Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[NH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([C:4]([C:3]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH:14]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=4[N:17]=3)[CH3:15])=[O:12])=[CH:10][C:2]=2[Cl:1])=[O:5])[CH2:29]1
Reactant: NCC1CCCNC1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCCC(CN)C2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-3-aminomethylpiperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.81 minutes; C23H25C12N5O2 (474.39); mass spectrum: (M−H)−=473/475/477 (chlorine isotope).
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC([O-])=O)C=CC=1OC.[CH2:26]([O:28][C:29]1[CH:30]=[C:31]([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=O)[CH3:27].C([N:47](CC)[C:48]([CH2:50]P(=O)([O-])[O-])=[O:49])C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[C:34]1([C:32]([C:31]2[CH:40]=[CH:41][C:42]([O:43][CH3:44])=[C:29]([O:28][CH2:26][CH3:27])[CH:30]=2)=[CH:50][C:48]([NH2:47])=[O:49])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCOc1cc(C(=O)c2ccccc2)ccc1OC
Reactant: CCN(CC)C(=O)CP(=O)([O-])[O-]
Agent: COc1ccc(C(=CC(=O)[O-])c2ccc(OC)c(OC)c2)cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCOc1cc(C(=CC(N)=O)c2ccccc2)ccc1OC

Procedure:
The acrylamide was prepared analogously to 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3-ethoxy-4-methoxybenzophenone (0.3 g, 1.2 mmol), diethylcarbamoylmethyl-phosphonate (0.25 g, 1.3 mmol) and lithium hexamethyldisilazide (1 mL, 1.3 mmol, 1.3M) with a reaction time of 54 hours at reflux. The crude mixture was purified by flash column chromatography (silica gel, 45% ethyl acetate/methylene chloride) to afford 0.06 g (17%) of a mixture of the E and Z isomers as an oil: 1H NMR (CDCl3) δ 7.54–7.19 (m, 10H), 7.00–6.65 (m, 6H), 6.34 (s, 2H), 5.54 (s, 1H), 5.55 (s, 1H), 5.24 (s, 1H), 5.04 (s, 1H), 4.16 (m, 4H), 3.92 (s, 3H), 3.87 (s, 3H), 1.60–1.33 (m, 6H); 13C NMR (CDCl3) δ 168.7, 168.6, 150.8, 150.4, 149.7, 148.4, 148.0, 140.7, 138.2, 133.0, 130.2, 129.2, 129.1, 128.8, 128.3, 128.0, 121.9, 121.6, 120.0, 113.7, 111.9, 111.4, 110.8, 64.4, 64.3, 55.9, 14.6; Anal. Calcd for C18H19NO3.0.35H2O. Theoretical: C, 71.19; H, 6.54; N, 4.61. Found: C, 71.19; H, 6.68; N, 4.45.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Li+].[O:7]1[C:9]([CH3:11])([CH3:10])[CH2:8]1.[NH:12]1[CH2:15][CH:14]([C:16]2[CH:17]=[CH:18][C:19]3[O:28][CH2:27][CH2:26][C:25]4[S:24][C:23]([C:29]5[N:30]([CH:34]([CH3:36])[CH3:35])[N:31]=[CH:32][N:33]=5)=[N:22][C:21]=4[C:20]=3[CH:37]=2)[CH2:13]1>C1COCC1>[CH:34]([N:30]1[C:29]([C:23]2[S:24][C:25]3[CH2:26][CH2:27][O:28][C:19]4[CH:18]=[CH:17][C:16]([CH:14]5[CH2:13][N:12]([CH2:8][C:9]([CH3:11])([OH:7])[CH3:10])[CH2:15]5)=[CH:37][C:20]=4[C:21]=3[N:22]=2)=[N:33][CH:32]=[N:31]1)([CH3:36])[CH3:35]
Reactant: CC1(C)CO1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CNC3)cc1-2
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CN(CC(C)(C)O)C3)cc1-2
Reaction time: 0.21 h
Yield: 35.7 %

Procedure:
Lithium perchlorate (52 mg, 0.49 mmol) was added to THF (5 mL) followed by 1,2-epoxy-2-methylpropane (0.43 mL, 4.9 mmol) and the mixture was stirred for 10-15 minutes giving a clear solution. 9-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.18 g, 0.49 mmol) was added and the reaction mixture was stirred for 72 hours then concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 0-10% MeOH in EtOAc) and the resulting solid extracted several times with ether. The ether extracts were concentrated in vacuo to give 377 (77 mg, 97%). LCMS: RT=7.45 min, [M+H]+=440. 1H NMR δ (ppm) (CDCl3): 8.28 (1 H, d, J=2.34 Hz), 7.90 (1 H, s), 7.16 (1 H, dd, J=8.29, 2.35 Hz), 7.02 (1 H, d, J=8.27 Hz), 5.93-5.83 (1 H, m), 4.40-4.34 (2 H, m), 4.04-3.95 (2 H, m), 3.89-3.79 (1 H, m), 3.46-3.36 (4 H, m), 2.55 (2 H, s), 1.63 (6 H, d, J=6.64 Hz), 1.15 (6 H, s). 1 Exchangeable proton not seen
Reaction SMILES: O/[C:2](/[C:9]([O:11][CH3:12])=[O:10])=[C:3](/O)\[C:4]([O:6][CH3:7])=[O:5].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>CO>[CH3:7][O:6][C:4](=[O:5])[C:3]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:2]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)/C(O)=C(\O)C(=O)OC
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CO
Product: COC(=O)C(Nc1ccccc1)=C(Nc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
In a round bottom flask with a teflon stirbar, 25 g (142 mmol) of dimethyl dihydroxyfumarate (prepared according to a procedure described in U.S. Pat. No. 3,334,102), 29.0 g (312.5 mmol) of aniline, 0.1 mL of concentrated HCl, and 90 mL of methyl alcohol were mixed and heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and left overnight in a refrigerator. The next morning, the resulting thick paste was filtered on a coarse frit, washed with a 50% (v:v) methanol-water mixture, and dried in a vacuum oven, yielding 30.1 g (65% yield) which, according to NMR analysis, was a mixture of E/Z isomers (E:Z˜1:2).
Reaction SMILES: P(Cl)(=O)[O-].[C:5]1([CH2:11][O:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C@H:20]([OH:38])[C:21]([N:23]2[CH2:37][CH2:36][CH2:35][C@H:24]2[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[O:22])=[O:14])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:55]([O:63][CH:64]([P:69](OC)([O:71][CH:72](NC(OCC1C=CC=CC=1)=O)CCCCC([C@]1(C(OCC2C=CC=CC=2)=O)CCCN1)=O)=[O:70])[CH2:65][CH2:66][CH2:67][CH3:68])(=[O:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>C(Cl)Cl>[C:55]([O:63][CH:64]([P:69]([O:71][CH3:72])([O:38][C@@H:20]([CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:13]([O:12][CH2:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:14])[C:21]([N:23]1[CH2:37][CH2:36][CH2:35][C@H:24]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:22])=[O:70])[CH2:65][CH2:66][CH2:67][CH3:68])(=[O:62])[C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1
Reactant: CCCCC(OC(=O)c1ccccc1)P(=O)(OC)OC(CCCCC(=O)[C@]1(C(=O)OCc2ccccc2)CCCN1)NC(=O)OCc1ccccc1
Reactant: O=C(NCCCC[C@H](O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: CN(C)c1ccccn1
Agent: O=[PH]([O-])Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(OC(=O)c1ccccc1)P(=O)(OC)O[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
The resulting crude phosphonochloridate is taken up in dry methylene chloride (2 ml.) and added dropwise to a methylene chloride (8 ml.) solution of 1-[(S)-6-[[(phenylmethoxy)carbonyl]amino]-2-hydroxy-1-oxohexyl]-L-proline, phenylmethyl ester (1.97 g., 4.2 mmole), triethylamine (0.66 g., 6.5 mmole) and dimethylaminopyridine (0.1 g.) at 0° under argon and stirred at 0°-15° for 2 hours. The mixture is partitioned between methylene chloride and 5% potassium bisulfate. The organic phase is washed with brine, dried over magnesium sulfate, and evaporated to dryness. The resulting crude oil is purified by chromatography (LPS-1 silica gel) eluting with (7:3) hexane:acetone. The product containing fractions are combined and concentrated in vacuo to yield 1.55 g. of 1-[(S)-2-[[[1-(benzoyloxy)pentyl]methoxyphosphinyl]oxy-1-oxo-6-[[(phenylmethoxy)carbonyl]amino]hexyl]-L-proline, phenylmethyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:36]=[C:37]([CH:44]=[CH:45][CH:46]=1)[C:38]([NH:40][CH:41]1[CH2:43][CH2:42]1)=[O:39].CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:19]=[C:20]([C:45]2[CH:46]=[CH:35][CH:36]=[C:37]([C:38](=[O:39])[NH:40][CH:41]3[CH2:43][CH2:42]3)[CH:44]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Reactant: O=C(NC1CC1)c1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1cccc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)c1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (93.7 mg, 0.21 mmol), 3-bromo-N-cyclopropyl-benzamide (50.0 mg, 0.21 mmol), and Pd[P(Ph)3]4 (12.8 mg, 5.3 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 5.1 mg. MS: 484.2 (M+H+); H1 NMR (DMSO-d6): δ (ppm) 0.54-0.78 (m, 4H), 1.77-2.05 (m, 3H), 2.14-2.37 (m, 1H), 2.80-2.94 (m, 1H), 3.40-3.58 (m, 2H), 4.30-4.44 (m, 1H), 4.38-5.14 (m, 2H), 7.00-8.07 (m, 13H), 8.49-8.59 (m, 1H), 10.10-10.09 (s, 1H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH:11]1([S:16]([CH2:19][C:20]2[CH:25]=[C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]3[CH3:32])[N:23]=[C:22]([C:33]3[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=3)[N:21]=2)(=[O:18])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])O.[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH:11]1([S:16]([CH2:19][C:20]2[CH:25]=[C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]3[CH3:32])[N:23]=[C:22]([C:33]3[CH:39]=[CH:38][C:36]([NH:37][C:2](=[O:3])[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:35][CH:34]=3)[N:21]=2)(=[O:17])=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)C2CCCC2)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)C2CCCC2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
Phenyl chloroformate (0.759 mL, 6.05 mmol) was added to 4-[4-(cyclopentylsulfonylmethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (1.68 g, 4.03 mmol) and sodium hydrogen carbonate (0.508 g, 6.05 mmol) in dioxane (20 mL) at 5° C. under nitrogen. The resulting mixture was stirred at RT for 2 hours. The reaction mixture was diluted with ethyl acetate (200 mL), and washed with water (125 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product which was triturated with a mixture of diethyl ether and isohexane to give the desired material as a white solid (2.10 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=[O:12].S(=O)(=O)(O)O.[CH3:19][CH2:20]O>>[CH2:19]([O:12][C:11](=[O:13])[CH2:10][C:3]1[CH:4]=[C:5]([OH:9])[C:6]([F:8])=[CH:7][C:2]=1[Br:1])[CH3:20]
Reactant: CCO
Reactant: O=C(O)Cc1cc(O)c(F)cc1Br
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (2-bromo-4-fluoro-5-hydroxy-phenyl)-acetic acid (5.06 g) in EtOH (100 ml) was added sulfuric acid (0.2 ml) and the mixture was stirred at room temperature for 24 hours. The mixture was heated at 70° C. with stirring for an additional 24 h. The mixture was evaporated to dryness under reduced pressure. Purification of the residue by flash chromatography (hexanes:EtOAc/9:1) gave (2-bromo-4-fluoro-5-hydroxy-phenyl)-acetic acid ethyl ester (4.66 g) as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[N:12]=[N:13][CH:14]=2)=[CH:3][C:2]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[F:23]
Reactant: OB(O)c1ccccc1F
Reactant: Fc1ccc(-c2nncc(-c3ccc(F)c(Br)c3)n2)c(F)c1
Product: Fc1ccc(-c2nncc(-c3ccc(F)c(-c4ccccc4F)c3)n2)c(F)c1

Procedure:
5-(3-Bromo-4-fluorophenyl)-3-(2,4-difluorophenyl)-[1,2,4]triazine was coupled to 2-fluorophenylboronic acid by the method of Example 12 to give 5-(2,2′-difluorobiphenyl-5-yl)-3-(2,4-difluorophenyl)-[1,2,4]triazine as a fluffy yellow solid: δH (400 MHz, CDCl3) 6.99-7.10 (2H, m), 7.21-7.23 (1H, m), 7.27-7.31 (1H, m), 7.37-7.48 (3H, m), 8.29-8.35 (3H, m), 9.64 (1H, s); m/z (ES+) 382.
Reaction SMILES: [CH:1]1([CH:7]2COCC[O:8]2)[CH2:6]C[CH2:4][CH2:3][CH2:2]1.C(C1COC(C2CCC(CCCCC)CC2)OC1)C.C(C1COC(C2CCC(CCCCCCC)CC2)OC1)CC.[CH2:54]([CH:59]1[CH2:64][CH2:63][CH:62]([C@H:65]2[CH2:70][CH2:69][C@H:68]([CH:71]=[O:72])[CH2:67][CH2:66]2)[CH2:61][CH2:60]1)[CH2:55][CH2:56][CH2:57][CH3:58]>>[CH2:2]([CH:1]1[CH2:7][O:8][CH:71]([CH:68]2[CH2:67][CH2:66][CH:65]([CH:62]3[CH2:63][CH2:64][CH:59]([CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:60][CH2:61]3)[CH2:70][CH2:69]2)[O:72][CH2:6]1)[CH2:3][CH3:4]
Reactant: C1CCC(C2COCCO2)CC1
Reactant: CCCCCC1CCC([C@H]2CC[C@H](C=O)CC2)CC1
Agent: CCCCCC1CCC(C2OCC(CC)CO2)CC1
Agent: CCCCCCCC1CCC(C2OCC(CCC)CO2)CC1
Product: CCCCCC1CCC(C2CCC(C3OCC(CCC)CO3)CC2)CC1

Procedure:
An example of the efficacy of compounds of the invention (compound I) in broadening the nematic temperature range of admixtures including two ring cyclohexyl dioxane compounds is as follows. A binary eutectic mixture comprising 0.745 mole fraction of 5-ethyl-2-(4-pentylcyclohexyl)-1,3-dioxane (compound A) and 0.255 mole fraction of 5-propyl-2-(4-heptylcyclohexyl)-1,3 dioxane (compound B) exhibits a nematic temperature range of 12.5° C. to 26.5° C. Addition of a three ring compound of the formula ##STR12## namely, 5-ethyl-2-(4-pentylcyclohexyl) cyclohexyl)-1,3 dioxane (compound C) to provide a eutectic mixture comprising 0.610 mole fraction of compound A, 0.189 lmole fraction of compound B and 0.201 mole fraction of compound C resulted in a measured nematic temperature range of 8.6° C. to 59.7° C. while the mixture retained low viscosity and low optical birefringence, e.g., Δn=0.04.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([CH3:25])[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: Cc1cccc2c1CCNC2C
Product: Cc1cccc2c1CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C
Yield: 19 %

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,5-Dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[C:23]([CH:24]=O)=[CH:22][CH:21]=[CH:20][N:19]=1.N1CCC[C@H]1C(O)=O>C(O)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:24][C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ncccc1C=O
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3cccnc3n2)CC1
Yield: 24.9 %

Procedure:
3.14 g of 1-tert-butoxycarbonyl-4-acetyl-piperidine and 1.83 g of 2-amino-3-formyl-pyridine were refluxed with 0.25 g of L-proline in n-butanol for 72 hours. After removing the solvent in vacuo the residue was combined with the residue obtained in an identical reaction and chromatographed on silica gel with ethyl acetate/n-heptane (1:1) to give 1.08 g of the title compound.
Reaction SMILES: [CH2:1]([C:7](=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:8]=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(OCC)(OCC)OCC.[C:27]([C@@H:32]([C@H:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[OH:35])O)([O:29][CH2:30][CH3:31])=[O:28]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:10](=[C:7]([CH:8]1[O:35][C@@H:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C@H:32]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[O:9]1)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCCCCCC(C=O)=Cc1ccccc1
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(OCC)OCC
Product: CCCCCCC(=Cc1ccccc1)C1O[C@@H](C(=O)OCC)[C@H](C(=O)OCC)O1
Yield: 108.9 %

Procedure:
A solution of α-hexylcinnamaldehyde (62.19 g, 0.288 mole), triethyl orthoformate (42.61 g, 0.288 mole), diethyl L-tartrate (51.5 g, 0.25 mole) in toluene (180 ml) containing p-toluene sulfonic acid (0.8 g) was refluxed for 1 hour. About 100 ml of ethanol-toluene mixture was distilled over a period of 2 hours, and after cooling the remaining solvent was removed on a rotary evaporator. The residue was dissolved in toluene (200 ml) and the solution was washed with aqueous NaHCO3 and then with water. The solution was dried over Na2SO4, and the solvent was evaporated under reduced pressure to provide a brown liquid (110.1 g).
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].[CH2:9]([O:16][C:17]1[C:18]([O:26][CH3:27])=[CH:19][C:20]([CH2:24]Br)=[C:21]([Br:23])[CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCCCCC.O1CCCC1>[CH2:9]([O:16][C:17]1[C:18]([O:26][CH3:27])=[CH:19][C:20]([CH2:24][CH2:7][C:6]#[N:8])=[C:21]([Br:23])[CH:22]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC#N
Reactant: COc1cc(CBr)c(Br)cc1OCc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(CCC#N)c(Br)cc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
To a solution of n-butyllithium (1.8 mL of a 2.5 M solution in hexane, 4.5 mmol) in 5 mL of tetrahydrofuran is added a solution of acetonitrile (1.0 mL, 19.1 mmol) in 5 mL of tetrahydrofuran. The reaction mixture is stirred at −78° C. for 15 min. A solution of 5-(benzyloxy)-1-bromo-2-(bromomethyl)-4-methoxybenzene (0.7 g, 1.8 mmol) in 3 mL of tetrahydrofuran is added and stirring is continued for 1 hour at −78° C. The reaction is quenched by the addition of 15 mL of water and the mixture is allowed to warm to room temperature. The mixture is extracted with ethyl acetate and the organic layers combined, then dried with sodium sulfate. After reducing in vacuo, the crude product is purified by flash chromatography using a gradient of 95:5 to 4:1 hexanes/ethyl acetate as an eluent. The clean fractions are combined, reduced in vacuo and dried to yield 0.343 g of 3-(4-benzyloxy-2-bromo-5-methoxyphenyl)-propionitrile as a white solid, mp 52-53° C.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[C:41](B4OC(C)(C)C(C)(C)O4)[CH:42]=3)[C:37]2=[O:54])[CH2:32][CH2:31]1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:41]3[CH:42]=[C:43]4[C:38](=[CH:39][CH:40]=3)[C:37](=[O:54])[N:36]([CH:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)[CH2:44]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Reactant: CN1CCC(N2Cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3C2=O)CC1
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc5c(c4)CN(C4CCN(C)CC4)C5=O)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 2-(1-methylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=520.2.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Cl:20]C1C=C2C(=CC=1)NC=C2>>[O:4]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCC2(C1)OCCO2
Reactant: Clc1ccc2[nH]ccc2c1
Product: Clc1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Yield: 96 %

Procedure:
This compound was prepared in the manner described above for intermediate 1a by replacing indole with 5-chloroindole (5 g, 33 mmol)) to afford 9.14 g (96%) of the title compound as a white solid: mp 178-181° C.; MS EI m/e 273 (M+).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[OH:20][CH2:21][C@H:22]([NH2:25])[CH2:23][CH3:24].CCN(C(C)C)C(C)C>>[OH:20][CH2:21][C@H:22]([NH:25][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1)[CH2:23][CH3:24]
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: CC[C@@H](N)CO
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](CO)NC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (R)-1-hydroxymethyl-propylamine and DIEA to give 2-((R)-1-hydroxymethyl-propylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 328 (MH+).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:10]([CH2:18][CH3:19])[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:20]([O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:33]2[CH:34]=[CH:35][C:30]([C:28]([O:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:29])=[CH:31][CH:32]=2)=[N:3][C:4]=1[C:9]1[N:10]([CH2:18][CH3:19])[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:17]=1
Reactant: CCn1c(-c2nc(Br)cnc2N)nc2cnccc21
Reactant: O=C(OCc1ccccc1)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(-c2nc(-c3ccc(C(=O)OCc4ccccc4)cc3)cnc2N)nc2cnccc21
Temperature: 200 °C
Yield: 8.4 %

Procedure:
5-bromo-3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine (0.032 g, 0.10 mmol) (made in example 2), 4-[(benzyloxy)carbonyl]phenylboronic acid (0.051 g, 0.20 mmol), Pd(PPh3)2Cl2 (0.0035 g, 0.005 mmol) and K2CO3 (0.050 g, 0.36 mmol) were combined in 0.5 mL of N,N-dimethylformamide and heated to 200° C. in the SmithSynthesizer microwave for 8 minutes. The reaction mixture was concentrated in vacuo and the residue purified by mass directed HPLC to give 0.0038 g of the title compound.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[CH2:6]([OH:11])[CH2:7][CH2:8][CH2:9][CH3:10].Cl>>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:11][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCO
Agent: Cl
Product: CCCCCOP(=O)(Cl)Cl
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
Phosphoryl trichloride (306 g; 2 moles) is placed in a 2-liter flask fitted with a condenser and mechanical stirrer, and cooled down to about 10° C. (external ice bath). Pentanol (159 g; 1.8 moles; 0.9 equivalents with respect to POCl3) is added at a rate such that the reaction temperature remains below 15° C. The reaction is exothermic and the HCl gas that evolves during this reaction is vented out with a flow of nitrogen using an aspirator operated at a slight vacuum (about 0.5 inches of mercury). When addition of alcohol is completed (about 1.5 hours), the ice bath is removed and the reaction mixture is allowed to warm to room temperature and then warmed to 60°-70° C. and stirred at this temperature for 1.5 hours to drive out most of the HCl gas. The product, pentyl phosphorodichloridate, is obtained as a clear light yellow free-flowing liquid.