Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C@@H:12]3[CH3:24])[C:5]=2[C@H:4]([CH3:25])[CH2:3]1.[ClH:26]>C(Cl)Cl>[ClH:26].[ClH:26].[CH3:25][C@H:4]1[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][C@@H:12]3[CH3:24])=[N:9][CH:8]=[N:7][C:6]=2[C@H:2]([OH:1])[CH2:3]1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)c21
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNC[C@@H]3C)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of the (S)-tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.106 g, 0.304 mmol) in DCM (20 mL) was added HCl (4M in dioxane, 4 mL). The mixture was stirred at room temperature overnight. The solvent was removed to afford (5R,7R)-5-methyl-4-((S)-2-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.098 g, 99%). MS (APCI+) [M+H] +249.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C(Cl)CCl.[CH:17]1[CH:18]=CC2N(O)N=[N:23][C:21]=2[CH:22]=1.CCN(CC)CC.N1CCCC1>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([N:23]1[CH2:18][CH2:17][CH2:22][CH2:21]1)=[O:12]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCNC1
Solvent: ClCCl
Product: O=C(c1cc2ccccc2[nH]1)N1CCCC1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
To a stirred solution of 0.300 g (1.86 mmol) of 1H-indole-2-carboxylic acid in CH2Cl2 (10 ml) was added 0.428 g (2.23 mmol) of EDC, 0.302 g (2.23 mmol) of HOBt, 0.28 ml (2.04 mmol) of Et3N and 0.17 ml (2.04 mmol) of pyrrolidine. The reaction mixture was stirred at RT over the night and then poured onto water and extracted with CH2Cl2. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Re-crystallization in Et2O afforded 0.31 g (78%) of (1H-indol-2-yl)-pyrrolidin-1-yl-methanone as white crystals.
Reaction SMILES: O1CCCC1.[OH-].[K+].[Cl:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[C:13]([Cl:15])[CH:14]=1.Br[C:20]([C:22]([F:25])([F:24])[F:23])=[CH2:21]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[Cl:8][C:9]1[CH:10]=[C:11]([C:20]([C:22]([F:25])([F:24])[F:23])=[CH2:21])[CH:12]=[C:13]([Cl:15])[CH:14]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: C=C(Br)C(F)(F)F
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Temperature: 75 °C
Yield: 40.1 %

Procedure:
To a mixture of tetrahydrofuran (33 mL), ethylene glycol dimethyl ether (33 mL), and 4 N aqueous potassium hydroxide (33 mL) in a 200 mL Fisher-Porter sealed tube was added 3,5-dichlorophenylboronic acid (8.72 g, 45.7 mmol) and 2-bromo-3,3,3-trifluoro-propene (10.0 g, 57.2 mmol), followed by the addition of tetrakis(triphenylphosphine)-palladium(0) (264 mg, 0.229 mmol). The mixture was heated to 75° C. for 3 h. Then the reaction mixture was partitioned between diethyl ether and water. The aqueous extract was washed with diethyl ether (2×20 mL). The organic extracts were combined, dried (MgSO4), and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel chromatography and eluted with hexane to afford 4.421 g of the title compound as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][C:26]=4[N:31]=3)[CH2:18]2)[N:3]=1.[NH2:32][NH2:33]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:32][NH:33]3)=[CH:14][CH:15]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:24][C:25]4=[CH:30][CH:29]=[N:28][CH:27]=[C:26]4[N:31]=3)[CH2:18]2)[N:3]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(N3CCOC(c4nc5cnccc5[nH]4)C3)nc(N)n2)cc1F
Solvent: CCO
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCOC(c3nc4cnccc4[nH]3)C2)n1
Reaction time: 1 h
Yield: 6.4 %

Procedure:
A mixture of 4-{2-amino-6-[2-(1H-imidazo[4,5-c]pyridin-2-yl)-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (380 mg, 0.913 mmol) and hydrazine (1.432 mL, 45.6 mmol) in ethanol (3 mL) was heated under microwave conditions with stirring for 1 hour. The mixture was concentrated. Water (20 mL) was added, and the resulting mixture was filtered to afford the crude title compound (135 mg) as a brown solid. This material was combined with another sample of the title compound (25 mg), and the combined material was purified by preparative HPLC using CH3CN in water (10 mmol ammonium hydrogen carbonate in water) from 40% to 60% in 9 min to afford the title compound (21 mg) as an off-white solid. LC-MS (ES) m/z=429 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 3.13-3.22 (m, 2H), 3.81-3.91 (m, 1H), 4.14 (d, J=11.2 Hz, 1H), 4.34 (d, J=11.6 Hz, 1H), 4.91 (dd, J=10.0 Hz, 2H), 5.39 (s, 2H), 6.25 (s, 2H), 6.72 (s, 1H), 7.54 (s, 1H), 7.62 (m, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.97 (s, 1H), 8.31 (d, J=5.6 Hz, 1H), 8.91 (s, 1H), 11.54 (s, 1H), 13.01 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.Cl.[CH3:16][C:17]1[C:18]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:19][C:20]([CH3:24])=[C:21]([CH3:23])[CH:22]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:28]2[CH2:29][CH2:30][N:25]([C:18]3[C:17]([CH3:16])=[CH:22][C:21]([CH3:23])=[C:20]([CH3:24])[N:19]=3)[CH2:26][CH2:27]2)=[O:8])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Agent: Cl
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)nc1C
Yield: 51.8 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 27 and using 4-bromo-2-methanesulfonylbenzoic acid (3.5 g) and 1-(3,5,6-trimethylpyridin-2-yl)piperazine hydrochloride (3 g) described in Preparation Example 52, the title compound (3 g) was obtained.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:6][NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CNC1CCN(CCO)CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 101.7 %

Procedure:
To a solution of [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (CAS m 558443-53-1) (5.71 g, 23 mmol) in tetrahydrofuran (100 ml) at 23° C. was added in portions lithium aluminum hydride (2.66 g, 70 mmol) and the mixture was stirred at 70° C. for 18 h. Then the reaction was cooled to 0° C., water (2.66 ml) was added very slowly, then NaOH 15% (7.98 ml) and water (2.66 ml). The mixture was stirred at 23° C. for 1.5 h, the precipitate was filtered off, washed with tetrahydrofuran and the organic layer was evaporated totally to give the title compound as a white solid (3.7 g, 100%), MS (ISP) m/e=159.3 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH:13]1[CH2:18][CH2:17][N:16]([S:19]([C:22]3[N:23]=[CH:24][N:25]([CH3:27])[CH:26]=3)(=[O:21])=[O:20])[CH2:15][CH2:14]1)=[N:8][CH2:7][CH2:6]2.[BH4-].[Na+]>CO.O.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH:13]1[CH2:18][CH2:17][N:16]([S:19]([C:22]3[N:23]=[CH:24][N:25]([CH3:27])[CH:26]=3)(=[O:21])=[O:20])[CH2:15][CH2:14]1)[NH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCN=C2C1CCN(S(=O)(=O)c2cn(C)cn2)CC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)CCNC2C1CCN(S(=O)(=O)c2cn(C)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
To a stirred solution of 6-methoxy-1-[1-(1-methyl-1H-imidazole-4-sulfonyl)-piperidin-4-yl]-3,4-dihydro-isoquinoline (0.077 g, 0.197 mmol) in MeOH (3 ml) cooled to 0° C. was added NaBH4. The reaction mixture was then stirred at RT for 2 hours and diluted with water (5 ml) and sat. NaHCO3 (5 ml). The mixture was extracted with EtOAc (3×10 ml). The combined organics were washed with brine (1×10 ml), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by radial chromatography (SiO2, 1 mm, CH2Cl2 to 5% MeOH/CH2Cl2) to give the product as an oil (0.055 g, 0.141 mmol, 71% yield).
Reaction SMILES: [CH2:1]([CH:4]1[C:9]([CH3:11])([CH3:10])[NH:8][C:7]([CH3:13])([CH3:12])[CH:6]=[C:5]1N1CCCCC1)[CH:2]=[CH2:3].C([O-])(=[O:22])C.[Na+].C(=O)(O)[O-].[Na+].N>C(O)(=O)C.O>[CH2:1]([CH:4]1[C:5](=[O:22])[CH2:6][C:7]([CH3:13])([CH3:12])[NH:8][C:9]1([CH3:11])[CH3:10])[CH:2]=[CH2:3]
Reactant: C=CCC1C(N2CCCCC2)=CC(C)(C)NC1(C)C
Reactant: CC(=O)[O-]
Agent: N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C=CCC1C(=O)CC(C)(C)NC1(C)C
Reaction time: 8 h

Procedure:
1.46 g of the 5-allyl-1,2,5,6-tetrahydro-2,2,6,6-tetramethyl-4-piperidinopyridine thus obtained were dissolved in a mixture of 3 ml of acetic acid, 1.5 g of sodium acetate and 3 ml of water, and the solution was allowed to stand overnight. To the solution were then added 6.0 g of sodium bicarbonate and 3 ml of concentrated aqueous ammonia; the solution was then extracted with hexane. The hexane extract was dried over magnesium sulphate and then treated with charcoal giving, after removal of the hexane, 0.91 g of 3-allyl-2,2,6,6-tetramethyl-4-piperidone. On thin layer chromatography using a 0.25 mm thick layer of alumina and a mixture of benzene, hexane, ethyl acetate and triethylamine (2 : 2 : 1 : 0.5 by volume) as developing solvent, the compound showed a single spot having an Rf value of 0.70.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N:4][C:3]=1[CH:26]=O.Cl.CN.[C:31]([BH3-])#[N:32].[Na+].Cl.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:31][NH:32][CH2:26][C:3]1[N:4]=[CH:5][N:6]([C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Product: CNCc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.9 %

Procedure:
A mixture of 5-methyl-1-(triphenylmethyl)-1H-imidazole-4-carboxaldehyde (3.2 g) and methylamine hydrochloride (3.6 g) in methanol (60 ml) was stirred at room temperature for 1h. The mixture was then cooled to 0°, treated with sodium cyanoborohydride (0.62 g) for 2h and water (40 ml) was added. The resulting mixture was then stirred at 20° for 0.5h, cooled to 0° and treated with concentrated hydrochloric acid (10 ml). The mixture was then allowed to warm to 20°, and stirred at 20 for a further 1h and basified (to pH9) with potassium carbonate. The alkaline aqueous mixture was diluted with water (100 ml) and extracted with ethyl acetate (×200 ml). The combined organic extracts were dried and evaporated to leave a foam (3.5 g) which was purified by FCC eluting with System A (100:8:1) to give the title compound (1.8 g) as a solid, t.l.c. (System A, 100:3:1) Rf 0.1.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[C:34]([S:36][CH3:37])[CH:33]=[CH:32][C:31]=3[O:38][CH3:39])[C@H:14]2[CH3:40])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1C=C(Cl)C=C(C(OO)=[O:51])C=1>C(Cl)Cl.CCOC(C)=O>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[C:34]([S:36]([CH3:37])=[O:51])[CH:33]=[CH:32][C:31]=3[O:38][CH3:39])[C@H:14]2[CH3:40])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1ccc(SC)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(S(C)=O)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: -20 °C

Procedure:
To a −60° C. solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-(methylthio)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (example 124) (32.5 mg, 0.0522 mmol) in CH2Cl2 (5 mL) was added m-CPBA (14.6 mg, 77% purity, 0.0652 mmol). The reaction was warmed slowly to −20° C. and then diluted with EtOAc (35 mL), washed with aq. NaHSO3, brine, saturated NaHCO3, and brine (15 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on slica gel (20 to 100% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-(methylsulfinyl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.10 (75% EtOAc/hexanes). LCMS=640.1 (M+1)+. 1H NMR (CDCl3, 600 MHz) δ 7.10-7.86 (m, 9H), 4.87-5.59 (m, 2H), 3.56-4.14 (m, 5H), 2.79 (s), 2.75 (s), 2.73 (s), 0.61 (d, J=6.5 Hz), 0.57 (d, J=6.4 Hz), 0.46 (d, J=6.4 Hz), 0.43 (d, J=6.5 Hz).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([O:22][CH3:23])=[O:21].N1C=CC=CC=1>ClCCl>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22][CH3:23])=[O:21])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1sccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)C)cc1
Yield: 64.5 %

Procedure:
Synthesized as described for 52 using commercially available 4-iso-propylbenzenesulfonyl chloride (1.0 g; 4.57 mmol), methyl 3-aminothiophene-2-carboxylate (0.72 g; 4.57 mmol), pyridine (0.55 mL; 6.86 mmol), and anhydrous dichloromethane (3 mL). This afforded the title compound as a white solid (1.0 g).
Reaction SMILES: C([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19](O)([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8](C(C)=CC2CCC(OC3C=C4C(=CC=3)N(C)C=C4CCO[Si](C(C)(C)C)(C)C)C(OC)C2)[CH:7]([CH3:74])[CH:6](O)[CH2:5][C:4]1=[O:76])C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH3:33][O:32][CH:24]1[CH:23]2[O:34][CH:19]([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH2:8][CH:7]([CH3:74])[CH2:6][CH2:5][C:4](=[O:76])[CH2:3][CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25]1
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5c(c4)c(CCO[Si](C)(C)C(C)(C)C)cn5C)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC1CC(C)CC(C)=CCC(=O)CCC(C)COC(=O)C2CCCCN2C(=O)C(=O)C2OC1C(OC)CC2C
Reaction time: 3 h

Procedure:
To a stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1-methyl-3-(2-t-butyldimethylsilyloxyethyl)indol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg.) in CH2Cl2 (6 mL.) and CH3OH (6 mL.) was added p-toluenesulfonic acid monohydrate (30 mg.). The reaction mixture was allowed to stir 3 hours. The reaction was quenched with saturated aqueous NaHCO3 and extracted 4× with CH2Cl2. The organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The product was purified by preparative TLC on silica gel (1:1 hexanes/acetone) and again (7% CH3OH/CH2Cl2) giving -(4"-(1-methyl-3-(2-hydroxyethyl)indol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=O)[CH:2]=1.[NH2:14][N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH2:20][O:21][CH3:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)C>[CH3:22][O:21][CH2:20][C@@H:16]1[CH2:17][CH2:18][CH2:19][N:15]1[N:14]=[C:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CCCCC1c1cccnc1
Reactant: COC[C@@H]1CCCN1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC[C@@H]1CCCN1N=C1CCCCC1c1cccnc1

Procedure:
A mixture of 2-(pyrid-3-yl)cyclohexanone (20.6 g, 117.6 mmol), [S]-(-)-1-amino-2-(methoxymethyl)pyrrolidine (`SAMP`) (15.4 g, 118 mmol) and p-toluenesulphonic acid (316 mg) was refluxed in toluene (475 ml) for 4 hours. The toluene was removed in vacuo to afford an oil which was dissolved in diethyl ether (340ml) and washed with aqueous saturated sodium bicarbonate solution (2×170 ml). The organic phase was dried over magnesium sulphate then filtered and concentrated in vacuo to afford [2S]-2-(methoxymethyl)-1-[2-(pyrid-3-yl)cyclohexylidenamino]pyrrolidine (30.8 g, 113 mmol) as a 50:50 mixture of diastereoisomers;
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[OH-].[Ca+2].[OH-].Br[CH2:8][CH:9]([OH:15])[CH2:10][C:11]([O:13]C)=[O:12].[C-:16]#[N:17].[Na+].Cl>O.C(OCC)(=O)C>[C:16]([CH2:8][CH:9]([OH:15])[CH2:10][C:11]([OH:13])=[O:12])#[N:17]
Reactant: [C-]#N
Reactant: COC(=O)CC(O)CBr
Agent: Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Product: N#CCC(O)CC(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.9 %

Procedure:
1.6 g of calcium chloride (15 mmol) and 0.6 g (8.1 mmol) of calcium hydroxide were dissolved in 3.7 ml of water and stirred at room temperature for 20 minutes. At the same temperature, 2.00 g (10 mmol) of methyl 4-bromo-3-hydroxybutanoate was added dropwise over 5 minutes. After stirring for further ten minutes, the mixture was cooled by ice, and 0.6 g (12 mmol) of sodium cyanide was added thereto. Then, the mixture was stirred at an internal temperature of 25 to 33° C. for 4.5 hours. Then, concentrated hydrochloric acid was added dropwise in the reaction solution, and ethyl acetate was used for extraction five times. The organic layer was concentrated under reduced pressure to get 1.2 g of 4-cyano-3-hydroxybutanoic acid. The purity of the obtained 4-cyano-3-hydroxybutanoic acid was 91% (high-performance liquid chromatography in area percentage).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:10]=1[O:11][CH2:12][CH2:13][NH:14][CH:15]1[CH2:17][CH2:16]1.[F:23][CH:24]([F:35])[C:25]1[C:29]([C:30](Cl)=[O:31])=[C:28]([F:33])[N:27]([CH3:34])[N:26]=1.O>ClCCl>[CH:15]1([N:14]([CH2:13][CH2:12][O:11][C:10]2[C:9]([Cl:8])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:22])[C:30]([C:29]2[C:25]([CH:24]([F:35])[F:23])=[N:26][N:27]([CH3:34])[C:28]=2[F:33])=[O:31])[CH2:16][CH2:17]1
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Reactant: Clc1cccc(Cl)c1OCCNC1CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1nc(C(F)F)c(C(=O)N(CCOc2c(Cl)cccc2Cl)C2CC2)c1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 73 %

Procedure:
In a 13 ml Chemspeed™ vial is weighted 73 mg (0.726 mmol) of triethylamine. Then 3 ml of a 0.23 molar solution of N-[2-(2,6-dichlorophenoxy)ethyl]cyclopropanamine (0.594 mmole) in dichloromethane is added followed by 3 ml of a 0.26 molar solution of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carbonyl chloride (0.66 mmole) in dichloromethane and stirred at ambient temperature for 15 hrs. 1 ml of water is then added and the mixture is deposited on a basic alumina cartridge (2 g) and eluted twice by 8 ml of dichloromethane. The solvents are removed to yield 183 mg (64%) of pure N-cyclopropyl-N-[2-(2,6-dichlorophenoxy)ethyl]-3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide as an oil (M+H=422).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.[CH3:52][N:53]1[C:57]([CH3:58])=[C:56]([CH2:59][N:60]2[CH2:65][CH2:64][N:63]([C:66]3[C:71]([C:72]4[CH:79]=[CH:78][C:75]([CH2:76][NH2:77])=[CH:74][CH:73]=4)=[N:70][CH:69]=[CH:68][N:67]=3)[CH2:62][CH2:61]2)[CH:55]=[N:54]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:52][N:53]1[C:57]([CH3:58])=[C:56]([CH2:59][N:60]2[CH2:61][CH2:62][N:63]([C:66]3[C:71]([C:72]4[CH:73]=[CH:74][C:75]([CH2:76][NH:77][C:6]([CH:3]5[CH2:4][CH2:5][O:1][CH2:2]5)=[O:8])=[CH:78][CH:79]=4)=[N:70][CH:69]=[CH:68][N:67]=3)[CH2:64][CH2:65]2)[CH:55]=[N:54]1
Reactant: Cc1c(CN2CCN(c3nccnc3-c3ccc(CN)cc3)CC2)cnn1C
Reactant: O=C(O)C1CCOC1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN2CCN(c3nccnc3-c3ccc(CNC(=O)C4CCOC4)cc3)CC2)cnn1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38.8 %

Procedure:
Dissolve racemic tetrahydro-furan-3-carboxylic acid (0.067 g, 0.58 mmol) in methylene chloride (5 mL). Add benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (PyBOP) (0.453 g, 0.87 mmol). Add 1-hydroxybenzotriazole (0.118 g, 0.87 mmol). Add 4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-benzylamine (0.24 g, 0.63 mmol) dissolved in methylene chloride (5 mL). Stir at rt for 5 min. Add diisopropylethylamine (0.113 g, 0.87 mmol). Stir at rt for 4 hr. Purify by normal phase chromatography (4% 7 N ammonia-methonal/ethyl acetate) to give racemic tetrahydro-furan-3-carboxylic acid 4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-benzylamide (0.107 g, 39%). MS (ES): m/z=476.3[M+H]. Dissolve this racemate (0.107 g, 0.23 mmol) in acetonitrile (1 mL) and water (4 mL). Add aq. 1 N HCl (1 eq., 0.23 mmol, 0.23 mL). Freeze the solution to −78° C. in a dry-ice/acetone bath. Place the solution in the lyophilizer for 48 hr. to give the title compound (0.110 g, 94%). MS (ES): m/z=476.3 [M+H].
Reaction SMILES: [CH2:1]([C:3]([CH2:9][CH3:10])=[C:4]([CH2:7][CH3:8])[CH2:5][CH3:6])[CH3:2].[CH3:11][SiH:12]([CH3:14])[Cl:13].[Al+3].[Cl-].[Cl-].[Cl-]>CCCCC>[CH2:1]([C:3]([Si:12]([CH3:14])([CH3:11])[Cl:13])([CH2:9][CH3:10])[CH:4]([CH2:7][CH3:8])[CH2:5][CH3:6])[CH3:2]
Reactant: C[SiH](C)Cl
Reactant: CCC(CC)=C(CC)CC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCC
Product: CCC(CC)C(CC)(CC)[Si](C)(C)Cl
Reaction time: 2 h

Procedure:
2.1 g of tetraethylethylene, 2 ml (18 mmol) of dimethylchlorosilane and 200 mg of AlCl3 are reacted according to Example 1. After 2 hours, the reaction mixture is diluted with pentane and the precipitate is filtered off. The pentane is stripped from the filtrate in vacuo and the residue is distilled. This gives 2.8 g (80% of theory) of product as a colourless liquid. Boiling point=75°-80° C./0.195 mbar.
Reaction SMILES: C(O[CH:4]=[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=O)C.Cl.[CH2:16]([C@H:21]1[CH2:26][CH2:25][C@H:24]([C:27]([NH2:29])=[NH:28])[CH2:23][CH2:22]1)[CH2:17][CH2:18][CH2:19][CH3:20].C[O-].[Na+].[Na]>CO>[CH2:16]([C@H:21]1[CH2:22][CH2:23][C@H:24]([C:27]2[N:28]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:6][N:29]=2)[CH2:25][CH2:26]1)[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCC(C=O)=COCC
Reactant: CCCCC[C@H]1CC[C@H](C(=N)N)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCCCCc1cnc([C@H]2CC[C@H](CCCCC)CC2)nc1

Procedure:
In an analogous manner to that described in Example 3, a mixture of 3.8 g of 3-ethoxy-2-heptylacrolein, 4.7 g of trans-4-pentylcyclohexanecarboxamidine hydrochloride and 40 ml of absolute methanol is treated with a sodium methylate solution prepared from 0.8 g of sodium in 25 ml of absolute methanol. The reaction duration, working-up and chromatography are as described in Example 3. The pure fractions eluted in the chromatography are combined and recrystallised twice from acetonitrile at about -20° C. There is obtained analytically pure trans-2-(4-pentylcyclohexyl)-5-heptylpyrimidine; m.p. 22° C., cl.p. 40.5° C. (smectic).