Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](CC(=C)C5[C@]4(C)CCCC5)[C@@H]2C3)C)O1.C([C@@H:31]1[CH:48]2[C@:43]([CH3:50])([CH2:44][CH2:45][C:46](=[O:49])[CH2:47]2)[C@@H:42]2[C@H:33]([C@H:34]3[C@@:38]([CH2:40][CH2:41]2)([CH3:39])[C:37](=[O:51])[CH2:36][CH2:35]3)[CH2:32]1)#N>>[CH2:1]=[C:32]1[CH2:31][CH:48]2[C@:43]([CH3:50])([CH2:44][CH2:45][C:46](=[O:49])[CH2:47]2)[C@@H:42]2[C@@H:33]1[C@H:34]1[C@@:38]([CH2:40][CH2:41]2)([CH3:39])[C:37](=[O:51])[CH2:36][CH2:35]1
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Product: C=C1CC2CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Yield: 87 %

Procedure:
The title compound II-bv was prepared in 87% yield from 3,3:17,17-bis(ethylendioxy)-6-methyleneandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 4.78 (m, 1H), 4.76 (m, 1H), 2.53-0.88 (m, 20H), 1.23 (s, 3H), 0.91 (s, 3H).
Reaction SMILES: I[C:2]1[N:19]=[C:18]2[C:5](=[N:6][CH2:7][N:8]2[C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[C:4]([NH:21][CH3:22])(N)[N:3]=1.[CH2:23]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:24]#[CH:25].C(N(CC)CC)C>CN(C)C=O.[Cu](I)I.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>[OH:16][CH2:15][C@H:14]1[O:17][C@@H:9]([N:8]2[CH:7]=[N:6][C:5]3[C:18]2=[N:19][C:2]([C:25]#[C:24][CH2:23][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:3][C:4]=3[NH:21][CH3:22])[C@H:10]([OH:11])[C@@H:12]1[OH:13]
Reactant: CNC1(N)N=C(I)N=C2C1=NCN2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#CCOc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNc1nc(C#CCOc2ccccc2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of 2-iodo-6-methylamino adenosine (50 mg) and prop-2-ynyloxybenzene (0.022 mL, 0.16 mmol) in N,N-dimethylformamide (1 ml) and triethylamine (0.021 mL, 0.16 mmol) at 23 C was added copper iodide (5 mg, 0.026 mmol) and dichlorobis-(triphenylphosphine)palladium(II) (22 mg, 0.031 mmol) catalyst. After being stirred in a sealed reaction-vial at 80° C. for 6 hours, the reaction was concentrated in vacuo, and the residue purified by preparatory thin layer chromatography (methylene chloride:methanol 9:1) to afford (4S,2R,3R,5R)-5-(hydroxymethyl)-2-[6-(methylamino)-2-(3-phenoxyprop-1-ynyl)purin-9-yl]oxolane-3,4-diol, a compound of Formula I. MS: 412.1 (M+1).
Reaction SMILES: [OH-:1].[K+].[NH2:3][CH2:4][C:5]1[C:10]2[N:11]([CH3:14])[CH:12]=[N:13][C:9]=2[CH:8]=[C:7]([C:15]#[N:16])[C:6]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23].Cl>OO.CO>[NH2:3][CH2:4][C:5]1[C:10]2[N:11]([CH3:14])[CH:12]=[N:13][C:9]=2[CH:8]=[C:7]([C:15]([NH2:16])=[O:1])[C:6]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23]
Reactant: Cn1cnc2cc(C#N)c(-c3ccccc3Cl)c(CN)c21
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CO
Product: Cn1cnc2cc(C(N)=O)c(-c3ccccc3Cl)c(CN)c21
Reaction time: 16 h
Yield: 68.2 %

Procedure:
A solution of KOH (30 mg, 0.54 mmol) in 30% H2O2 (2 mL) was added to a solution of Example 23 (80 mg, 0.27 mmol) in methanol (6 mL) at r.t. After stirring for 16 h, the solution was neutralized with 1N HCl and concentrated in vacuo. Purification by Prep-HPLC yielded 58 mg (50%) of the title compound as a white solid. 1H NMR (400 MHz, MeOD-d4): δ 9.19 (s, 1H), 8.10 (s, 1H), 7.43-7.60 (m, 4H), 4.41 (qAB, 2H, J=158.8, 14.8 Hz), 4.32 (s, 3H). MS (ES) [m+H] calc'd for C16H15N4OCl, 315, 317; found 315, 317.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[NH:10][C@H:11]1[CH2:15][CH2:14][C@H:13]([O:16][CH2:17][C:18]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)=CC2C=CC=CC=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:34]=[O+][O-]>ClCCl>[CH2:1]([O:8][C:9](=[O:33])[NH:10][C@H:11]1[CH2:15][CH2:14][C@H:13]([O:16][CH2:17][C:18](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[O+][O-]
Reactant: Cc1ccc(C(=Cc2ccccc2)CO[C@H]2CC[C@H](NC(=O)OCc3ccccc3)C2)cc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)CO[C@H]2CC[C@H](NC(=O)OCc3ccccc3)C2)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 10 g of trans [3-(3-phenyl-2-p-tolyl-allyloxy)-cyclopentyl]-carbamic acid benzyl ester in 500 mL of dichloromethane cooled to −78° C. was dispersed a stream of ozone from an ozone generator until a blue color persisted. The excess ozone was purged with nitrogen until the blue color dissipated, and 20 mL of methyl sulfide was added. After warming to room temperature over 30 min, the solution was concentrated under reduced pressure. Chromatography over silica gel eluting with a gradient of 5%-45% ethyl acetate in hexane gave 6.5 g of product as a white crystalline solid: MS (m+1)=368.3; 1H NMR (400 MHz, CDCl3) 7.35 (m, 2H), 7.1 (m, 5H), 7.0 (m, 2H), 5.1 (s, 2H), 4.7 (m, 1H), 4.2 (s, 2H), 4.1 (m, 1H), 2.35 (s, 3H), 2.2 (m, 2H), 1.95 (m, 1H), 1.74 (m, 1H), 1.6 (m, 1H), 1.4 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:22][CH2:21][C:5]2[N:6]([CH2:14][CH2:15][C:16](OCC)=[O:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:23]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([NH:28][C:16](=[O:17])[CH2:15][CH2:14][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:22][CH2:21][C:5]2=3)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCOC(=O)CCn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: NC1CCCC1
Product: Cc1ccc2c(c1)c1c(n2CCC(=O)NC2CCCC2)CCN(C)C1
Temperature: 110 °C
Yield: 15.2 %

Procedure:
A mixture of ethyl 3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoate (100 mg, 0.33 mmol) and cyclopentylamine (1 ml, 10 mmol) was heated at 100-120° C. for 3-4 h to obtain 17 mg of N-cyclopentyl-3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanamide after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:17][CH:16]3[C:18]([O:20]CC)=[O:19])=[CH:11][CH:10]=2)O1.Br[C:25]1[CH:26]=[C:27]([N:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][N:39]=3)[C:34](=[O:41])[C:33]([C:42]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[O:43])=[CH:32]2)[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)CC.CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:44]1([C:42]([C:33]2[C:34](=[O:41])[C:35]3[C:40](=[N:39][CH:38]=[CH:37][CH:36]=3)[N:31]([C:27]3[CH:26]=[C:25]([C:9]4[CH:10]=[CH:11][C:12]([C@@H:15]5[CH2:17][C@H:16]5[C:18]([OH:20])=[O:19])=[CH:13][CH:14]=4)[CH:30]=[CH:29][CH:28]=3)[CH:32]=2)=[O:43])[CH2:45][CH2:46][O:47][CH2:48][CH2:49]1
Reactant: CCOC(=O)C1CC1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=C(c1cn(-c2cccc(Br)c2)c2ncccc2c1=O)N1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCO
Solvent: CN(C)C=O
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(-c2cccc(-n3cc(C(=O)N4CCOCC4)c(=O)c4cccnc43)c2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of acid from step 2 (1 eq), amide from step 1 (1 eq), Na2CO3 (3.5eq.; 2M in H2O), Pd(PPh3)4 (0.15eq.) in n-propanol-DMF (1:1, 0.1M) was stirred at 80° C. for 2 h. The mixture was cooled to rt, quenched with brine and diluted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CHCl3:THF; 50:50), triturated in ether/acetone and then isolated by filtration to afford the title compound as a solid.
Reaction SMILES: Cl.C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=3[F:28])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:29][CH3:30])C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[F:28][C:22]1[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[CH:19][C:10]([OH:9])=[C:11]([O:29][CH3:30])[CH:12]=2)[N:17]=[CH:16][N:15]=1
Reactant: COc1cc2c(Nc3ccc(C)cc3F)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3ccc(C)cc3F)ncnc2cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
A solution of 7-benzyloxy-4-(2-fluoro-4-methylanilino)-6-methoxyquinazoline hydrochloride (2 g, 4.7 mmol) in TFA (20 ml) was heated at 80° C. for 5 hours and stirred at ambient temperature overnight. The volatiles were removed under vacuum and the residue was suspended in water (50 ml). Solid sodium hydrogen carbonate was added until the pH was approximately 7. The precipitate was then collected by filtration, washed with water and dried under vacuum. The solid was purified by column chromatography eluting with methanol/methylene chloride (5/95). After removal of the solvent by evaporation, the solid was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(2-fluoro-4-methylanilino)-7-hydroxy-6-methoxyquinazoline (1.04 g, 74%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.Cl.[CH3:37][N:38]([CH2:40][C:41](Cl)=[O:42])[CH3:39]>>[CH3:37][N:38]([CH2:40][C:41]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:33])([F:35])[F:34])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1)=[O:42])[CH3:39]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Product: CN(C)CC(=O)N1CCC(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 30 (Step 6) starting from N-{3-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and dimethylaminoacetyl chloride hydrochloride (Lancaster, Cat. No. L18475). LCMS (M+H)+: m/z=570.2.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:15]=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1.[O:16]1[C:20]2([CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1>C1COCC1>[O:11]1[C:10]2[CH:14]=[CH:15][C:7]([C:23]3([OH:26])[CH2:24][CH2:25][C:20]4([O:19][CH2:18][CH2:17][O:16]4)[CH2:21][CH2:22]3)=[CH:8][C:9]=2[O:13][CH2:12]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1ccc2c(c1)OCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc3c(c2)OCO3)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 24 mL, 60 mmol) was dropped slowly into a solution of 5-bromo-benzo[1,3]dioxole (Aldrich, 10.0 g, 50 mmol) in THF (100 mL) at −78° C. over 10 min. The reaction was stirred for additional 20 min. at −78° C. A solution of 1,4-dioxa-spiro[4.5]decan-8-one (Aldrich, 8.60 g, 55 mmol) in THF (20 mL) was slowly dropped into the reaction. After addition, the reaction was stirred for additional 2 hours at −78° C. The reaction was then quenched with diluted NH4Cl solution and warmed to room temperature. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow solid, which was then purified by silica gel column on a CombiFlash® system (Teledyne Isco, Inc, Lincoln, Nebr.) using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[C:18]1[C:27]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[N:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:35]([O:37][CH3:38])=[O:36])[CH:24]=2)[N:19]=1.CCN(C(C)C)C(C)C>CN(C)C=O>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:27]2[C:18]([N:12]3[CH2:11][CH2:10][CH:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=4)[CH2:14][CH2:13]3)=[N:19][C:20]3[C:25]([N:26]=2)=[CH:24][C:23]([C:35]([O:37][CH3:38])=[O:36])=[CH:22][CH:21]=3)=[CH:33][CH:32]=1
Reactant: FC(F)(F)c1ccc(C2CCNCC2)cc1
Reactant: COC(=O)c1ccc2nc(Cl)c(-c3ccc(F)cc3)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(N3CCC(c4ccc(C(F)(F)F)cc4)CC3)c(-c3ccc(F)cc3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 20-mL sealed tube, was placed a solution of 4-(4-(trifluoromethyl)phenyl)piperidine (420 mg, 1.83 mmol, 3.00 equiv), methyl 2-chloro-3-(4-fluorophenyl)quinoxaline-6-carboxylate (150 mg, 0.47 mmol, 1.00 equiv), DIEA (305 mg, 2.36 mmol, 5.00 equiv) in N,N-dimethylformamide (10 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 200 mg (83%) of methyl 3-(4-fluorophenyl)-2-(4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[C:4]([N:6](CC)CC)=[O:5].Cl.[O:17](N)[CH3:18].C(N(CC)CC)C>>[NH2:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[C:4]([NH:6][O:17][CH3:18])=[O:5]
Reactant: CCN(CC)C(=O)c1cc(Br)ccc1N
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Product: CONC(=O)c1cc(Br)ccc1N
Yield: 65 %

Procedure:
Prepared analogously to Compound 3D replacing diethylamine with a mixture of methoxylamine hydrochloride (2.07 g, 24.8 mmol) and triethylamine (6.9 mL, 50 mmol) to afford 2.64 g of the title compound (65%). 1H NMR (400 MHz, CD3OD) δ=7.45 (d, J=2.3 Hz, 1H), 7.27 (dd, J=2.3, 8.8 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 3.77 (s, 3H).
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:23])[CH2:6][C:7]1[C:8](=[O:22])[NH:9][CH2:10][CH2:11][CH2:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)([CH3:3])[CH3:2].[CH:24](=O)[CH3:25].C([BH3-])#N.[Na+].Cl>C(#N)C.C(O)(=O)C>[CH:1]([N:4]([CH:5]([CH3:23])[CH2:6][C:7]1[C:8](=[O:22])[NH:9][CH2:10][CH2:11][CH2:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH2:24][CH3:25])([CH3:2])[CH3:3]
Reactant: CC=O
Reactant: COc1ccc(C2=C(CC(C)NC(C)C)C(=O)NCCC2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCN(C(C)C)C(C)CC1=C(c2ccc(OC)cc2)CCCNC1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4.78 ml of glacial acetic acid are added dropwise to the ice-cooled mixture of 7.6 g of 3-(2-isopropylaminopropyl)-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 13.3 ml of acetaldehyde, 4.5 g of sodium cyanoborohydride and 90 ml of acetonitrile. The mixture is stirred at room temperature for 90 minutes, cooled in an ice-bath, acidified to pH=1 with concentrated hydrochloric acid and evaporated. The residue is taken up in 150 ml of water, the solution washed with diethyl ether, filtered, basified with 3 N aqueous sodium hydroxide and extracted with diethyl ether. The extract is dried, evaporated, the residue crystallized from petroleum ether and further purified by suspension in hexane, to yield the 3-[2-(N-isopropyl-N-ethylamino)-propyl]-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone melting at 64°-66°.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[N:19]=[C:18]([CH2:20][OH:21])[CH:17]=[N:16]3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1.[CH2:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:21][CH2:20][C:18]1[CH:17]=[N:16][N:15]([CH:12]2[CH2:13][CH2:14][N:9]([C:6]3[N:5]=[CH:4][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:8][N:7]=3)[CH2:10][CH2:11]2)[N:19]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OCc1ccccc1
Reactant: OCc1cnn(C2CCN(c3ncc(C(F)(F)F)cn3)CC2)n1
Product: FC(F)(F)c1cnc(N2CCC(n3ncc(COCc4ccccc4)n3)CC2)nc1

Procedure:
The title compound was synthesized from (2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)-2H-1,2,3-triazol-4-yl)methanol (Intermediate 27) and benzyl alcohol in a manner similar to that described in Example 29. 1H NMR (CDCl3): δ 8.50 (2H, s), 7.60 (1H, s), 7.36-7.30 (5H, m), 4.86-4.82 (2H, m), 4.79-4.72 (1H, m), 4.62 (2H, s), 4.59 (2H, s), 3.33-3.26 (2H, m), 2.30-2.16 (4H, m).
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH2:4][CH2:3]1.[Li+].CC([N-]C(C)C)C.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Br)=[C:25]([Cl:31])[CH:24]=1>C1COCC1>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:10]2[CH2:11][CH2:12][N:8]([C@H:5]3[CH2:6][CH2:7][C@@H:2]([F:1])[CH2:3][CH2:4]3)[C:9]2=[O:13])=[C:25]([Cl:31])[CH:24]=1
Reactant: O=C1CCCN1[C@H]1CC[C@@H](F)CC1
Reactant: Clc1cc(Br)ccc1CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C(Cc2ccc(Br)cc2Cl)CCN1[C@H]1CC[C@@H](F)CC1
Reaction time: 8 h

Procedure:
To a solution of cis-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one (Preparation 26) (190 mg, 1.03 mmol) in 5 mL dry THF, add 1.29 mL of 2M LDA (2.5 eq.) in THF dropwise at −78° C. Then, add 16 mg of 4-Bromo-1-bromomethyl-2-chloro-benzene (2 eq) at −78° C. Allow the resulting solution to stand at room temp for overnight. Quench the mixture with saturated aqueous NH4Cl and extract with CH2Cl2. Wash the organic layer with water, brine, dry over Na2SO4, filter and concentrate. Purify the crude material by chromatography to afford the title compound: mass spectrum (m/z): 389 (M+1).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].I[CH2:15][CH2:16][C@H:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH3:18].O>C1COCC1>[Si:20]([O:19][C@H:17]([CH3:18])[CH2:16][CH2:15][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:21])[CH3:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C[C@H](CCI)O[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC[C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3 g of diethyl malonate in 5 ml of THF was added dropwise into a suspension of 0.05 g of sodium hydride in THF. After the dropwise addition, the mixture was stirred at room temperature for 30 minutes, and a solution of 0.65 g of (R)-1-iodo-3-t-butyldimethylsilyloxybutane in THF was added to the mixture. Then, the mixture was stirred at room temperature overnight, water was added to the mixture, and the majority of THF was removed by distillation. The residue was extracted with ether, and the ether extract was washed with dilute hydrochloric acid and then with water and dried over magnesium sulfate. The solvent was removed by distillation and the residue was subjected to distillation under a reduced pressure to obtain diethyl (R)-3-t-butyldimethylsilyloxybutylmalonate. The obtained compound was dissolved in 10 ml of THF and 2 ml of a 1M solution of tetrabutyl ammonium fluoride in THF was added to the solution, and the mixture was stirred at room temperature overnight and concentrated under a reduced pressure. Water was added to the concentrate and the mixture was extracted with ether. The ether extract was washed with water and dried over magnesium sulfate. Ether was removed by distillation, the residue was dissolved in benzene, p-TsOH was added to the solution and the mixture was refluxed for 5 hours. The reacted solution was washed with an aqueous solution of sodium hydrogen carbonate and dried, the solvent was removed by distillation, and the residue was purified by the silica gel column chromatography to obtain (2RS,5R)-2-ethoxycarbonyl-5-methyl-δ-valerolactone. The obtained compound was reduced with sodium borohydride to obtain (2RS,5R)-2-hydroxymethyl-5-methyl-δ-valerolactone. In the same manner as described in Example 1, the obtained compound was reacted with 4-(4'-octyloxy)biphenol by using triphenylphosphine and diethyl azodicarboxylate. The reacted solution was purified by the silica gel column chromatography to obtain (2RS,5R)-2-(4'-octyloxybiphenyl)oxymethyl-5-methyl-δ-valerolactone. The obtained product was further fractionated and purified by HPLC to obtain (2R,5R)-2-(4'-octyloxybiphenyl)oxymethyl-5-methyl-δ-valerolactone and (2S,5R)-2-(4'-octyloxybiphenyl)-oxymethyl-5-methyl-δ-valerolactone. They showed the following phase transitions. ##STR39##
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C:4]2([NH:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15](/[CH:18]=[CH:19]/[C:20]([NH:22][O:23]C4CCCCO4)=[O:21])[CH:16]=[CH:17][C:9]=3[O:8]2)[CH2:3]1.Cl>C(Cl)Cl.O1CCOCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C:4]2([NH:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15](/[CH:18]=[CH:19]/[C:20]([NH:22][OH:23])=[O:21])[CH:16]=[CH:17][C:9]=3[O:8]2)[CH2:3]1
Reactant: CN1CCCC2(C1)NC(=O)c1cc(/C=C/C(=O)NOC3CCCCO3)ccc1O2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN1CCCC2(C1)NC(=O)c1cc(/C=C/C(=O)NO)ccc1O2
Yield: 64.2 %

Procedure:
A solution of (±)-(E)-3-{1′-methyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (210 mg, 0.52 mmol) in DCM (6 ml) was treated with 4 M HCl in dioxane (1.0 ml) as described in Example 30, STEP C to give (±)-(E)-3-{1′-methyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-hydroxy-acrylamide (106 mg, hydrochloride salt) as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH2:21]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>O1CCOCC1>[CH2:29]([N:28]([CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C1Nc2cccnc2N(C(=O)CN(Cc2ccccc2)Cc2ccccc2)c2ccccc21

Procedure:
6 gm of 11-chloroacetyl-5,11-dihydro-6H-pyrido [2,3-b][1,4]benzodiazepin-6-one, 4.2 gm of dibenzylamine and 2.1 gm of triethylamine were refluxed in 100 ml of absolute dioxane for 15 hours. After cooling, the formed triethylamine hydrochloride was separated, and the filtrate was evaporated in vacuo to dryness. The residue was then recrystallized twice from ethanol.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH2:29][CH3:30])[C:16]3[C:21]([C:22]=2[C:23]#[N:24])=[CH:20][CH:19]=[C:18]([C:25]([F:28])([F:27])[F:26])[CH:17]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:29]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[C:18]([C:25]([F:27])([F:28])[F:26])[CH:17]=2)[C:22]([C:23]#[N:24])=[C:14]1[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH3:30]
Reactant: CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)c(C#N)c2ccc(C(F)(F)F)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(N2CCNCC2)c(C#N)c2ccc(C(F)(F)F)cc21
Yield: 10.2 %

Procedure:
4-(3-cyano-1-ethyl-6-trifluoromethyl-1H-indol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.26 g, 6.1 mmol) was treated with TFA (5 mL) in dichloromethane (5 mL) for 1 hr at room temperature. After the removal of the volatiles, the residue was treated with saturated NaHCO3 and the precipitate was collected via filtration, washed with water thoroughly and dried in air to furnish essentially pure 1-ethyl-2-piperazin-1-yl-6-(trifluoromethyl)-1H-indole-3-carbonitrile (0.20 g, 100%).