Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[S:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C(O)(=O)C.Cl>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([C:19]2[CH2:20][CH2:21][S:16][CH2:17][CH:18]=2)[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCSCC1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C2=CCSCC2)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.7 %

Procedure:
A mixture consisting of 17 g (0.082 mol) of 2,4-di-tert-butylphenol, 4.8 g (0.041 mol) of tetrahydrothiopyran-4-one and 5 ml of acetic acid is melted together and is then saturated, with stirring, with hydrochloric acid gas at 40-45° C. After stirring for 12 hours at room temperature, the reaction mixture is diluted with toluene and washed with water, sodium chloride solution and sodium hydrogencarbonate solution. The organic phase is dried over magnesium sulfate and concentrated on a rotary-evaporator. The residue is crystallised from methanol, affording 9.2 g (74%) of 2,4-di-tert-butyl-6-(3,6-dihydro-2H-thiopyran-4-yl)phenol, m.p. 115-119° C. (compound (104), Table 1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([Mg]Cl)(C)C.[C:16]1([CH:22]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[C:24]2=[O:33])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.ClCCl>[C:34]1([CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([C:5]3[CH:6]=[C:7]([O:8][CH3:9])[C:2]([F:1])=[CH:3][C:4]=3[OH:10])([OH:32])[C:24]2=[O:33])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: COc1ccc(O)cc1F
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(C2(O)C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)c(O)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.8 %

Procedure:
To a solution of 3-fluoro-4-methoxyphenol (Niemann, M. B. J. Am. Chem. Soc. (1941), 63:609) (4.60 g, 32.4 mmol) in tetrahydrofuran (60 mL) at 5° C. was added a 2 M solution of isopropylmagnesium chloride in tetrahydrofuran (18.0 mL, 36.0 mmol). Tetrahydrofuran was removed under reduced pressure and dichloromethane (60 mL) was added. To the solution was added a solution of 1-(diphenylmethyl)-1H-indole-2,3-dione (8.00 g, 25.5 mmol) in dichloromethane (60 mL) at 5° C. and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with saturated ammonium chloride solution (5 mL). The reaction mixture was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was subjected to column chromatography with 40% to 90% gradient of ethyl acetate in hexanes to afford 1-(diphenylmethyl)-3-(4-fluoro-2-hydroxy-5-methoxyphenyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one (6.60 g, 57%) as a pink solid: MS (ES+) m/z 438.3 (M−17).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].C(N(CC)CC)C.[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:29]([C:21]1[S:20][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=1)(=[O:30])=[O:31])[CH3:4]
Reactant: CCOC(=O)CNCCN
Reactant: O=S(=O)(Cl)c1nc2ccccc2s1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To a solution of N-(2-aminoethyl)-glycine ethyl ester 2HCl (1.10 g, 5.0 mmol), prepared as described by Will (D. W. Will et al., Tetrahedron, 1995, 51, 12069.), in dichloromethane (50 mL) was slowly added triethylamine (2.02 g, 20 mmol) at room temperature. Then benzothiazole-2-sulfonyl chloride (1.19 g 5.0 mmol) in dichloromethane (10 mL) was added to the reaction mixture at room temperature for 5 min. The resulting reaction mixture was stirred for additional 2 h, at room temperature and washed with water (30 mL). The organic layer was dried over MgSO4 and filtered. The filtrate was evaporated to remove solvent to give desired product (1.60 g, 92%) as a solid. 1H NMR (500 MHz; DMSO-d6) δ 8.28 (d, 1H), 8.19 (d, 1H), 7.69˜7.63 (m, 2H), 4.03 (q, 2H), 3.24 (s, 2H), 3.13 (t, 2H), 2.62 (t, 2H), 1.15 (t, 3H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:19]([O:20]C(=O)C)[C@H:18]([O:24][C@H:25]2[O:42][C@H:41]([CH2:43][O:44]C(=O)C)[C@@H:36]([O:37]C(=O)C)[C@H:31]([O:32]C(=O)C)[C@H:26]2[O:27]C(=O)C)[C@@H:17]([CH2:48][O:49]C(=O)C)[O:16][C@H:6]1[S:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)(=O)C.C(N(CC)CC)C>CO.CO.O>[C@H:25]1([O:24][C@@H:18]2[C@@H:17]([CH2:48][OH:49])[O:16][C@@H:6]([S:7][C:8]3[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=3)[C@H:5]([OH:4])[C@H:19]2[OH:20])[O:42][C@H:41]([CH2:43][OH:44])[C@@H:36]([OH:37])[C@H:31]([OH:32])[C@H:26]1[OH:27]
Reactant: COc1ccc(S[C@@H]2O[C@H](COC(C)=O)[C@@H](O[C@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(S[C@@H]2O[C@H](CO)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)cc1
Reaction time: 8 h
Yield: 81.7 %

Procedure:
A mixture comprising 2.6 g of 4-methoxyphenyl 2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-1-thio-β-D-glucopyranoside in 25 ml of cold methanol was combined with a cold mixture of 2N triethylamine in methanol:water (6:2). This mixture was refrigerated overnight, then evaporated in vacuo to a solid which was triturated with ether, giving 1.3 g of the desired intermediate, UV 225-245 nm.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]([O:15][C:16]1[CH:33]=[CH:32][C:31]2[C@@H:30]3[C@H:21]([C@H:22]4[C@@:26]([CH2:28][CH2:29]3)([CH3:27])[C:25]([C:35]([F:38])([F:37])[F:36])([OH:34])[CH2:24][CH:23]4[CH2:39][CH2:40][CH2:41][CH2:42][OH:43])[CH2:20][CH2:19][C:18]=2[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[CH2:8]([O:15][C:16]1[CH:33]=[CH:32][C:31]2[C@@H:30]3[C@H:21]([C@H:22]4[C@@:26]([CH2:28][CH2:29]3)([CH3:27])[C:25]([OH:34])([C:35]([F:38])([F:36])[F:37])[CH2:24][CH:23]4[CH2:39][CH2:40][CH2:41][CH2:42][O:43][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[CH2:20][CH2:19][C:18]=2[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1C(CCCCO)CC2(O)C(F)(F)F
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCCCCC1CC(O)(C(F)(F)F)[C@@]2(C)CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@H]12
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
Pivaloylchloride (0.50 ml; 4.10 mmol) was added dropwise to a solution of 3-Benzyloxy-15-(4-hydroxybutyl)-17-trifluoromethyl-estra-1,3,5(10)-trien-17-ol (1.65 g; 3.28 mmol) in pyridine (15 ml) at 0° C. After stirring for 2 h, the reaction mixture was poured into ice water and stirred for another h. After extraction with DCM, the combined organic phases were dried over MgSO4. After evaporation of the solvent, the residue was purified by column chromatography (SiO2, DCM) yielding the title compound (1.85 g, 96%) as colourless oil.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO.[C].[Pd]>[CH2:10]([N:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)C1CCCNC1
Reactant: O=Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)C1CCCN(Cc2ccccc2)C1
Yield: 63 %

Procedure:
Nipecotic acid (1.31 g, 10.2 mmol), benzaldehyde (1.12 g, 10.6 mmol) and 5% palladium-carbon (0.18 g) in methanol (10 mL) was stirred at room temperature for one day under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in methanol (50 mL) was stirred with benzaldehyde (4.40 g, 41.5 mmol) and 5% palladium-carbon (0.118 g) at room temperature for one day. The reaction mixture was filtered, and the filtrated was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1→5/1 (v/v)) to give the title compound as a colorless oil (1.41 g, yield 63%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:23])[C:11]([OH:22])([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[CH2:2]2.[O:24]([CH2:31][CH2:32][CH2:33][Br:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC#N.C(Cl)(Cl)Cl>[Br-:34].[OH:22][C:11]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[C:10]([O:9][C@@H:3]1[CH:4]2[CH2:7][CH2:8][N+:1]([CH2:33][CH2:32][CH2:31][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([CH2:6][CH2:5]2)[CH2:2]1)=[O:23]
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1cccs1)c1cccs1
Reactant: BrCCCOc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: O=C(O[C@H]1C[N+]2(CCCOc3ccccc3)CCC1CC2)C(O)(c1cccs1)c1cccs1
Product: [Br-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 90 %

Procedure:
0.6 mmol of 2-hydroxy-2,2-dithien-2-ylacetic acid 1-azabicyclo[2.2.2]oct-3(R)yl ester are suspended in 4 ml of CH3CN and 6 ml of CHCl3. 0.48 ml of 3-phenoxypropyl bromide were added to the resulting suspension and the mixture was stirred for 72 h at room temperature in an inert atmosphere. The solvents were subsequently evaporated to yield (90%) of 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide. The product is isolated by filtration at room temperature and the level of 3-phenoxypropyl bromide is determined to be 117 ppm.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH:17]=O)[C@H:10]([OH:16])[C@@H:11]([CH2:14][OH:15])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O.[NH3:31]>C(O)C.[Pd]>[CH2:1]([O:8][C@H:9]1[C@H:10]([OH:16])[C@@H:11]([CH2:14][OH:15])[CH2:12][NH:31][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C[C@H](CO)[C@@H](O)[C@@H](C=O)OCc1ccccc1
Reactant: N
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCO
Product: OC[C@H]1CNC[C@@H](OCc2ccccc2)[C@@H]1O
Yield: 78 %

Procedure:
To a solution of 4-O-benzyl-2-deoxy-2-C-hydroxymethyl-D-xylo-pentodialdose (1.77 g) in ethanol (40 ml), 0.29M NH3 in ethanol (162 ml) and 5% palladium on charcoal (300 mg) was added. The mixture was hydrogenated at 500 Psi at 20° C. for 15 hours. The reaction mixture was filtrated and concentrated. The residue (1.85 g) was flash chromatographed using ethanol/NH4OH (25% aqueous)/trimethylamine (122:2:1) as eluent giving the product as a colourless sirup (getting coloured after storing) in 78% yield. 13C-NMR (62.9 MHz, D2O): δ138.1, 128.1, 127.3 (Ph); 80.6 (C-3), 74.9 (C-4); 71.8 (OCH2Ph); 62.5 (C-5'); 48.0 (C-2); 46.8 (C-6); 45.0 ppm (C-5). 1H-NMR (500 MHz, D2O): δ7.3 (s, 5H, Ph); 4.65, 4.51 (2 d, 2H, OCH2Ph, Jgem =12 Hz); 3.66 (dd, 1H, H-5a', J5a',5b' =10 Hz, J5',5 =5.5); 3.57 (dd, 1H, H-5'b, J5a', 5b'=10 Hz, J5b',5 =4.5); 3.41 (dd, 1H, H-4, J3,4 =11 Hz, J4,5 =9 Hz); 3.3 (broad, N--H); 3.27 (dd, 1H, H-3, J3,2zx =11 Hz, J3,2eq =4 Hz); 3.22 (dd, 1H, H-2eq, J2eq,2ax =11, J2eq,3 =4 Hz); 2.97 (dd, 1H, H-6 eq, J6eq,6ax =12 Hz, J6eq,5 =4 Hz); 2.38 (t, 1H, H-2ax, J2ax,2eq =J2ax,3=11 Hz); 2.31 (t, 1H, H-6ax, J6ax,6eq=J6ax,5 =12 Hz); 1.80 ppm (m, 1H, H-5).
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].ClCCl.CCN=C=N[CH2:16][CH2:17][CH2:18][N:19](C)C.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C:30]1[C:34]([C:35]([OH:37])=O)=[C:33]([CH3:38])[O:32][N:31]=1>CN(C1C=CN=CC=1)C.CC(C)=O.ClCCl>[C:3]1([C:1]([NH:19][CH2:18][C@@H:17]2[CH2:16][CH2:33][CH2:34][C@H:30]([NH:31][C:35]([C:34]3[C:30]([C:24]4[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=4[F:22])=[N:31][O:32][C:33]=3[CH3:38])=[O:37])[CH2:24]2)=[O:2])[CH:23]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1onc(-c2ccc(F)cc2F)c1C(=O)O
Reactant: O=C(O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1onc(-c2ccc(F)cc2F)c1C(=O)N[C@H]1CCC[C@@H](CNC(=O)c2ccccc2)C1
Yield: 90 %

Procedure:
In a fashion similar to that described for preparation 108, a compound from preparation 105 (0.1 g, 0.3 mmol), TFA (2 mL), dichloromethane (1.5 mL), EDCI (0.086 g, 0.45 mmol), DMAP (0.007 g, 0.06 mmol), 3-(2,4-difluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid (0.086 g, 0.36 mmol), and dichloromethane (1.5 mL) gave the title compound (0.123 g, 90%) after column chromatography (silica gel, acetone/dichloromethane gradient). Mass Spectrum (FIA) (m/z) 454.2 [M+1].
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]4[C:15]=3[CH:16]=[CH:17][N:18]=[C:19]4[NH:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([N:36]4[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]4)[CH:27]=3)=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:42]1(NC2C3SC=C(C(O)=O)C=3N=CN=2)[CH2:44][CH2:43]1>>[CH:42]1([NH:1][C:2]2[C:3]3[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]4[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]5[C:15]=4[CH:16]=[CH:17][N:18]=[C:19]5[NH:25][C:26]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([N:36]5[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]5)[CH:27]=4)=[O:12])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:44][CH2:43]1
Reactant: Cc1cn(-c2cc(Nc3nccc4c(NC(=O)c5csc6c(N)ncnc56)c(C)ccc34)cc(C(F)(F)F)c2)cn1
Reactant: O=C(O)c1csc2c(NC3CC3)ncnc12
Product: Cc1cn(-c2cc(Nc3nccc4c(NC(=O)c5csc6c(NC7CC7)ncnc56)c(C)ccc34)cc(C(F)(F)F)c2)cn1
Yield: 54.2 %

Procedure:
The procedures of <Step 3> of Example 1 were repeated, except for using 6-methyl-N1-(3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl)-isoquinolin-1,5-diamine (0.012 g, 0.03 mmol) obtained in Example 5 and 4-cyclopropylamino-thieno[3,2-d]pyrimidine-7-carboxylic acid (see WO 2011009687, 0.04 mmol) to obtain the title compound (10 mg, 57%).
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]([F:13])([F:12])[C:5]1[CH:6]=[C:7](O)[CH:8]=[CH:9][CH:10]=1.[OH2:14]>>[F:3][C:4]([F:13])([F:12])[C:5]1[CH:6]=[C:7]([CH2:4][CH2:5][CH2:10][C:9]([OH:14])=[O:1])[CH:8]=[CH:9][CH:10]=1
Reactant: [OH-]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: O
Agent: [Na+]
Product: O=C(O)CCCc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a solution of sodium hydroxide (4.0 g, 100 mmol) in water (50 mL) was added 3-trifluoromethyl-phenol (5.4 g, 33.4 mmol) and the mixture was refluxed for 6 hrs. The pH of the solution was kept at about 10 by adding more of aqueous sodium hydroxide. The mixture was cooled to ambient temperature and extracted with ethyl acetate. The aqueous layer was treated with 3N HCl and extracted with ethyl acetate. The combined organic layers was concentrated to obtain 2.5 g of the title compound, which was used directly in the next step. 1H NMR (300 MHz, d6-DMSO) δ 12.40 (broad s, 1H), 7.51 (t, J 7.5 Hz, 1H), 7.24 (m, 3H), 4.23 (t, J 6.0 Hz, 2H), 2.71 (t, J 6.0 Hz, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=2)[CH:6]=[C:7]([O:9]C)[CH:8]=1.C[Mg]I.O.Cl>C1(C)C(C)=CC=CC=1.C(OCC)C>[OH:19][CH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:5]2[CH:6]=[C:7]([OH:9])[CH:8]=[C:3]([OH:2])[CH:4]=2)=[CH:12][CH:13]=1
Reactant: COc1cc(OC)cc(-c2ccc(CCO)cc2)c1
Agent: C[Mg]I
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1C
Product: OCCc1ccc(-c2cc(O)cc(O)c2)cc1

Procedure:
17.0 g (65.2 mmol) of 2-(3′,5′-dimethoxybiphenyl-4-yl)ethanol are dissolved in 1 l of xylene, and, after addition of 110 ml (330 mmol) of a 3 M solution of methylmagnesium iodide in diethyl ether, the mixture is heated under reflux for 3 d. The batch is subsequently carefully hydrolysed by addition of water and acidified using dil. hydrochloric acid. The org. phase is separated off, washed with water and dried over sodium sulfate. The solvent is removed in vacuo, and the crude product is recrystallised from toluene, giving 4′-(2-hydroxyethyl)biphenyl-3,5-diol as a colourless solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.[N:17]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[C:19](=[O:25])[CH2:18]2.[OH-].[Na+]>C(OCC)C>[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[C:19]1([OH:25])[CH:20]2[CH2:23][CH2:24][N:17]([CH2:22][CH2:21]2)[CH2:18]1
Reactant: Brc1ccc2ccccc2c1
Reactant: O=C1CN2CCC1CC2
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: OC1(c2ccc3ccccc3c2)CN2CCC1CC2
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Butyllithium (31 ml, 72 mmol) was added to a mixture of 2-bromonaphthalene (14.9 g, 72.1 mmol) and diethyl ether (300 ml) at −70° C. The resulting mixture was stirred at −70° C. for 30 minutes. A mixture of 3-quinuclidinone and diethyl ether (150 ml) was added at −70° C. The mixture was stirred at −70° C. for 1 hour and was then allowed to reach room temperature. Aqueous sodium hydroxide (400 ml, 1 M) was added. The phases were separated and the aqueous phase was extracted with diethyl ether (100 ml). The combined organic phases were purified by chromatography on silica gel with dichloromethane, methanol and conc. ammonia (89:10:1) gave the title compound. Yield 2.03 g (11%).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([OH:18])=[CH:5][C:6]([OH:17])=[C:7]([CH:16]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])[CH3:2].Br[CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25]>>[C:8]([C:7]1[C:6]([OH:17])=[CH:5][C:4]([O:18][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])=[C:3]([CH2:1][CH3:2])[CH:16]=1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#CCCCCBr
Reactant: CCc1cc(C(=O)c2ccccc2)c(O)cc1O
Product: CCc1cc(C(=O)c2ccccc2)c(O)cc1OCCCCC#N
Yield: 38.2 %

Procedure:
Following the procedure of Example 16, 0.726 g of 5-ethyl-2,4-dihydroxybenzophenone and 0.53 g of 5-bromopentanenitrile were allowed to react and provided 0.37 g of the desired title product, m.p.=42°-44° C.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>O>[CH2:20]([O:19][C:17]([N:1]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=[O:4])=[O:18])[CH3:21]
Reactant: CCOC(=O)Cl
Reactant: O=C(O)C1CCCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)N1CCCCC1C(=O)O

Procedure:
15.0 g (0.116 moles) of (±) pipecolic acid were dissolved in 180 ml of water. 25.5 g (0.185 moles) of potassium carbonate were added and the solution cooled to +5° C. 19.83 g (0.183 moles) of ethyl chloroformate were added dropwise under mechanical stirring, maintaining the temperature below +10° C. After 4 hours the reaction mixture was extracted with methylene chloride; the aqueous layer were treated with conc. HCl to acidic pH, extracted with methylene chloride (400 ml) which was dried over Na2SO4 and the solvent evaporated to dryness to afford 23.8 g of the crude product. Crystallization from isopropyl ether/n-hexane gave 21.7 g (93% of the theoretical) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][CH:7]=1.[CH2:9]([C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]2)[CH2:14][CH2:13]1)[CH2:10][CH3:11]>>[CH2:9]([C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][CH:5]=3)[CH2:24][CH2:25]2)[CH2:14][CH2:13]1)[CH2:10][CH3:11]
Reactant: Fc1cccc(Br)c1
Reactant: CCC[C@H]1CC[C@H](CCC2CCC(=O)CC2)CC1
Product: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](c3cccc(F)c3)CC2)CC1

Procedure:
3-[Trans-4'-(trans-4"-propylcyclohexylethyl)cyclohexyl]fluorobenzene (C-N point: 48.4° C., N-I point: 79.4° C.) (50 g) obtained from 3-fluorobromobenzene and 4-(trans-4'-propylcyclohexylethyl)cyclohexanone in the same manner as in Example 1, was dissolved in nitrobenzene (100 cc), followed by adding anhydrous aluminum chloride (50.5 g) to the solution, agitating it, dropwise adding acetyl chloride (29 g) to the mixture, heating the resulting mixture on a water bath at 40° C. for 2 hours after completion of heat generation to complete reaction, adding the reaction material to a mixture of ice (500 g) with conc. hydrochloric acid (100 cc), vigorously agitating the mixture to decompose the resulting aluminum chloride complex, extracting the freed oily substance with toluene (200 cc), washing the extract solution with water until the wash water became neutral, drying it over anhydrous sodium sulfate, filtering off the drying agent, distilling off toluene and nitrobenzene and recrystallizing a remaining oily substance from ethyl acetate to obtain 2-fluoro-4-[trans-4'-(trans-4"-propylcyclohexylethyl)cyclohexyl]acetophenone (20.2 g). This product exhibited a liquid crystal phase over 62.1° C. (C-N point) to 161.4° C. (N-I point).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[CH:12]=[C:11]([NH:14][C:15](=[O:21])OC(C)(C)C)[N:10]=[CH:9][C:8]=3[CH:7]=[CH:6]2)[CH2:3][CH2:2]1.N1C=CC=CC=1.ClC([C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1)=O>Cl.O1CCOCC1>[CH:1]1([CH2:4][N:5]2[C:13]3[CH:12]=[C:11]([NH:14][C:15]([C:31]4[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=4)=[O:21])[N:10]=[CH:9][C:8]=3[CH:7]=[CH:6]2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)Nc1cc2c(ccn2CC2CC2)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)Nc2cc3c(ccn3CC3CC3)cn2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.6 %

Procedure:
A mixture of tert-butyl 1-(cyclopropylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamate (2C, 260 mg, 0.91 mmol) in 4M HCl in dioxane (3 ml) was stirred at room temperature for 15 h. The mixture was concentrated in vacuo and dissolved in pyridine (3 ml, 37 mmol). To the mixture, methyl 4-(chlorocarbonyl)benzoate (270 mg, 1.4 mmol) was added and stirred at room temperature for 3 hours. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude mixture was purified by chromatography (NH—SiO2, EtOAc) to give methyl 4-(1-(cyclopropylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamoyl)benzoate (2D, 270 mg, 0.77 mmol, 85% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.39-0.47 (m, 2H) 0.50-0.59 (m, 2H) 1.17-1.33 (m, 1H) 3.89 (s, 3H) 4.06 (d, J=7.07 Hz, 2H) 6.57-6.59 (m, 1H) 7.52 (d, J=3.28 Hz, 1H) 8.03-8.09 (m, 2H) 8.14-8.19 (m, 2H) 8.34 (s, 1H) 8.65 (s, 1H) 10.86 (s, 1H). ESI-MS: m/z 350.0 (M+H)+.
Reaction SMILES: CC(O[C:5]([CH3:7])=[O:6])=O.[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][CH2:13][CH2:12]2>O1CCOCC1.O>[CH2:14]1[C:15]2[C:11](=[CH:10][C:9]([NH:8][C:5](=[O:6])[CH3:7])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)CCC2
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc2c(c1)CCC2
Temperature: 20 °C
Reaction time: 48 h
Yield: 94.9 %

Procedure:
Ac2O (44.6 mL, 473 mmol) was added dropwise to a stirred solution of 5-indanamine (1) (30 g, 225 mmol) in dioxane (120 mL) at 0° C. and the solution stirred at 20° C. for 48 h. The solution was diluted with water (500 mL), stirred 20 min and the precipitate filtered. The solid was washed with water (3×30 mL) and air-dried to give acetamide 16 (37.4 g, 95%) as a tan solid: mp 99-101° C.; 1H NMR δ 7.38-7.43 (m, 2H, H-4, NH), 7.10-7.16 (m, 2H, H-6, H-7), 2.85 (br q, J=7.7 Hz, 4H, H-1, H-3), 2.13 (s, 3H, CH3), 2.06 (br, p, J=7.4 Hz, 2H, H-2); 13C NMR δ 168.3, 145.1, 140.3, 136.0, 124.4, 118.2, 116.6, 33.0, 32.3, 25.6, 24.4.
Reaction SMILES: [CH3:1]O.[CH2:3]([OH:5])[CH3:4].[CH2:6]([OH:9])[CH2:7]C>C(O)(C)C>[CH3:3][O:5][C:6]([OH:9])([CH3:7])[CH3:1].[CH2:3]([O:5][CH:6]([OH:9])[CH3:7])[CH3:4]
Reactant: CO
Reactant: CCCO
Reactant: CCO
Solvent: CC(C)O
Product: CCOC(C)O
Product: COC(C)(C)O

Procedure:
The 4,5-diacyl-[1,4,5]-oxadiazepines obtained in this reaction step can be obtained especially by precipitation from alcohols such as methanol, ethanol, propanol, isopropanol, methoxyisopropanol and ethoxyethanol. They are generally obtained in yields of from 40 to 76% and in a purity of more than 95%. It is not necessary, however, to isolate those intermediates; they can be introduced directly into the next step by replacing the solvent of reaction step (1) by the solvent of reaction step (2).