Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]34[CH2:21][CH:16]5[CH2:17][C:18]([NH2:20])([CH2:19]3)[CH:14]([CH2:15]5)[CH2:13]4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[C:37]#[N:38])=[O:31]>CS(C)=O.CCOC(C)=O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]34[CH2:21][CH:16]5[CH2:17][C:18]([NH:20][CH2:29][C:30]([N:32]6[CH2:36][CH2:35][CH2:34][C@H:33]6[C:37]#[N:38])=[O:31])([CH2:19]3)[CH:14]([CH2:15]5)[CH2:13]4)=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: NC12CC3CC1CC(c1ccc(-n4cccc4)cc1)(C3)C2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(c1ccc(-n4cccc4)cc1)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.2 %

Procedure:
To a stirred mixture of the compound obtained from step II (0.41 g, 1.5 mmol) and K2CO3 (0.62 g, 4.5 mmol) in DMSO (6 mL) at ice bath temperature under N2 atmosphere was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.26 g, 1.5 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-[4-(1H-pyrrol-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a (1H)-yl]glycyl}pyrrolidine-2-carbonitrile as a white solid (0.2 g) in 32% yield as off-white solid. m/z (M+1) 415; 1H NMR (CDCl3) 300 MHz δ 7.38-7.26 (m, 4H), 7.10-7.05 (m, 2H), 6.36-6.32 (m, 2H), 4.84-4.78 (m, 1H), 3.75-3.40 (m, 2H), 3.50 (s, 2H), 2.50-2.42 (m, 1H), 2.38-2.28 (m, 2H), 2.25-2.0 (m, 6H), 2.0-1.70 (m, 7H).
Reaction SMILES: N1C=CC=CC=1O.C([Zn][CH2:11][CH3:12])C.[CH:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([CH:13]([OH:20])[CH2:11][CH3:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: CC[Zn]CC
Agent: Oc1ccccn1
Product: CCC(O)c1ccccc1

Procedure:
A dry Schlenk flask under argon was charged with 0.05 equiv. of the pyridinyl alcohol. The flask was evacuated twice and flushed with argon. Then, 5 mL of freshly distilled toluene were added followed by 1.5 equiv. of neat diethylzinc while stirred. After stirring for 20 min at room temperature, 1.0 equiv. of benzaldehyde (10) was added at the given temperature (see Table). The proceeding of the reaction was monitored by thin layer chromatograpy. After full conversion of the aldehyde, the reaction was quenched by careful addition of 10 mL of 2 M HCl, and the resulting mixture was extracted three times with 25 mL of dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane/methyl tert-butylether=10:1) followed by Kugelrohr distillation to give 1-phenylpropanol (11) as a colorless oil. The enantiomeric excess of 11 was determined by HPLC on a stationary phase [CHIRALCEL OD, n-heptane/iso-propanol=98:2, 1 0 mL/min; tR=17.2 min (R); 21.5 min (S)], and the absolute configuration was determined by correlation of the optical rotation with the values reported in the literature (Soai, K.; Ookawa.; Kaba, T.; Ogawa, K.; J. Arn. Chem. Soc. 1987, 109, 7111).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[NH:5][C:4](=O)[C:3]=1[CH:13]([CH3:15])[CH3:14].O(C)[Na].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:4]1[C:3]([CH:13]([CH3:15])[CH3:14])=[C:2]([CH3:1])[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=1
Reactant: Cc1nc(C(F)(F)F)[nH]c(=O)c1C(C)C
Reactant: O=P(Cl)(Cl)Cl
Agent: CO[Na]
Product: Cc1nc(C(F)(F)F)nc(Cl)c1C(C)C
Yield: 58 %

Procedure:
6-Methyl-5-(2-propyl)-2-trifluoromethyl-4H-pyrimidin-4-one of Example 3 (1.66 g, 7.5 mmol) was converted to a Na salt with NaOCH3 then refluxed with phosphorus oxychloride (6 mL) for 3 h. The reaction mixture was concentrated to a small volume, poured into crushed ice, and extracted with Et2O. The organic layer was washed with H2O (twice), dried over Na2SO4, and evaporated to give 1.05 g (58%) of a light yellow oil.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[CH:6]=1)[CH2:3][OH:4].[OH-].[Na+].[Cl:15][CH2:16][C:17](Cl)=[O:18]>C(Cl)Cl>[Cl:15][CH2:16][C:17]([NH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[CH:6]=1)[CH2:3][OH:4])=[O:18]
Reactant: O=C(Cl)CCl
Reactant: NC(CO)c1ccc(F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCl)NC(CO)c1ccc(F)c(F)c1
Reaction time: 0.25 h

Procedure:
To a solution of 2-amino-2-(3,4-difluorophenyl)-ethanol 2.6 g, 15.0 mmol) in CH2Cl2 (15 mL) and 20% (by wt.) NaOH (15 mL) was added a solution of chloroacetyl chloride (1.32 mL, 16.5 mmol) in 15 mL of CH2Cl2 at −10° C. dropwise under argon atmosphere. After the addition was complete, the reaction mixture was stirred for 15 min and then it was transferred to a separatory funnel. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic extracts were washed with a solution containing 10 mL of brine and 5 drops of concentrated HCl. The organic layer was dried over MgSO4, filtered and the solvent was removed in vacuo to give a white solid. It was further purified with flash column chromatography on silica gel with 1:1 hexane/EtOAc followed by EtOAc as the eluting system. 2-Chloro-N-[1-(3,4-difluorophenyl)-2-hydroxy-ethyl]-acetamide was obtained as a white solid (2.6 g, 69.5% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:10][C@H:9]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[C:21]([F:34])=[CH:22][C:23](Br)=[C:24]([N:26]4[C:30](=[O:31])[N:29]([CH3:32])[N:28]=[N:27]4)[CH:25]=3)[N:13]=2)[CH2:8][C@H:7]2[N:3]1[CH2:4][CH2:5][CH2:6]2.C(=O)([O-])[O-].[Na+].[Na+].[CH:42](B1OC(C)(C)C(C)(C)O1)=[CH2:43]>C(COC)OC.C(O)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>[CH3:1][C:2]1([CH3:35])[CH2:10][C@H:9]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[C:21]([F:34])=[CH:22][C:23]([CH:42]=[CH2:43])=[C:24]([N:26]4[C:30](=[O:31])[N:29]([CH3:32])[N:28]=[N:27]4)[CH:25]=3)[N:13]=2)[CH2:8][C@H:7]2[N:3]1[CH2:4][CH2:5][CH2:6]2
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: Cn1nnn(-c2cc(Nc3ncc(F)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)c(F)cc2Br)c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: C=Cc1cc(F)c(Nc2ncc(F)c(N[C@@H]3C[C@@H]4CCCN4C(C)(C)C3)n2)cc1-n1nnn(C)c1=O
Temperature: 110 °C
Yield: 93.6 %

Procedure:
1-(5-(4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-5-fluoropyrimidin-2-ylamino)-2-bromo-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one (301.9 mg, 0.55 mmol) was weighed out and added to a reaction tube with magnetic stir bar. It was dissolved in 24 mL of a solution of dimethoxyethane, ethanol, and water in a ratio of 7:3:2, respectively. Sodium carbonate (174.6 mg, 1.65 mmol) was weighed out, and vinylboronic acid pinacol ester (0.205 mL, 1.21 mmol) was then added. The solution was subjected to vigorous sub-surface nitrogen sparging. Bis(triphenylphosphine)palladium(II) dichloride (17.3 mg, 0.025 mmol) was weighed out and added, the tube was sealed under nitrogen, and the reaction was heated overnight at 110° C. The reaction solution was then combined with a 0.162 mmol pilot reaction run under the same conditions. This was concentrated directly onto silica, and purified by column chromatography. Pure fractions were combined, concentrated, and dried under high vacuum to give 256.0 mg of the title compound (72% total).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[H-].[Na+].[Cl:16][C:17]1[C:22]([CH3:23])=[C:21](Cl)[CH:20]=[CH:19][N:18]=1>CC(N(C)C)=O.CCOCC>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][C:21]2[CH:20]=[CH:19][N:18]=[C:17]([Cl:16])[C:22]=2[CH3:23])[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1c(Cl)ccnc1Cl
Reactant: CC(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: Cc1c(OC2CCN(C(=O)OC(C)C)CC2)ccnc1Cl
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 27 %

Procedure:
4-Hydroxy-piperidine-1-carboxylic acid isopropyl ester (0.496 mL, 2.90 mmol) was dissolved in anhydrous dimethylacetamide (DMA, 5 mL), NaH (60% oil dispersion, 116 mg, 2.90 mmol) was added and this mixture was stirred at 23° C. for 45 min, then this mixture was added dropwise to 2,4-dichloro-3-methyl-pyridine, which was dissolved in anhydrous DMA (4 mL). This mixture was stirred at 23° C. for 2 h then heated at 50° C. for 15 h, after which time the mixture was diluted with Et2O (140 mL), washed with water (14 mL), then brine twice (2×14 mL). The organic layer was separated, dried with MgSO4, and the solvent was evaporated in vacuo to give an oil which was purified by flash chromatography using hexanes-EtOAc, 75:25, v/v, then hexanes-EtOAc, 50:50, v/v, to give 4-(2-chloro-3-methyl-pyridin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester as a solid (223 mg, 27%). 1H NMR (CDCl3, 400 MHz) δ 8.09 (d, 1H), 6.69 (d, 1H), 4.91 (m, 1H), 4.60 (m, 1H), 3.61 (m, 2H), 3.52 (m, 2H), 2.24 (s, 3H), 1.91 (m, 2H), 1.80 (m, 2H), 1.24 d, 6H). LRMS calculated for C15H21ClN2O3: 312.12, Found: (MH)+ 313.4.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C@@H:11]2[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]3[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=3)=[O:17])[CH2:12]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:32][C:33]([O:36][C:37]([NH:39][CH2:40][C@H:41]1[CH2:46][CH2:45][C@H:44]([C:47](O)=[O:48])[CH2:43][CH2:42]1)=[O:38])([CH3:35])[CH3:34]>>[CH3:35][C:33]([O:36][C:37]([NH:39][CH2:40][C@H:41]1[CH2:46][CH2:45][C@H:44]([C:47]([N:14]2[CH2:15][C@@H:11]([N:8]3[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]3)[CH2:12][C@H:13]2[C:16]([NH:18][C:19]2[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[CH:21][CH:20]=2)=[O:17])=[O:48])[CH2:43][CH2:42]1)=[O:38])([CH3:32])[CH3:34]
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCN(S(C)(=O)=O)CC3)CN2)cc1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)N2C[C@@H](N3CCN(S(C)(=O)=O)CC3)C[C@H]2C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)CC1

Procedure:
Following the procedure described in Example 8, the compound prepared in Example 6 was treated with trans-4-[({[(2-methyl-2-propanyl)oxy]carbonyl}amino)methyl]cyclohexanecarboxylic acid to give the title compound as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH2:4][CH2:3]1.[CH2:18]([O:20][C:21](=[O:30])[C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:19].C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CCO.CCOCC>[CH2:18]([O:20][C:21](=[O:30])[CH:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH:1][C@H:2]1[CH2:3][CH2:4][C@@H:5]([C:8]([OH:17])([C:13]([F:14])([F:15])[F:16])[C:9]([F:11])([F:12])[F:10])[CH2:6][CH2:7]1)[CH3:19].[CH2:18]([O:20][C:21](=[O:30])[CH:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:8]([OH:17])([C:13]([F:14])([F:15])[F:16])[C:9]([F:11])([F:12])[F:10])[CH2:6][CH2:7]1)[CH3:19]
Reactant: CCOC(=O)C(=O)c1ccccc1
Reactant: NC1CCC(C(O)(C(F)(F)F)C(F)(F)F)CC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(N[C@H]1CC[C@@H](C(O)(C(F)(F)F)C(F)(F)F)CC1)c1ccccc1
Product: CCOC(=O)C(N[C@H]1CC[C@H](C(O)(C(F)(F)F)C(F)(F)F)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
A solution of 300 mg (1.0 mmol) of the acetate salt of 2-(4-amino-cyclohexyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (example 2.1) in 5 mL of EtOH was treated with 227 mg (1.0 mmol) of oxo-phenyl-acetic acid ethyl ester and with 87 mg (1.0 mmol) of sodium cyanoborohydride. The mixture was stirred overnight at RT and distributed between a saturated aqueous solution of NaHCO3 and Et2O. Drying of the combined organic phases over Na2SO4 and chromatography on silica gel with heptane/EtOAc 4:1 yielded ca. 100 mg (25%) of cis phenyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexylamino]-acetic acid ethyl ester and ca. 100 mg (25%) of trans phenyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexylamino]-acetic acid ethyl ester as a colorless oil, MS: 428 (M+H)+.
Reaction SMILES: P(=O)(O)(O)O.[I-:6].[F:7][C:8]([F:15])([F:14])[CH:9]([CH3:13])[CH2:10][CH2:11]O>>[F:7][C:8]([F:15])([F:14])[CH:9]([CH3:13])[CH2:10][CH2:11][I:6]
Reactant: CC(CCO)C(F)(F)F
Reactant: [I-]
Agent: O=P(O)(O)O
Product: CC(CCI)C(F)(F)F
Temperature: 0 °C

Procedure:
To a mixture of 19 g phosphoric acid (98%) and 19 g pottasium iodide are added at 40° under stirring 4.75 g (33.4 mMol) of 4,4,4-trifluoro-3-methyl-butan-1-ol over a period of 10 minutes. The mixture is then heated at 120° for 16 hours, a cooling poured into ice-water and extracted with diethylether. The etheric extracts are washed with 10% sodium thiosulfate and brine acid dried over sodium sulphate. After filtration, the solvent is removed through a 15 cm Vigreux-column at atmospheric pressure, followed by fractionation giving 4,4,4-trifluoro-3-methyl-1-iodo-butane, b.p. 76-77° at 140 mbar.
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:34]=[CH:33][C:13]2[N:14]([CH3:32])[C:15]([NH:17][C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].COCCN(S(F)(F)[F:45])CCOC>>[F:45][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:34]=[CH:33][C:13]2[N:14]([CH3:32])[C:15]([NH:17][C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][C:28]([F:30])([F:31])[F:29])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCOCCO)ccc21
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCOCCF)ccc21

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(2-fluoro-ethoxy)-ethyl]-amide (53 mg) was prepared by following General Procedure H starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide (50 mg) and bis(2-methoxyethyl)aminosulfur trifluoride (47 uL). LC/MS: m/z 498.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.39 (bs, 1H), 8.51 (s, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.86-7.62 (m, 2H), 7.49 (d, 1H), 7.36 (d, 1H), 4.63-4.46 (m, 1H), 3.80-3.69 (m, 2H), 3.68-3.52 (m, 6H), 3.46 (q, 2H).
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)[C@H:12]([CH:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:22]([OH:24])=[O:23])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=CC=1)([O-])=O.Cl.[CH3:31][O:32][C:33](=[O:43])[C@H:34]([CH2:36][C:37]1[CH2:38][CH:39]=[CH:40][CH2:41][CH:42]=1)[NH2:35].CN(C)C=O.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:31][O:32][C:33](=[O:43])[C@H:34]([CH2:36][C:37]1[CH2:42][CH:41]=[CH:40][CH2:39][CH:38]=1)[NH:35][C:11](=[O:10])[C@H:12]([CH:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:22](=[O:23])[OH:24])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)Oc1ccc([N+](=O)[O-])cc1)C(C(=O)O)C(C)(C)C
Reactant: COC(=O)[C@@H](N)CC1=CCC=CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CC1=CCC=CC1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C(=O)O)C(C)(C)C

Procedure:
β-tert.-butyl-Nα-tert.-butyloxycarbonyl-L-aspartic acid p-nitrophenyl ester (26.7 g.) is added to a mixture of 2,5-dihydro-L-phenylalanine methyl ester hydrochloride (11.8 g.), dimethylformamide (50 ml.) and triethylamine (7.6 ml.). After two hours at room temperature the reaction mixture is diluted with ethyl acetate and washed with 20% aqueous citric acid, water, saturated sodium bicarbonate and water. After drying over magnesium sulfate the solvent is removed in vacuo. Yield: 13.2 g.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22](=O)[CH2:23][C@@H:24]([CH3:27])[CH2:25][CH3:26])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.NN.C(O)COCCO.[OH-].[K+]>O>[CH2:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C@@H:24]([CH3:27])[CH2:25][CH3:26])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)C[C@@H](C)CC)cc2)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ccc(CC[C@@H](C)CC)cc2)cc1
Reaction time: 4 h
Yield: 56.7 %

Procedure:
4-Octyloxy-4'-((S)-3-methyl-pentanoyl)biphenyl (24.6 g, 0.065 mol) obtained in Example 23 described later, 80% hydrazine hydrate (50 ml) and diethylene glycol (85 ml) were placed in a 500 ml three-neck flask, followed by heating with stirring, keeping the mixture at 120° C. for one hour, then cooling, adding, at a stroke, a solution of potassium hydroxide (8.8 g, 0.157 mol) in water (5 ml) while keeping the temperature at 50° C., distilling off so that the temperature of the system might become 200° C., reacting at 200° C. for 4 hours, then cooling, adding water (200 ml) and toluene (50 ml), transferring the contents into a separating funnel, water-washing the organic layer till the washing liquid became neutral, distilling off the solvent, distilling under reduced pressure to collect a fraction having a boiling point of 210°-213° C./3 mmHg, and recrystallizing it from ethyl alcohol (20 ml) and ethyl acetate (5 ml) to obtain 4-octyloxy-4'-((S)-3-methyl-pentyl)biphenyl (IIIb1) (13.5 g) which was a smectic liquid crystal exhibiting SC* phase and SH* phase, and whose phase transition points were as follows as shown in Table 2, column of Example 24: C-S1 point, 43.0° C.; Sl-SH* point, 57.9° C.; SH*-SC* point, 62.5° C; SC*-I point, 65.1° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1(=[O:15])[O:10][C:8](=[O:9])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]12.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([OH:21])=[CH:19][C:18]=1[OH:24]>[N+](C1C=CC=CC=1)([O-])=O>[C:8]([C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[C:5](=[O:15])[C:22]1[CH:23]=[C:17]([Cl:16])[C:18]([OH:24])=[CH:19][C:20]=1[OH:21])([OH:10])=[O:9]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Oc1ccc(Cl)c(O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)c1ccccc1C(=O)c1cc(Cl)c(O)cc1O
Reaction time: 8 h

Procedure:
AlCl3 (40.0 g, 300 mmol) was added to a solution of phthalic anhydride (20.0 g, 135 mmol) and 4-chlororesorcinol (18.8 g, 130 mmol) in 225 ml nitrobenzene and purged with N2. After stirring overnight, the solution was poured into a vigorously stirred biphasic solution of 750 ml hexanes and 1.0 L 0.5 M aqueous HCl. The solution was allowed to stir for 2 h and the light tan precipitate that formed was filtered and washed with 200 ml aqueous 0.1 M HCl and 300 ml hexanes. The crude product was crystallized from hot MeOH/H2O (12.1 g, 32%). 1H NMR (CD3OD) δ 6.48 (1H, s), 6.95 (1H, s), 7.39 (1H, dd, J 7.2 1.5), 7.62–7.52 (2H, m), 8.12 (1H, dd, J=1.2, 7.8).
Reaction SMILES: [CH3:1]N(C=O)C.C(Cl)(=O)C(Cl)=O.[CH2:12]([O:19][C:20]1[CH:29]=[C:28]2[C:23](C(=O)N[CH:26]=[N:27]2)=[CH:22][C:21]=1[O:31][CH3:32])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.[CH:34]([Cl:37])(Cl)Cl>C(Cl)Cl>[CH2:12]([O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:34]([Cl:37])=[CH:1][CH:26]=[N:27]2)=[CH:22][C:21]=1[O:31][CH3:32])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)C=O
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Reactant: ClC(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Temperature: 0 °C
Yield: 48 %

Procedure:
Dry DMF (8.0 ml, 103 mmol) was dissolved in dry CHCl3 (40 ml) and cooled in an ice bath. Oxalyl chloride (9.0 ml, 105 mmol) in CH2Cl2 (10 ml) was added dropwise with stirring at 0° C. When the bubbling had ceased, this solution was added slowly to an ice-cold solution of 7-benzyloxy-6-methoxy-3H-quinazolin-4-one (10.0 g, 35.4 mmol) in dry CHCl3 (60 ml) and the mixture was then heated to reflux for 2-3 hrs. After cooling to room temperature, H2O (100 ml) was added and the phases were separated. The aqueous phase was further extracted with CHCl3 (2×). The combined CHCl3 extractions were washed with sat'd NaCl (1×), dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by flash chromatography (1:1 hexanes:EtOAc, followed by 100% EtOAc) to give 7-benzyloxy-4-chloro-6-methoxy-quinoline (5.11 g, 48%). LC/MS Calcd for [M+H]+ 301.1, found 301.1.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1cnc2ccc(Oc3ccccc3)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2ccc(Oc3ccccc3)cc2c1Cl

Procedure:
Prepared as in Example 1b from ethyl 4-hydroxy-6-phenoxyquinoline-3-carboxylate (Example 8c) and POCl3 as a tan solid (96%). 1H NR (400 MHz, DMSO-d6) δ 1.36 (t, J=8.0 Hz, 3H), 4.40 (q, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 7.29 (t, J=8.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 2H), 7.63 (d, J=4.0 Hz, 1H), 7.76 (dd, J=8.0 Hz, 1H), 8.21 (d, J=8.0 Hz, 1H), 9.06 (s, 1H). MS 328, 330 (MH+).
Reaction SMILES: C([Li])CCC.I[C:7]1[C:8]2[CH:15]=[CH:14][N:13]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[C:9]=2[N:10]=[CH:11][N:12]=1.[CH:26]1([CH:32]=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH:26]1([CH:32]([C:7]2[C:8]3[CH:15]=[CH:14][N:13]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[C:9]=3[N:10]=[CH:11][N:12]=2)[OH:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(I)ncnc21
Reactant: O=CC1CCCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(O)C3CCCCC3)ncnc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
n-Butyllithium (1.6 M solution in hexane, 0.23 mL, 0.380 mmol) was gradually added dropwise to 4-iodo-7-(triisopropylsilyl)-7H-pyrrolo[2,3-d]pyrimidine (126 mg, 0.310 mmol) in tetrahydrofuran (1.5 mL) cooled to −78° C., and the reaction mixture was stirred at −78° C. for 30 minutes. After addition of cyclohexanecarbaldehyde (42 μL, 0.35 mmol) in tetrahydrofuran (1.5 mL), the reaction mixture was gradually warmed from −78° C. to room temperature and stirred for one day. After addition of saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hi Flash column amino type manufactured by Yamazen Corporation: hexane/ethyl acetate=10/1→7/1→4/1 (v/v)) to give the title compound as a colorless oil (65.5 mg, yield 55%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:8][CH2:7]2)[CH2:2]1.CCN(C(C)C)C(C)C.[CH3:31][N:32]=[C:33]=[O:34]>C(Cl)Cl>[CH3:31][NH:32][C:33]([N:1]1[CH2:5][CH2:4][CH:3]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:8][CH2:7]2)[CH2:2]1)=[O:34]
Reactant: CN=C=O
Reactant: O=C(OCc1ccccc1)N1CCN(C2CCNC2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)N1CCC(N2CCN(C(=O)OCc3ccccc3)CC2)C1
Reaction time: 0.5 h

Procedure:
45-3 (0.27 g, 0.93 mmol) was dissolved in methylene chloride (4 mL) and DIEA (0.60 g, 4.67 mmol) and then a methylene chloride solution (1 mL) of methylisocyanate (0.050 g, 0.93 mmol) was added. The solution was then stirred for 30 minutes, after which it was concentrated and purified on a C18 preparative hplc column to afford 45-4. 1H-NMR (CD3OD): 7.37(m, 5H); 5.17(s, 2H); 3.89(m, 4H); 3.59(m, 4H); 3.36(m, 5H); 2.74(s, 3H); 2.47(m, 1H); 2.24(m, 1H).