentrate. Load the mixture onto an SCX column (10 g), wash with methanol, and elute with 2M ammonia/methanol. Concentrate the eluent to obtain the free base of the title compound as an oil (0.152 g, 78%). Dissolve the oil in dichloromethane (10 mL), treat with 1M hydrogen chloride in ether, concentrate and dry under vacuum to obtain the title compound. HRMS Obs. m/z 408.0384, Calc. m/z 408.0381; m.p. 195-200° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1.[CH2:13]=[O:14]>CO.CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([CH2:9][CH2:13][OH:14])[CH:8]=1
Reactant: C=O
Reactant: COc1ccc([N+](=O)[O-])c(C)c1
Solvent: CO
Solvent: CS(C)=O
Product: COc1ccc([N+](=O)[O-])c(CCO)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 47.7 %

Procedure:
Triton B (2 ml, 35% in MeOH) was added at 80° C. to a mixture of 5-methoxy-2-nitrotoluene (25 g, 150 mmol) and paraformaldehyde (2.3 g, 73 mmol) in DMSO (20 ml, synthesis quality, additionally dried for 2 d over molecular sieve 4 Å). After being stirred 2.5 h at this temperature, it was cooled to room temperature and neutralized with a few drops of conc. HCl. The mixture was diluted with H2O (50 ml) and extracted with EtOAc (5×100 ml). The organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to a distillation in a high vacuum (p=0.1 torr), whereby a fraction containing starting material (12.1 g) was obtained at 70° C. The residual crude product was purified by column chromatography (240 g SiO2, solvent: toluene/EtOAc 8:1 1400 ml, 7:1 1600 ml, 6:1 400 ml, 5:1 400 ml, 3:1 400 ml, 2:1 600 ml and 1:1 600 ml). 2-(5-methoxy-2-nitrophenyl)ethanol (6.87 g, 48%) was obtained as a yellow oil.
Reaction SMILES: O[CH2:2][C@H:3]([NH:10][C:11]([C:13]1[CH:17]=[C:16]([CH3:18])[N:15]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[N:14]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].C(NS([N+](CC)(CC)CC)(=O)=O)(OC)=O>C1COCC1.O>[CH3:18][C:16]1[N:15]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[N:14]=[C:13]([C:11]2[O:12][CH2:2][CH:3]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:10]=2)[CH:17]=1
Reactant: Cc1ccc(Cn2nc(C(=O)N[C@@H](CO)c3ccccc3)cc2C)cc1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(Cn2nc(C3=NC(c4ccccc4)CO3)cc2C)cc1
Temperature: 70 °C
Yield: 69.4 %

Procedure:
A mixture of N-[(1R)-2-hydroxy-1-phenylethyl]-5-methyl-1-(4-methylbenzyl)-1H-pyrazole-3-carboxamide (Step 1, 350 mg, 1.0 mmol) and carbomethoxysulfamoyltriethylammonium hydroxide inner salt (Burgess' reagent, 310 mg, 1.03 mmol) in THF (20 mL) was heated at 70° C. for 1 h. After being cooled to rt, the mixture was diluted with water (10 mL), and the organic phase was extracted with ethyl acetate (1×25 mL), washed with brine (1×25 mL), dried (Na2SO4), filtered, and concentrated to dryness. The crude was then purified with an ISCO CombiFlash Companion using gradient elution from 0% to 20% EtOAc in hexanes to afford the title compound as a yellow oil (230 mg, 69%): 1H NMR (300 MHz, DMSO-d6) δ 7.31-7.34 (m, 2H), 7.24-7.28 (m, 3H), 7.12 (d, 2H), 7.01 (d, 2H), 6.52 (s, 1H), 5.27-5.32 (m, 1H), 5.29 (s, 2H), 4.69-4.75 (m, 1H), 4.06-4.12 (m, 1H), 2.25 (s, 3H), 2.22 (s, 3H); ES-MS m/z 332.20, HPLC RT (Method B) 3.20 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:32]([OH:34])=O)=[N:11][C:12]([CH2:16][C:17]2([C:22]3[C:31]4[C:26](=CC=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:35](N(CC)C(C)C)(C)[CH3:36].[Si:44]([O:51][CH2:52][CH2:53][NH:54][CH3:55])([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(OCC)(=O)C>[Si:44]([O:51][CH2:52][CH2:53][N:54]([CH3:55])[C:32]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[C:31]4[C:26](=[CH:25][CH:24]=[CH:29][CH:30]=4)[CH:36]=[CH:35][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:34])([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:45])[CH3:46]
Reactant: CNCCO[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Yield: 75 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (345) (300 mg, 0.66 mmol) in dimethylformamide (7.5 mL) were added N,N-diisopropylethylamine (0.33 mL, 1.98 mmol), [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amine (8a) (187 mg, 0.99 mmol) and HATU (301 mg, 0.79 mmol) and the reaction mixture was stirred at room temperature for 1.5 h (silica TLC, 50% ethyl acetate in hexane/SiO2/UV, Rf=0.6) The reaction mass was diluted with ethyl acetate (100 ml) and washed with brine (3×50 mL). The organic phase was thereafter dried and concentrated in vacuo to get a crude mass which was purified by Combi-Flash using a mixture of ethyl acetate and hexane as eluting solvent to get pure 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (350) (310 mg, 75%) as a light yellow sticky solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[C:9](N)[CH:10]=1)=[O:4].C(I)[I:20].[N+]([O-])([O-])=O>>[I:20][C:9]1[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=1
Reactant: COC(=O)c1cc(N)cc(-c2ccc(C)cc2)c1
Reactant: ICI
Agent: O=[N+]([O-])[O-]
Product: Cc1ccc(-c2cc(I)cc(C(=O)O)c2)cc1

Procedure:
5-Amino-4′-methyl-biphenyl-3-carboxylic acid methyl ester was treated with methylene iodide and isoamy nitrate using the procedure of step 5 of preparation 5, to afford 5-iodo-4′-methyl-biphenyl-3-carboxylic acid, MS (M+H)=353.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11]O.P(Br)(Br)[Br:14]>ClCCl>[BrH:14].[Br:14][CH2:11][C:3]1[N:2]([CH3:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=1
Reactant: BrP(Br)Br
Reactant: Cn1c(CO)nc2ccccc21
Solvent: ClCCl
Product: Br
Product: Cn1c(CBr)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1-methyl-1H-benzimidazol-2-yl)methanol (1.1 g, 6.8 mmol) in anhydrous dichloromethane (60 mL) was added dropwise phosphorus tribromide (1.3 mL, 14.0 mmol). The mixture was stirred at room temperature overnight. Dichloromethane was evaporated. The residue was dried in vacuo, affording 2-(bromomethyl)-1-methyl-1H-benzimidazole hydrobromide. The product was used without further purification.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5]([O:22][CH2:23][CH3:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:21])([CH3:20])[O:14][SiH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:9][CH:8]=1)C.C(C1C=C(CC(OCC)C(O)=O)C=CC=1O)C1C=CC=CC=1>>[C:16]([SiH2:15][O:14][C:13]([CH3:20])([CH3:21])[C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:22][CH2:23][CH3:24])[C:4]([OH:25])=[O:3])=[CH:8][CH:9]=1)([CH3:18])([CH3:19])[CH3:17]
Reactant: CCOC(=O)C(Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1)OCC
Agent: CCOC(Cc1ccc(O)c(Cc2ccccc2)c1)C(=O)O
Product: CCOC(Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1)C(=O)O

Procedure:
The title compound was prepared from 3-[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-2-ethoxy-propionic acid ethyl ester (1.1 g, 30 mmol) in the same manner as described for 3-(3-benzyl-4-hydroxy-phenyl)-2-ethoxy-propionic acid. The crude product was obtained as a solid and used in the next step without further purification (0.73 g, 65%). 1H NMR (400 MHz, CDCl3): δ 7.11-7.18 (m, 4H), 4.63 (s, 2H), 3.96-3.99 (m, 1H), 3.48-3.52 (m, 1H), 3.31-3.37 (m, 1H), 3.01-3.05 (dd, 1H), 2.87-2.92 (dd, 1H), 1.07 (t, 3H), 0.85 (s, 9H), 0.00 (s, 6H).