Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:15][C:16]2[N:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][N:17]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:29](I)[CH3:30].O>CN(C=O)C>[CH2:29]([N:15]([C:16]1[N:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][N:17]=1)[C:7]1[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=1)[CH3:30]
Reactant: CCI
Reactant: CCOC(=O)c1cnc(Nc2cc(C(C)(C)C)cc(C(C)(C)C)c2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc(N(CC)c2cc(C(C)(C)C)cc(C(C)(C)C)c2)nc1
Yield: 99 %

Procedure:
Ethyl 2-[N-(3,5-di-tert-butylphenyl)amino]pyrimidine-5-carboxylate (50 mg) was dissolved in dry DMF (2 ml), and the solution was added with a suspension of NaH (45 mg) in DMF (1 ml). The mixture was then added with ethyl iodide (0.3 ml) and stirred. After the disappearance of the materials was observed with TLC, the reaction mixture was poured into water, and extracted with CH2Cl2. The organic layer was dried over Na2SO4, and the solvent was evaporated. The residue was purified by silica gel flash column chromatography (n-hexane: AcOEt=10:1) to obtain white crystals of ethyl 2-[N-ethyl-N-(3,5-di-tert-butylphenyl)amino]pyrimidine-5-carboxylate (53 mg, 99%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]1[C:21]1[C:26]([C:27]([O:29]CC)=O)=[CH:25][CH:24]=[CH:23][N:22]=1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C(O)(C(F)(F)F)=O.CO>[N:22]1[C:21]2[CH:9]3[CH2:10][NH:11][CH2:12][CH2:13][N:8]3[C:27](=[O:29])[C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cccnc1C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2cccnc2C2CNCCN12
Temperature: 25 °C
Yield: 41.6 %

Procedure:
To a solution of 2-(3-ethoxycarbonyl-pyridin-2-yl)-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (may be prepared as described in Intermediate 6; 1.55 g) in DCM (100 mL), TFA (5.0 mL) was added at 0° C. and then reaction mixture was allowed to warm to room temperature. TLC showed disappearance of starting material in 4 h. Reaction mixture was fully evaporated under vacuum to give 1.70 g of crude intermediate. Crude intermediate was dissolved in methanol (100 mL), and then potassium carbonate (4.0 eq) was added. Reaction mixture was stirred at room temperature. TLC showed disappearance of intermediate in 5 h. The reaction mixture was filtered through celite, and the filtrate was concentrated under vacuum to get 800 mg of the crude product. The crude product was purified by column chromatography over 100-200 mesh silica gel by using 0%-10% methanol in chloroform as solvent, which gave the title compound (280 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:25][C@@:23]3([CH3:24])[C@@H:19]([CH2:20][C@@H:21]([CH3:31])[C@@H:22]3[C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[C@H:18]3[C:9]2=[C:10]2[C:15]([CH2:16][CH2:17]3)=[CH:14][C:13](=[O:32])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:33][O:34][C:35]1[N:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[CH:28]1([C:26]([C@H:22]2[C@H:21]([CH3:31])[CH2:20][C@H:19]3[C@H:18]4[C:9]([C@@H:8]([C:5]5[CH:6]=[CH:7][C:2]([C:38]6[CH:39]=[N:40][C:35]([O:34][CH3:33])=[CH:36][CH:37]=6)=[CH:3][CH:4]=5)[CH2:25][C@:23]23[CH3:24])=[C:10]2[C:15](=[CH:14][C:13](=[O:32])[CH2:12][CH2:11]2)[CH2:16][CH2:17]4)=[O:27])[CH2:30][CH2:29]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(Br)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Product: COc1ccc(-c2ccc([C@H]3C[C@@]4(C)[C@@H](C[C@@H](C)[C@@H]4C(=O)C4CC4)[C@@H]4CCC5=CC(=O)CCC5=C43)cc2)cn1
Yield: 54 %

Procedure:
Reaction of (11β,16α,17β)-11-(4-bromophenyl)-17-cyclopropylcarbonyl-16-methylestra-4,9-dien-3-one and 6-methoxy-3-pyridinylboronic acid using the procedure described in example 1 step h afforded the title compound (54% yield). 1H NMR (400 MHz, CDCl3): δ 0.35 (s, 3H), 0.84-0.99 (m, 6H), 1.08-1.15 (m, 1H), 1.33-1.39 (m, 1H), 1.45-1.54 (m, 1H), 1.62-1.70 (m, 2H), 1.91-1.97 (m, 1H), 2.01-2.08 (m, 1H), 2.24-2.53 (m, 6H), 2.58-2.64 (m, 2H), 2.68-2.85 (m, 3H), 3.98 (s, 3H), 4.44 (d, J=8 Hz, 1H), 5.80 (s, 1H), 6.80 (d, J=8 Hz, 1H), 7.23 (d, J=7 Hz, 2H), 7.44 (d, J=7 Hz, 2H), 7.75-7.79 (m, 1H), 8.36-8.38 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)[N:5]=[C:4]([O:17][CH3:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.COC1C=C(C2C=CC=CC=2)N=C(N2C=CC(C(F)(F)F)=N2)N=1>>[CH3:18][O:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)[N:5]=1
Reactant: COc1cc(Cl)nc(-n2ccc(C(F)(F)F)n2)n1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: COc1cc(-c2ccccc2)nc(-n2ccc(C(F)(F)F)n2)n1
Product: COc1cc(-c2ccc(Cl)cc2)nc(-n2ccc(C(F)(F)F)n2)n1
Yield: 45 %

Procedure:
4-Methoxy-6-(4-chloro-phenyl)-2-(3-trifluoromethyl-pyrazol-1-yl)-pyrimidine 307e was synthesized from compound 305 (1 g, 3.59 mmol) and (4-chloro-phenyl)-boronic acid 306e (842 mg, 5.39 mmol), according to the procedure as described for compound 307b, was a beige solid in 45% yield. MS (ESI, EI+) m/z=355 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([C:25]([OH:27])=[O:26])[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38].C(O)(=O)C>CN(C)C=O>[CH3:38][C:37]([CH3:40])([CH3:39])[C:36](=[O:41])[CH2:35][O:26][C:25]([C:11]1([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:22])[Cl:23])=[O:18])[CH2:12]1)=[O:27]
Reactant: CC(C)(C)C(=O)CBr
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCCC(C(=O)O)(C(=O)OCc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)COC(=O)C1(C(=O)OCc2ccccc2)CCCN(C(=O)OCC(Cl)(Cl)Cl)C1
Temperature: 60 °C

Procedure:
A mixture of piperidine-1,3,3-tricarboxylic acid 1-(2,2,2-trichloroethyl) 3-benzyl ester (3.9 g 8.8 mmol), potassium carbonate (1.83 g 13 mmol) and bromopinacolone (2.31 g 13 mmol) in N,N-dimethylformamide (55 mL) is heated at 60° C. for 2 h. The mixture is cooled back to room temperature, neutralized with acetic acid (13 mmol) and concentrated under reduced pressure. the residue is dissolved in ethyl acetate, washed with water and concentrated. Cristallization in diethyl oxide gives piperidine-1,3,3-tricarboxylic acid 1-(2,2,2-trichloroethyl) 3-benzyl 3-(3,3-dimethyl-2-oxobutyl)ester melting at 114° C.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[NH:18][CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1>CC#N.O>[C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[N:18]([CH2:37][C:36]3[CH:39]=[CH:40][C:33]([Cl:32])=[CH:34][CH:35]=3)[CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc(CBr)cc1
Reactant: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3[nH]ccc23)ccc2c1CCCO2
Solvent: O
Solvent: CC#N
Product: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2ccc(Cl)cc2)ccc2c1CCCO2

Procedure:
The title compound was prepared in a manner similar to that described in Example 41 from 2-(tert-butoxy)-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetic acid and 4-chlorobenzylbromide and was isolated by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min) on an achiral column. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.27-7.34 (m, 2H) 7.19-7.26 (m, 2H) 6.95-7.03 (m, 1H) 6.68-6.80 (m, 1H) 5.69-5.89 (m, 2H) 5.16-5.48 (m, 1H) 4.15-4.27 (m, 2H) 3.64-3.71 (m, 3H) 2.63-2.77 (m, 2H) 2.05-2.16 (m, 2H) 1.93-2.04 (m, 3H) 1.01-1.19 (m, 9H); LCMS (m/z) ES+=549 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CCN2CCCCC2)cc1
Solvent: CCO
Product: Nc1ccc(CCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 86 h
Yield: 100.3 %

Procedure:
In ethanol (100 ml) was dissolved 1-[2-(4-nitrophenyl)ethyl]piperidine (24.8 g), and to the mixture was added dried 10% palladium on carbon (1.24 g). Under hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 86 hours. The palladium was filtered off, and the filtrate was concentrated to give 1-[2-(4-aminophenyl)ethyl]-piperidine (21.7 g) as pale brown oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C@@H:8]([NH:18][C:19](=[O:31])[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[C:5]([C:32]2[CH:33]=CC(F)=[C:36]([CH:40]=2)C(N)=O)=[CH:4][CH:3]=1.NC1N=C(C(NC(=O)CC2C3C(=CC=C(F)C=3)NC=2)CC2C=C(F)C=C(F)C=2)C(Br)=CC=1.[CH3:74][O:75][C:76]1C=C(B(O)O)C=C[N:77]=1>>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]([NH:18][C:19](=[O:31])[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[C:5]([C:32]2[CH:40]=[CH:36][N:77]=[C:76]([O:75][CH3:74])[CH:33]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(B(O)O)ccn1
Reactant: NC(=O)c1cc(-c2ccc(N)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)ccc1F
Agent: Nc1ccc(Br)c(C(Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)n1
Product: COc1cc(-c2ccc(N)nc2C(Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)ccn1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 1H of Example 1 utilizing 1G and (2-methoxypyridin-4-yl)boronic acid. 1H NMR (400 MHz, DMSO) δ 10.89 (s, 1H), 7.96 (d, J=5.2 Hz, 1H), 7.25 (dd, J=8.9, 4.3 Hz, 2H), 7.14-7.10 (m, 3H), 6.88-6.80 (m, 3H), 6.67 (d, J=5.2 Hz, 1H), 6.45-6.38 (m, 5H), 5.00 (d, J=7.3 Hz, 1H), 3.75 (s, 2H), 2.89 (m, 2H). MS (m/z) 532.4 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]([C:17](=[O:22])N(OC)C)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[C:24]([NH:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[CH3:37])([CH3:27])([CH3:26])[CH3:25]>>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:17](=[O:22])[CH2:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[C:29](=[O:38])[NH:28][C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Reactant: Cc1cc(F)ccc1C(=O)NC(C)(C)C
Product: CC(C)(C)NC(=O)c1ccc(F)cc1CC(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 2 with [(R)-2-(2-Fluoro-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (1.6 g, 3.9 mmol) and N-tert-Butyl-4-fluoro-2-methyl-benzamide (3.0 g, 14 mmol) followed by purification by silica gel flash column chromatography gives the title compound.
Reaction SMILES: C(N(CC)CC)C.CS([Cl:12])(=O)=O.O[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1>ClCCl>[Cl:12][CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1
Reactant: COc1ccc2nccc(CO)c2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2nccc(CCl)c2c1

Procedure:
1.16 ml of triethylamine and 0.64 ml of methanesulfonyl chloride are successively added to a solution of 1.2 g of 4-hydroxymethyl-6-methoxyquinoline in 45 ml of dichloromethane, under an inert atmosphere of argon at a temperature in the region of 20° C. Stirring is maintained at this temperature for 3 hours. The reaction medium is concentrated under reduced pressure to give a brown residue. The product is used without further purification in the following step.
Reaction SMILES: CO[CH2:3][C:4]1OC(C)=CC(=O)C=1OCC1C=CC=CC=1.[OH:20][CH:21]([C:23]1[O:24][C:25]([CH3:38])=[CH:26][C:27](=[O:37])[C:28]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:22].ICC>>[CH2:3]([O:20][CH:21]([C:23]1[O:24][C:25]([CH3:38])=[CH:26][C:27](=[O:37])[C:28]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:22])[CH3:4]
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C(C)O)o1
Reactant: COCc1oc(C)cc(=O)c1OCc1ccccc1
Solvent: CCI
Product: CCOC(C)c1oc(C)cc(=O)c1OCc1ccccc1
Yield: 94 %

Procedure:
In an analogous procedure in the preparation of 2-methoxymethyl-3-benzyloxy-6-methyl-pyran-4(1 H)-one using 2-(1-hydroxyethyl)-3-benzyloxy-6-methyl-pyran-4(1H)-one (5.2 g, 20 mmol, 1 eq.) and 9.36 g iodoethane (60 mmol, 3 eq.) yielded the title compound as an orange oil (5.4 g, 94% Crude). Further purification by column chromatography on silica gel (eluant: EtOAc) furnished the pure product as a bright yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][C:19]2C=[CH:25][C:24]([F:27])=[CH:23][C:20]=2C#N)=[CH:4][C:5]([NH:8][C:9]2[N:13]([CH:14]([CH3:16])[CH3:15])[N:12]=[C:11]([CH3:17])[CH:10]=2)=[N:6][CH:7]=1.[OH-].[Na+].[C:30]([O:33]CC)(=[O:32])[CH3:31]>O1CCOCC1>[Cl:1][C:2]1[C:3]([NH:18][C:19]2[CH:20]=[CH:23][C:24]([F:27])=[CH:25][C:31]=2[C:30]([OH:33])=[O:32])=[CH:4][C:5]([NH:8][C:9]2[N:13]([CH:14]([CH3:15])[CH3:16])[N:12]=[C:11]([CH3:17])[CH:10]=2)=[N:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: Cc1cc(Nc2cc(Nc3ccc(F)cc3C#N)c(Cl)cn2)n(C(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(Nc3ccc(F)cc3C(=O)O)c(Cl)cn2)n(C(C)C)n1
Yield: 27.2 %

Procedure:
A solution of 2-[(5-chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]-5-fluorobenzonitrile (1.3 g, 3.38 mmol) in sodium hydroxide −1 M (10 mL, 10.00 mmol) and 1,4-dioxane (10 mL) was refluxed overnight. Ethyl acetate was added and the layers were separated. The organic layer was washed with 1 M NaOH (40 ml). The combined aqueous layers were washed with ethyl acetate, and neutralized with acetic acid. The product was isolated by filtration. 2-[(5-Chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]-5-fluorobenzoic acid (1.1 g, 2.72 mmol, 27.2% yield) was isolated as a yellow solid. 1H NMR (400 MHz, DMSO-d6) ppm 1.27 (d, J=6.57 Hz, 6 H) 2.11 (s, 3 H) 4.39 (quin, J=6.57 Hz, 1 H) 5.95 (s, 1 H) 6.70 (s, 1 H) 7.51 (td, J=8.40, 3.16 Hz, 1 H) 7.61 (dd, J=9.09, 4.80 Hz, 1 H) 7.72 (dd, J=9.22, 3.16 Hz, 1 H) 8.00 (s, 1 H) 8.53 (s, 1 H) 9.66 (br. s., 1 H) 13.88 (br. s., 1 H); HPLC Rt=2.44 min, MS (ESI): 404.3 [M+H]+.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:20][CH2:21][NH2:22])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].[OH-].[Na+].[O:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[Cl:3][C:2]1[N:1]=[C:8]([NH:22][CH2:21][CH2:20][C:14]2[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[CH:13]=2)[N:7]=[C:5]([NH:22][CH2:21][CH2:20][C:14]2[CH:13]=[CH:12][C:29]([O:28][CH3:27])=[C:30]([O:25][CH3:26])[CH:15]=2)[N:4]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C1COCCO1
Reactant: COc1ccc(CCN)cc1OC
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(CCNc2nc(Cl)nc(NCCc3ccc(OC)c(OC)c3)n2)cc1OC
Temperature: 25 °C

Procedure:
Cyanuric chloride (2.0 g, 10.85 mM) was dispersed in dioxane (80 mL) with stirring and 2-(3,4-dimethoxyphenyl)ethylamine (3.93 g, 21.68 mM) was introduced dropwise over 2 minutes. Sodium hydroxide (1N, 24 mL) was added dropwise over 5 minutes then the whole was brought to reflux for 18 hours. Cooling to ambient temperature caused a white solid to precipitate. Diethyl ether (100 mL) was introduced to fully precipitate the product which was filtered, rinsed with diethyl ether and dried. 5.05 g, (98%), mp=186°-186.5° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=3)[C:20]([NH:22][NH2:23])=[O:21])[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:27]=1.[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29]>C1COCC1>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:20]4[O:21][C:28](=[O:29])[NH:23][N:22]=4)[CH:24]=[CH:25][CH:26]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:27]=1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)NN)c1)C2=O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3n[nH]c(=O)o3)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
(S)-3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoic hydrazide (1.0 g, 2.60 mmol) obtained in Step 2 of Example 56 was dissolved in THF (12 mL), and the mixture was stirred at room temperature for 2 hours after adding 1,1′-carbonyldiimidazole (464 mg, 2.86 mmol). After concentrating the mixture under reduced pressure, water was added to the resulting residue, and the pH was adjusted to 4 by addition of a 6 mol/L aqueous hydrochloric acid solution. The precipitated white solid was then filtered off to give (S)-5-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,3,4-oxadiazol-2(3H)-one (1.07 g, quantitative).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([CH3:10])[S:7][C:6]=1[NH2:11])=[O:4].O[Li].O>CO.O.C1COCC1>[NH2:11][C:6]1[S:7][C:8]([CH3:10])=[CH:9][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cc(C)sc1N
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)c(N)s1
Temperature: 50 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a solution of 2-amino-5-methylthiophene-3-carboxylic acid methyl ester (13.7 g, 80 mmol) in MeOH/H2O/THF (400 mL, 1:1:1) is added LiOH.H2O (16 g, 400 mmol). The solution is heated to 50° C. After 4 hours, the solution is concentrated. The resulting residue is dissolved in water. The pH of the solution is adjusted to between 5-6 using 1 N HCl. The precipitate is collected by filtration, washed with a small amount of water and is dried under vacuum. The title compound (12 g, 76 mmol) is obtained as a yellow solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([F:30])[CH2:26][CH2:25]1)[CH2:10][N:11]([CH3:22])[C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][C@@H:9]([CH2:23][C@H:24]1[CH2:25][CH2:26][C@H:27]([F:30])[CH2:28][CH2:29]1)[CH2:10][N:11]([CH3:22])[C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN(C[C@H](C[C@H]1CC[C@H](F)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C[C@@H](N)C[C@H]1CC[C@H](F)CC1)C(=O)OCc1ccccc1

Procedure:
A solution of benzyl (S)-2-(t-butoxycarbonylamino)-3-(trans-4-fluorocyclohexyl)-propyl(methyl)carbamate (200 mg, 0.47 mmol) in TFA/CH2Cl2 (15 mL, v/v 20%) was stirred for 1 h at rt, then quenched by addition of sat'd aq NaHCO3 solution until gas evolution ceased. The mixture was extracted with CH2Cl2 (2×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to obtain benzyl (S)-2-amino-3-(trans-4-fluorocyclohexyl)propyl(methyl)carbamate (140 mg, yield 93%). 1HNMR (CDCl3, 400 MHZ): δ 1.42(m, 4 H), 1.64(m, 4 H), 2.98(d, 3 H), 3.21(m, 1 H), 3.50(m, 1 H), 3.90(m, 1 H), 5.13(d, 2 H), 7.33(m, 5 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.B1([C:15]2[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=2)OCCCO1>C(O)C>[Br:8][C:4]1[CH:3]=[C:2]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: Brc1cccc(Br)c1
Solvent: CCO
Product: Brc1cccc(-c2cccnc2)c1
Yield: 63.8 %

Procedure:
This reaction was carried out as described in Example 37, step a, using 1,3-dibromobenzene (8.7 g, 36.8 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (4.0 g, 24.5 mmol) in ethanol (60 ml) for 14 h. The resulting crude residue was purified by column chromatography (silica gel, 80% Et2O/hexane) to yield the title compound (3.66 g, 64%): 1H NMR (360 MHz, CDCl3) δ 7.30-7.42 (2H, m), 7.47-7.60 (2H, m), 7.72 (1H, s), 7.84 (1H, dt, J 8.0, 2.0 Hz), 8.62 (1H, dd, J 4.8, 1.5 Hz), 8.83 (1H, s).
Reaction SMILES: S([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28]O)(C1C=CC(C)=CC=1)(=O)=O.[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C)C=O>[N:30]([CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][OH:11])=[N+:31]=[N-:32]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCCOCCO)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOCCOCCOCCOCCOCCO

Procedure:
To a solution of 2-[2-(2-{2-[2-(2-tosyloxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethanol (Loiseau, F. A.; Hii, K. K.; Hill, A. M. J. Org. Chem. 2004, 69, 639) (4.5 g) in dimethylformamide (30 mL), was added sodium azide (0.89 g). The solution was stirred at 70° C. for 18h and solvent was then removed in vacuo to a residue. Dichloromethane was added and the resulting precipitate was filtered off. The organic layer was concentrated in vacuo to give 2-[2-(2-{2-[2-(2-Azido-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethanol (3.1 g):
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([O:14]C2C=CC3C(=CC=C(C#N)C=3)C=2)=O)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C([C@H]1CC[C@H](C(O)=O)CC1)CCCC.S(Cl)([Cl:43])=O>>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([Cl:43])=[O:14])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=S(Cl)Cl
Reactant: CCCCC[C@H]1CC[C@H](C(=O)Oc2ccc3cc(C#N)ccc3c2)CC1
Agent: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Product: CCCCC[C@H]1CC[C@H](C(=O)Cl)CC1

Procedure:
Preparation of 6-cyano-2-naphthyl trans-4-n-pentylcyclohexane-1-carboxylate by the following route: ##STR17## trans-4-n-Pentylcyclohexane-1-carboxylic acid chloride is prepared (step A9) by the standard procedure of heating a solution of trans-4-n-pentylcyclohexane-1-carboxylic acid (0.01 mole) in an excess of thionyl chloride for 2 hours. Removal of the excess of thionyl chloride gives a residue of the acid chloride which is mixed with dry pyridine (40 ml) and cooled to 0°-5° C. 6-Cyano-2-naphthol (0.012 mole), as prepared in Example 4 above, is then added and the solution stirred at room temperature for 20 hours; during this time the reaction mixture is protected from atmospheric moisture by a calcium chloride guard tube. The pyridine is then removed by rotary evaporation. The residual solid is purified by column chromatography on silica gel, using chloroform or chloroform:hexane (2:1) mixture as eluent. The purified ester is isolated and crystallised from hexane or methanol until constant transition temperatures are obtained: crystal-nematic liquid crystal (C-N); 86.5° C.; nematic liquid crystal-isotropic liquid (N-I), 168.3° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[O:17][CH3:18])[CH:5]=[CH:6][CH:7]=1.[CH2:20](C([Sn])=C(CCCC)CCCC)[CH2:21]CC>O1CCOCC1>[CH3:18][O:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:20]=[CH2:21])[C:3]1=[O:19]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cccc(Br)c1=O
Solvent: C1COCCO1
Product: C=Cc1cccn(-c2ccc([N+](=O)[O-])cc2OC)c1=O

Procedure:
100 g (308 mmol) of the compound from Example 19A are dissolved in 1.4 l of anhydrous dioxane, and 8.9 g (7.7 mmol) of tetrakis(triphenylphospine)palladium and 117 g (370 mmol) of tributylvinyltin are added. The mixture is heated at reflux for 16 h. The reaction solution is then allowed to cool and filtered through kieselguhr. The filtrates are concentrated to dryness under reduced pressure. The residue is chromatographed on silica gel using a gradient of cyclohexane and ethyl acetate. The product-containing fractions are combined and concentrated to dryness under reduced pressure. Petroleum ether is added until crystallization sets in. The crystals are filtered off and dried under reduced pressure. This gives 37 g (41% of theory) of the desired product.