Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C@@H:6]2[OH:13].N1C=CN=C1.[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O.O>[Br:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C@@H:6]2[O:13][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25]
Reactant: N#Cc1ccc2c(c1Br)CC[C@@H]2O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCc2c1ccc(C#N)c2Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-4-Bromo-1-hydroxy-indan-5-carbonitrile (0.90 g, 3.78 mmol), imidazole (0.64 g, 9.45 mmol) and tert-butyldimethylchlorosilane (0.80 g, 5.29 mmol) are suspended in dry N,N-dimethylformamide and stirred at room temperature for 3 hours. The mixture is diluted with water and extracted with ethyl acetate. The organic extracts are dried and the solvent removed to give the crude product which is used directly in the next step (Yield 1.20 g).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:19]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]4[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=4)[C:29]([OH:31])=O)=[N:18][CH:17]=[N:16][C:15]=3[S:14][CH:13]=2)=[CH:8][CH:7]=1.[NH2:35][NH2:36]>O1CCCC1>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:20]3[C:19]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]4[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=4)[C:29]([NH:35][NH2:36])=[O:31])=[N:18][CH:17]=[N:16][C:15]=3[S:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: NN
Reactant: O=C(O)c1cccc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: NNC(=O)c1cccc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
Thionyl chloride (13 mg, 0.11 mmol) was added to a solution of 3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)benzoic acid (43 mg, 0.10 mmol) in tetrahydrofuran (2.0 mL) with stirring at 70° C. Stirring continued for one hour at 70° C. and then the mixture was cooled to 25° C. and added to a solution of hydrazine (32 mg, 1.0 mmol) in tetrahydrofuran (2.0 mL). The reaction was stirred at room temperature for one hour and the solvent was then removed in vacuo. The residue was dissolved in ethyl acetate (30 mL), washed with of aqueous sodium bicarbonate solution (20 mL), concentrated, and purified by column chromatography over silica gel using 2% methanol in ethyl acetate as eluant to give 22 mg (50%) of 3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)benzohydrazide as a white solid. MS [M+H] 439.2, 1H NMR (CDCl3) δ (ppm) 8.65 (s, 1H), 7.50-7.35 (m, 2H), 7.32-7.21 (m, 3H), 7.18 (s, 1H), 7.10-6.97 (m, 2H), 6.94 (d, J=2.7 Hz, 1H), 4.59 (t, J=6.9 Hz, 2H), 4.11 (s, 2H), 3.74 (t, J=6.0 Hz, 2H), 2.09 (m, 2H).
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]2=O)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].Cl>O1CCCC1>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:15]3[CH2:16][CH2:17][CH:12]([C@H:9]4[CH2:10][CH2:11][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]4)[CH2:13][CH:14]=3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1CCC(C2CCCCC2=O)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2ccc(C3=CCC([C@H]4CC[C@H](CCCCC)CC4)CC3)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-pentyl-4'-bromobiphenyl (2.8 g, 0.0092 mol) dissolved in tetrahydrofuran (50 ml) was reacted with Mg (0.22 g, 0.0092 mol) in nitrogen current to obtain 4-pentyl-4'-biphenylmagnesium bromide. The reaction liquid was cooled to 0° C. and to this liquid was added a tetrahydrofuran solution (50 ml) of 4-pentylcyclohexylcyclohexanone (2.3 g, 0.0092 mol). The mixture was refluxed at 50° C. for 2 hours and 3N hydrochloric acid (50 ml) was then added, followed by extracting the product with toluene (200 ml), washing with water, distilling off the solvent, adding potassium hydrogen sulfate (4 g) and dehydrating at 200° C. for 2 hours in nitrogen atmosphere. After cooling, toluene (200 ml) was added and potassium hydrogen sulfate was filtered off, followed by washing with water till the washing water became neutral, dehydrating with anhydrous sodium sulfate, distilling off the solvent and recrystallizing from toluene to obtain crystals of 4-pentyl-4'-[4-(trans-4-pentylcyclohexyl)cyclohexen-1-yl]biphenyl. This product (1.4 g, 0.0031 mol) was dissolved in n-heptane (200 ml) and to the solution was added Raney Ni (0.7 g), followed by catalytic reduction under ordinary pressure at 60° C. The reaction was traced by gas chromatography, and when the raw material disappeared, that is, after 12 hours, reduction was completed. Since the resulting material was a mixture of cis-form and trans-form substances, it was recrystallized from toluene to take out the trans-form substance, that is, an objective product, 4-pentyl-4'-[trans-4-(trans-4-pentylcyclohexyl)cyclohexyl]-biphenyl. Yield: 0.5 g (0.001 mol). This product had such a very broad liquid-crystalline temperature range as a C-Sm point of room temperature or lower and a Sm-I point of 300° C. or higher.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[NH2:19][CH2:20][CH2:21][CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:33]=[CH:34][C:35](=[O:38])[NH:36][N:37]=2)=[CH:28][CH:27]=1)(=[O:25])=[O:24]>>[CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][CH2:22][S:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH2:33][CH2:34][C:35](=[O:38])[NH:36][N:37]=3)=[CH:30][CH:31]=2)(=[O:24])=[O:25])=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: NCCCS(=O)(=O)c1ccc(-c2ccc(=O)[nH]n2)cc1
Reactant: CC(C)COCCc1ccc(OCC2CO2)cc1
Product: CC(C)COCCc1ccc(OCC(O)CNCCCS(=O)(=O)c2ccc(C3=NNC(=O)CC3)cc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2isobutoxyethyl)phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropylsulphonyl]phenyl]-3(2H)-pyridazinone.
Reaction SMILES: [NH:1]([C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:5]=2[N:4]=1)[NH2:2].[CH:21]([O-])([O-])OCC.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:5]2[N:4]3[CH:21]=[N:2][N:1]=[C:3]3[CH2:9][N:8]=[C:7]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:6]=2[CH:16]=1
Reactant: CCOC([O-])[O-]
Reactant: Cc1ccc2c(c1)C(c1ccccc1)=NCC(NN)=N2
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2c(c1)C(c1ccccc1)=NCc1nncn1-2
Reaction time: 0.5 h

Procedure:
To a mixture of 5.3 parts of 2-hydrazino-7-methyl-5-phenyl-3H-1,4-benzodiazepine prepared in Example 5, 14.8 parts of ethyl orthoformate and 150 parts by volume of ethanol, is added dropwise 4 parts of fconcentrated sulfuric acid under cooling. The whole mixture is stirred for about 30 minutes and neutralized with a saturated aqueous solution of sodium bicarbonate, followed by extraction with chloroform. The chloroform layer is washed with water and dried over sodium sulfate. After evaporation of the solvent, the residue is treated with n-hexane, whereby 8-methyl-6-phenyl-4H-s-triazolo [4,3-a][1,4] benzodiazepine is yielded as crystals. Recrystallization from ethyl acetate yields pale yellow prisms melting at 177° C to 178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Li]CCCC.CCCCCC.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C.Cl>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][C:7]([B:22]([OH:27])[OH:23])=[CH:8][C:4]=2[CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Clc1ccc2sccc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: OB(O)c1cc2cc(Cl)ccc2s1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To a solution of 5-chloro-benzo[b]thiophene (compound PRE10) (2.1 g, 12.46 mmol) in anhydrous THF (17 mL) was added dropwise at −60° C. n-BuLi 1.6M in hexane (8.55 mL, 13.69 mmol). After stirring for 30 min at −60° C., was added dropwise triisopropyl borate (3.17 mL, 13.69 mmol). The cooling bath was taken off and the reaction mixture was heated slowly to 0° C. and was added 1N HCl (30 mL) and ethyl acetate (30 mL). The organic layer was dried over Na2SO4 and concentrated to give 2.15 g of compound dd (white powder;
Reaction SMILES: [CH:1]([OH:3])=O.[CH2:4]([O:6][CH2:7][CH2:8][CH2:9][NH2:10])[CH3:5].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH2:4]([O:6][CH2:7][CH2:8][CH2:9][NH:10][CH:1]=[O:3])[CH3:5]
Reactant: CCOCCCN
Reactant: O=CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOCCCNC=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.8 %

Procedure:
Formic acid (9.4 mL, 0.208×1.2 mol) was added to a toluene (250 mL) solution of 3-ethoxypropylamine (25 mL, 0.208 mol) at room temperature, and heated under reflux for 17 hours while removing water formed as a by-product with a Dean-Stark tube. After cooling to room temperature, K2CO3 (14 g, 0.208×0.5 mol) was added and it was stirred for 90 minutes. Insoluble materials were removed by filtration, washed with toluene, and the filtrate was concentrated to dryness. The residue was purified by vacuum distillation with a Vigreux fractionating column (15 cm) (fraction at 0.6 kpa, 114° C. to 115° C. collected), and N-(3-ethoxypropyl)formamide (21.79 g, 0.166 mol, 80%) was obtained as a colorless transparent liquid.
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH:53]([OH:55])[CH3:54])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH:53]([OH:55])[CH3:54])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]([F:51])([F:50])[F:52])=[CH:43][CH:42]=1
Reactant: CC(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(F)(F)F)cc4)c3)(O1)[C@H](O)[C@@H](O)[C@@H]2O
Temperature: 25 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
To a solution of 1-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-(2,2,2-trifluoroethoxyl) phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethanol 17n (350.0 mg, 0.45 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 15 mL) were added o-dichlorobenzene (0.25 mL, 2.25 mmol) and 10% Pd/C (50.0 mg, 0.04 mmol) at room temperature. The mixture was stirred at room temperature under H2 for 3 hours and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=3/1 to give a few white solid. Then the solid was further purified by prep-HPLC to give the title compound 17 as a white solid (70.5 mg, 30.7%, HPLC: 90.5%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 505.20 [M+H]+; and 1H NMR (600 MHz, DMSO-d6) δ(ppm): 7.41 (m, 2H), 7.31 (d, 1H), 7.15 (d, 2H), 6.97 (d, 2H), 5.31 (m, 1H), 4.85 (m, 2H), 4.68 (m, 2H), 4.64 (d, 1H), 4.02 (m, 1H), 3.98 (d, 2H), 3.83 (q, 1H), 3.76 (d, 1H), 3.54 (m, 1H), 3.43 (m, 2H), 1.16 (d, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Br:13])[NH:4][C:3]1=O.[CH:15]1([C:18]2[O:22][N:21]=[C:20]([CH2:23][N+:24]#[C-:25])[N:19]=2)[CH2:17][CH2:16]1>>[CH:15]1([C:18]2[O:22][N:21]=[C:20]([C:23]3[N:24]=[CH:25][N:4]4[C:5]5[C:10](=[C:9]([Br:13])[CH:8]=[CH:7][CH:6]=5)[C:11](=[O:12])[N:2]([CH3:1])[C:3]=34)[N:19]=2)[CH2:17][CH2:16]1
Reactant: Cn1c(=O)[nH]c2cccc(Br)c2c1=O
Reactant: [C-]#[N+]Cc1noc(C2CC2)n1
Product: Cn1c(=O)c2c(Br)cccc2n2cnc(-c3noc(C4CC4)n3)c12

Procedure:
M.p. 206,6° C. by reaction between 3-methyl-5-bromo-1,2,3,4-tetrahydro-2,4-dioxo-quinazoline and 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:27][C:8]1[NH:9][C:10]2[C:15]([C:7]=1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
To a solution (0.14 M) of methyl 3-cyclohexyl-1H-indole-6-carboxylate (from Step 2) in CCl4 was added freshly crystallized NBS (1.1 eq.) portionwise over a period of 1 h at RT. The resulting mixture was stirred for 2 h at RT, then washed with water (3×) and a saturated aqueous solution of sodium thiosulfate (2×). After phase cut, the aqueous phases were back-washed with EtOAc and die combined organic phases dried over Na2SO4 and evaporated. The resulting brown solid was dissolved in hot DCM and filtered rapidly over a pad of silica-gel using DCM as the eluant to give the title compound (49.6%) as a solid, 1H NMR (300 MHz, DMSO-d6, 300 K) δ 1.32-1.48 (m, 3H), 1.65-1.99 (m, 7H), 2.69-2.89 (m, 1H), 3.89 (s, 3H), 7.59 (d, J 7.6, 1H), 7.75 (d, J 7.6, 1H), 7.92 (s, 1H), 12.02 (br s, 1H); MS (ES+) m/z 337 (M+H)+.
Reaction SMILES: [CH:1]([Si:3]([CH:8]=[CH2:9])([CH:6]=[CH2:7])[CH:4]=[CH2:5])=[CH2:2].[CH3:10][SiH:11]([CH3:16])[O:12][SiH:13]([CH3:15])[CH3:14]>[Pt].C(C([SiH2]O[SiH3])C=C)=C>[CH:1]([Si:3]([CH:8]=[CH2:9])([CH:6]=[CH2:7])[CH2:4][CH2:5][Si:11]([CH3:16])([CH3:10])[O:12][Si:13]([CH2:9][CH2:8][Si:3]([CH:6]=[CH2:7])([CH:4]=[CH2:5])[CH:1]=[CH2:2])([CH3:15])[CH3:14])=[CH2:2]
Reactant: C[SiH](C)O[SiH](C)C
Reactant: C=C[Si](C=C)(C=C)C=C
Agent: [Pt]
Agent: C=CC(C=C)[SiH2]O[SiH3]
Product: C=C[Si](C=C)(C=C)CC[Si](C)(C)O[Si](C)(C)CC[Si](C=C)(C=C)C=C
Temperature: 70 °C
Yield: 28.8 %

Procedure:
To the 25 ml round bottomed flask equipped with a reflex condenser was charged 10.17 g of tetravinylsilane (75 mmol), 1 g of 1,1,3,3-tetramethyldisiloxane (7.5 mmol) and 10 μL of platinum-divinylmethyldisiloxane (5% Pt). The mixture was stirred and heated at 70° C. until it turned light yellow. (Scheme 5). From this mixture, 0.88 g (29% yield) of 1,3-di-[2-(trivinylsilyl)ethyl]-1,1,3,3-tetramethyldisiloxane (7) was isolated by distillation at 115° C. and 0.1 mm Hg. 1H NMR 300 MHz, CDCl3 :δ 6.22** (AXY,JAX =18 Hz, JAY =2 Hz Z.Z H), 6.20** (AXY, JAX =18 Hz, JAY =2 Hz), 6.15 (AXY,JAX =18Hz, JAY =2 Hz), 6.12 (AXY,JAX =7 Hz, JAY =2 Hz), 6.11* (AXY, JAX =7 Hz, JAY =2 Hz), 6,08** (AXY,JAX =7 Hz, JAY =2 Hz), 6.07** (AXY,JAX =7 Hz, JAY =Hz), 5.82** (AXY,JAX =18 Hz, JAY =7 Hz), 5.80* (AXY,JAX =18 Hz, JAY =7 Hz), 5.79 (AXY,JAX =18 Hz, JAY =7 Hz), 5.76** (AXY,JAX =18 Hz, JAY =7 Hz), 5.75* (AXY,JAX =18 Hz, JAY =7 Hz), 1.09** (d, 0.1 H), 1.07* (d,1.5H), 0.67 (m 1.2H), 0.47 (m 1.2 (H), 0.12* (m, 0.1H), 0.08* (s, 1H), 0.06* (s, 1H), 0.05 (s, 5H). 13NMR 75 MHz, CDCl3 :δ 135.089*, (CH); 134,628, (CH); 134,4, (CH2); 10.137, (CH2); 6.869*, (CH); 4.21*, (CH 2); 4.131, (CH2); 1.347*, (CH3); -0.34, (CH3). 29Si NMR 99.4 MHz, CDCl3 with Cr(acac)3 δ-18.12, 8.00. IR (neat liquid on NaCl): cm-1 3180(w), 3050(s), 3010(m), 2960(s), 2910(m), 2880(m), 2790(w), 1610(m), 1400(s), 1250(s), 1130(s), 1050(s), 1010(s), 955(s), 840(s), 800(m), 770(s), 730(s), 625(W), 550(m), 525(m). C20H/38Si4O calc. C 59.04, H 9.41, Si 27.61, 0 3.96; found C 57.76, H 9.02. ##STR11##
Reaction SMILES: [CH:1]([CH:3]([NH:8][C:9](=[O:19])[C@H:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:11][C:12](=[O:14])[CH3:13])[CH2:4][CH2:5][CH2:6][CH3:7])=O.[CH2:20]([SH:23])[CH2:21][SH:22].B(F)(F)F.CCOCC>C(Cl)Cl>[S:22]1[CH2:21][CH2:20][S:23][CH:1]1[CH:3]([NH:8][C:9](=[O:19])[C@H:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:11][C:12](=[O:14])[CH3:13])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: SCCS
Reactant: CCCCC(C=O)NC(=O)[C@H](CC(C)C)NC(C)=O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCC(NC(=O)[C@H](CC(C)C)NC(C)=O)C1SCCS1
Yield: 73.7 %

Procedure:
In 20 ml of methylene chloride was dissolved 1.8 g of N-acetyl-L-leucine-(1-formyl)pentylamide obtained in the same manner as in Example 16-(c), and 700 mg of 1,2-ethanedithiol and 1.5 ml of boron trifluoride ethyl etherate were added thereto. The mixture was allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by medium-pressure column chromatography on silica gel to obtain 1.7 g of the titled compound as a colorless crystal.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][N+:9]([O-])=[C:8]([CH3:13])[CH:7]=2)[CH2:3][CH2:2]1.[C:14]([O:17]C(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:17][CH2:13][C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:11]=[CH:10][N:9]=1)(=[O:16])[CH3:15]
Reactant: Cc1cc(OCC2CC2)cc[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCc1cc(OCC2CC2)ccn1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
4-cyclopropylmethoxy-2-methylpyridine-1-oxide (3.8 g 0.021 mol) was dissolved in acetic anhydride (10 ml) and was added dropwise to acetic anhydride (20 ml) (warmed to 90° C.). After the addition the temperature was raised to 110° C. and the mixture was stirred at 110° C. for 1 h and then the solvent was distilled off and the crude product was used without purification. NMR data is given below.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[F:33][C:34]([F:39])([F:38])[CH2:35][CH:36]=O>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([CH2:36][CH2:35][C:34]([F:39])([F:38])[F:33])[CH2:17][CH2:18]1)=[N:7]2
Reactant: O=CCC(F)(F)F
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: Cc1c(N2CCN(CCC(F)(F)F)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure L using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (25.0 mg, 0.056 mmol) and 3,3,3-trifluoropropanal to give 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(4-(3,3,3-trifluoropropyl)piperazin-1-yl)quinolin-4-amine. 1H NMR (DMSO-d6) δ ppm 2.07 (br s, 3H), 2.50 (m(buried), 2H), 2.60 (br s, 6H), 3.04 (br s, 4H), 3.29-3.31 (m, 4H), 3.69 (br s, 4H), 6.49 (s, 1H), 7.10-7.16 (m, 1H), 7.26-7.28 (m, 1H), 7.51 (s, 1H), 7.77 (s, 1H), 8.32 (s, 1H). Mass Spectrum (ESI) m/e=537.1 (M+1).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([OH:8])=O.S(Cl)(Cl)=O.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([N:23]1[CH2:22][CH2:21][N:20]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:25][CH2:24]1)=[O:8]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)[C@H]1CCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)[C@H]2CCCO2)CC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a solution of (R)-tetrahydro-2-furoic acid (5 g, 43.06 mmol) in toluene (75 mL) was added thionyl chloride (7.68 g, 64.6 mmol). The mixture was stirred at 90° C. for 2 h, then slowly cooled to 0° C. To a separate flask was charged a solution of N-Boc piperazine (8.02 g, 43.06 mmol) in toluene (40 mL), and aqueous sodium hydroxide (10.3 g, 258 mmol) in water (80 mL). This biphasic solution was cooled in an ice bath, followed by the addition of the cold acid chloride prepared above. The mixture was stirred vigorously for 2 h. The organic phase was collected, and washed with 1M H3PO4, dried and evaporated, to provide the title intermediate (9.87 g).
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)=O)C>C1COCC1>[F:23][C:20]([F:21])([F:22])[C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)=[CH:19][CH:18]=1
Reactant: FC(F)(F)c1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(C2=CCNCC2)cc1
Temperature: -20 °C
Reaction time: 3 h

Procedure:
1-Benzyl-4-(4-trifluoromethylphenyl)-1,2,3,6-tetrahydro-pyridine was dissolved in THF (10 mL). The reaction was cooled to −20° C. and 1-chloroethylchloroformate (0.5 mL) in THF (2 ml) was added. The reaction was stirred at −10° C. for 3 h and then concentrated. MeOH (10 mL) was added to the crude mixture and refluxed for 2 h. The solvent was removed to provide 4-(4-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine (HCl) which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 2H), 7.74 (m, 4H), 6.39 (m, 1H), 3.79 (m, 2H), 3.33 (m, 2H), 2.74 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:8]([OH:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.O[C:16]1[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:18]([CH3:29])[CH:17]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.C(P(CCCC)CCCC)CCC>C1COCC1>[Br:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:8]([O:13][C:16]2[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:18]([CH3:29])[CH:17]=2)[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC(O)c1cccc(Br)c1C
Reactant: CCOC(=O)COc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.4 %

Procedure:
To a solution of 1-(3-bromo-2-methylphenyl)-1-pentanol (495 mg, 1.92 mmol) in anhydrous THF (40 mL) under nitrogen at 0° C. was added portion-wise ethyl (4-hydroxy-2-methylphenoxy)acetate (405 mg, 1.93 mmol), followed by slow addition (over 25 min) of ADDP (971 mg, 3.85 mmol) and drop-wise addition of tributylphosphine (0.96 mL, 3.85 mmol). The resulting mixture was then stirred for 16 h with gradual warming to ambient temperature. The solvent was then removed under vacuum and the residue partitioned between EtOAc (100 mL) and water (150 mL), the layers separated, and the aqueous re-extracted with EtOAc (100 mL). The combined organic layer was then dried (Na2SO4), filtered and reduced under vacuum and the resulting residue purified by SPE (silica, 50 g cartridge), eluting with cyclohexane:EtOAc (gradient 99:1 to 4:1) to afford the title compound as a colourless oil (495 mg).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH3:5][CH:6]([CH2:11][NH:12][CH3:13])[C:7]([O:9][CH3:10])=[O:8]>C1(C)C=CC=CC=1>[CH3:13][N:12]([CH2:11][CH:6]([C:7]([O:9][CH3:10])=[O:8])[CH3:5])[C:1]([Cl:4])=[O:2]
Reactant: CNCC(C)C(=O)OC
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)C(C)CN(C)C(=O)Cl
Temperature: 20 °C

Procedure:
To a solution of 16 g of phosgene in 70 ml of toluene, a solution of 17.4 g of methyl 2-methyl-3-methylaminopropionate in 30 ml of toluene was added dropwise with stirring at 20° C. The mixture was stirred at room temperature for 4 hours and evaporated to dryness. The residue was stirred for 10 min. with 100 ml of ethyl ether, filtered, the filtrates are evaporated to dryness and the residue was distilled at high vacuum to give the N-methyl-N-(2-methoxycarbonylpropyl)carbamoyl chloride, bp. 97°-100°/1 mm Hg.