Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20].C(N(CC)CC)C>O1CCCC1>[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:20]([CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:16]([Cl:15])[CH:17]=2)[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: NCc1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
To a solution of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.5 g) in tetrahydrofuran (10 ml) was added a solution of 3-chlorobenzylamine (0.45 g) (Table 1-1, amine 19) and triethylamine (0.32 g) in tetrahydrofuran (3 ml) under ice-cooling, and the mixture was allowed to warm to room temperature and stirred for 18 hr. The reaction mixture was concentrated, and the crystals were collected by filtration. The obtained crystals were added to a mixture of dimethylsulfoxide (5 ml)-water (5 ml), and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, the residue was purified by preparative HPLC, and the obtained fraction was treated with PL-HCO3MP (200 mg cartridge, Polymer Laboratories) to give the title compound (0.33 g).
Reaction SMILES: [CH:1](/[CH:5]1[CH2:10][O:9][CH:8](CCCCC(CO)CO)[O:7][CH2:6]1)=[CH:2]\[CH2:3][CH3:4].FC1C=C(C=CC=1F)C=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH:1](/[CH:5]1[CH2:10][O:9][CH2:8][O:7][CH2:6]1)=[CH:2]\[CH2:3][CH3:4]
Reactant: CC/C=C/C1COC(CCCCC(CO)CO)OC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=Cc1ccc(F)c(F)c1
Solvent: c1ccccc1
Solvent: O
Product: CC/C=C/C1COCOC1

Procedure:
A solution of 1.72 g of (E)-2-[4-(5-but-1-enyl-1,3-dioxan-2-yl)butyl]-1,3-propanediol and 1.0 g of 3,4-difluorobenzaldehyde in 30 ml of benzene is heated to slight boiling with 35 mg of p-toluenesulfonic acid monohydrate for 1 hour. After neutralization of the solution with a few drops of triethylamine the mixture is washed with water, dried over sodium sulfate, filtered and the filtrate is evaporated. The crude product is chromatographed on 40 g of silica gel with hexane/ethyl acetate 5% (v/v). Two-fold crystallization of the resulting isomer mixture from hexane yields pure (E)-trans-2-(3,4-difluorophenyl)-5-[4-(trans-5-but-1-enyl-1,3-dioxane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1C=CC(S(O[CH2:44][C:45]#[C:46][CH:47]2[CH2:49][CH2:48]2)(=O)=O)=CC=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:44][C:45]#[C:46][CH:47]2[CH2:49][CH2:48]2)=[CH:24][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)OCC#CC2CC2)cc1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCC#CC4CC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 2 h

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D1) (20 mg, 0.0526 mmol) in 1 mL of DMF was added Cs2CO3 (21 ng, 0.063 mmol) and 3-cyclopropylprop-2-ynyl 4-methylbenzenesulfonate (intermediate AU) (20 mg, 0.079 mmol) at room temperature. After stirring for 2 h, the reaction was quenched with 1 mL of ice water. The mixture was extracted 3× with ethyl acetate (5 mL each). The combined organic layers were washed 2× with water (5 mL each) and brine prior to drying over Na2SO4. Concentration of the solution and purification of the crude product by preparative LC-MS afforded compound AV (10 mg). 1H NMR (CD3OD): δ 7.37˜7.34 (2H, m), 7.30˜7.28 (1H, dd, J=8.8, 2 Hz), 7.13˜7.11 (2H, d, J=8.8 Hz), 6.87˜6.83 (2H, d, J=8.8 Hz), 4.61 (2H, d, J=2 Hz), 4.11 (1H, d, J=9.2 Hz), 4.10˜4.04 (2H, dd, J=23.6, 14.8 Hz), 3.90˜3.87 (1H, m), 3.72˜3.68 (1H, m), 3.49˜3.39 (3H, m), 3.31˜3.28 (1H, m), 1.31˜1.24 (1H, m), 0.79˜0.75 (2H, m), 0.62˜0.59 (2H, m).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]2[CH2:17][CH2:16]2)[C:10]([CH2:19][CH3:20])([CH3:18])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[OH-].[Pd+2]>[CH:15]1([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]2([CH2:19][CH3:20])[CH3:18])[CH2:17][CH2:16]1
Reactant: [H][H]
Reactant: CCC1(C)CN(Cc2ccccc2)CCC1NC1CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1(C)CNCCC1NC1CC1

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.5 g) and 1-benzyl-4-cyclopropylamino-3-ethyl-3-methylpiperidine (3.54 g, 13.00 mmol) in methanol (70 ml) was stirred in hydrogen atmosphere (1 atm.) at 60° C. for 48 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford 4-cyclopropylamino-3-ethyl-3-methylpiperidine. Yield 2.3 g (93%), C11H22N2, m/z 183 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:9][C@H:8]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCN(Cc2cccnc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CCCCN(Cc2cccnc2)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 106.8 %

Procedure:
In a round bottomed flask, to a stirred solution of (S)-tert-butyl 2-oxo-1-(pyridin-3-ylmethyl)azepan-3-ylcarbamate (150 mg, 0.470 mmol) in DCM (3 mL) was added 2,2,2-trifluoroacetic acid (0.186 mL, 2.35 mmol) at rt under argon. The reaction mixture was stirred at rt for 4 hr. The reaction mixture was concentrated and the residue was dried under vacuum to give (S)-3-amino-1-(pyridin-3-ylmethyl)azepan-2-one (110 mg, 0.502 mmol, 100% yield). Anal. Calcd. for C12H17N3O m/z 219.3. found: 220.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH2:29]([N:36]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:37]1[NH:41][C:40]2[CH:42]=[CH:43][CH:44]=[CH:45][C:39]=2[N:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:46]([N:36]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:37]1[N:41]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:17][CH2:18]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:3]=2)[C:40]2[CH:42]=[CH:43][CH:44]=[CH:45][C:39]=2[N:38]=1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: c1ccc(CN(Cc2ccccc2)c2nc3ccccc3[nH]2)cc1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(N(Cc4ccccc4)Cc4ccccc4)nc4ccccc43)nc21

Procedure:
2-(1-((2-Chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (0.35 g) was reacted with N,N-dibenzyl-1H-benzo[d]imidazol-2-amine.via General Procedure J for Buchwald coupling to give 255 mg of 2-(1-((2-(2-(dibenzylamino)-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol following flash chromatography.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH:6]=[N:5]2.[C:20]([N:22]([CH2:28][CH3:29])[C:23](=[O:27])[CH:24](Br)[CH3:25])#[N:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:20]([N:22]([CH2:28][CH3:29])[C:23](=[O:27])[CH:24]([O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:7]2[CH:6]=[N:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[N:8]=2)=[CH:14][CH:15]=1)[CH3:25])#[N:21]
Reactant: Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1
Reactant: CCN(C#N)C(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(C#N)C(=O)C(C)Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1
Yield: 47.9 %

Procedure:
10 g (0.039 mole) of 4-(6-fluoroquinoxalin-2-yloxy)phenol, 9.6 g (0.047 mole) of 2-bromopropionic acid N-cyano-N-ethylamide and 8.1 g (0.058 mole) of potassium carbonate are stirred for 14 hours at room temperature in 100 ml of acetonitrile. The precipitated salts are removed by filtration and the filtrate is concentrated by evaporation. The residue is chromatographed through silica gel eluted with ethyl acetate/hexane (1:3), affording 7.1 g (48% of theory) of 2-[4-(6-fluoroquinoxalin-2-yloxy)phenoxy]propionic acid N-cyano-N-ethylamide with a melting point of 108°-111° C.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:20][CH3:21])=[C:14]([S:16](Cl)(=[O:18])=[O:17])[CH:15]=1>C(Cl)Cl.N1C=CC=CC=1>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][S:16]([C:14]1[CH:15]=[C:10]([Br:9])[CH:11]=[CH:12][C:13]=1[O:20][CH3:21])(=[O:17])=[O:18]
Reactant: Nc1ccccc1N
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Br)cc1S(=O)(=O)Nc1ccccc1N
Temperature: 25 °C
Yield: 59.9 %

Procedure:
To a solution of o-phenylenediamine (5 mmol) in DCM (25 mL) and pyridine (5 mL) at 0° C., 5-bromo-2-methoxybenzenesulfonyl chloride (5.5 mmol) was added in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (25 mL). The organic phase was washed with water (2×25 mL) and 25 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to give 1.07 g of N-(2-aminophenyl)-5-bromo-2-methoxybenzene sulfonamide. 1H NMR (CDCl3, 400 MHz): δ 4.08 (s, 3H), 4.22(bs, 2H), 6.52 (m, 2H), 6.75 (m, 2H), 7.01 (d, 1H), 7.03 (m, 1H), 7.65(dd, 1H), 7.88 (d, 1H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([N:11]1[CH2:12][CH2:13][C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)([O:14][CH3:15])[CH2:10]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC1(c2ccc(F)c(F)c2)CCNC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2ccc(F)c(F)c2)CCN(Cc2ccccc2)C1
Yield: 54.9 %

Procedure:
Preparation according to Preparation 14. 3-(3,4-Difluorophenyl)-3-methoxypyrrolidine (1.15 g, 5.4 mmol), dry dimethyl formamide (5 mL), sodium hydride (60% dispersion in mineral oil, 0.259 g, 6.48 mmol). Benzylbromide (0.642 mL, 5.4 mmol) in dry dimethyl formamide (5 mL). Work up according to Preparation 14. Purification by flash column chromatography on silica gel (ethyl acetate) gave the title compound (0.9 g, 55%). MS m/z (rel. intensity, 70 eV) 288 (12), 273 (14), 133 (53), 132 (30), 91 (bp).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:26])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:23][CH2:24][OH:25])[CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:29][C@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][N:31]1[C:36]1[N:40]2[CH:41]=[C:42]([O:45][C@H:46]3[C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[C@@H:49]([NH2:56])[CH2:48][CH2:47]3)[CH:43]=[CH:44][C:39]2=[N:38][N:37]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:56][C@@H:49]2[C:50]3[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=3)[C@H:46]([O:45][C:42]3[CH:43]=[CH:44][C:39]4[N:40]([C:36]([N:31]5[CH2:32][CH2:33][CH2:34][CH2:35][C@@H:30]5[CH3:29])=[N:37][N:38]=4)[CH:41]=3)[CH2:47][CH2:48]2)=[O:26])[N:8]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:23][CH2:24][OH:25])[CH:17]=2)[N:9]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccnc(OCCO)c2)n1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccnc(OCCO)c4)c4ccccc43)cn12
Temperature: 60 °C
Yield: 84.6 %

Procedure:
Intermediate 67d (74 mg, 0.16 mmol) and Intermediate B (62 mg, 0.16 mmol) were suspended in 1,4-dioxane (5 mL) and DIPEA (32 mg, 42 μL, 0.25 mmol) added and the reaction heated to 60° C. for 18 h. The reaction was cooled, concentrated in vacuo and subjected to FCC, eluting with 0-5% 2M NH3 in MeOH/DCM, to afford the title compound (92 mg, 83%). LCMS (Method 3) Rt 3.51 min, 680.4 [MH+].
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.F[C:17]1[C:18]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:19]([CH3:34])[C:20]([C:32]#[N:33])=[C:21]2[C:25]=1[O:24][C:23]([CH2:26][C:27]1[O:28][CH:29]=[CH:30][CH:31]=1)=[N:22]2>CS(C)=O>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([C:17]2[C:18]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:19]([CH3:34])[C:20]([C:32]#[N:33])=[C:21]3[C:25]=2[O:24][C:23]([CH2:26][C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)=[N:22]3)[CH2:4]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cc3ccco3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(Cc3ccco3)nc2c1C#N
Temperature: 95 °C
Reaction time: 1 h
Yield: 13.7 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (88 μl, 0.695 mmol) and triethylamine (97 μl, 0.695 mmol) were added to a dimethyl sulfoxide (4 ml) solution of 7-fluoro-2-(2-furylmethyl)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-271) (154 mg, 0.463 mmol), followed by stirring in an oil bath at 95° C. for 1 hour. The reaction liquid was concentrated under reduced pressure, then the residue was dissolved in ethyl acetate, and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by silica gel column chromatography and preparative TLC (eluent, chloroform:methanol=20:1, v/v) to obtain the entitled compound (27 mg, 14%) as a pale brown foamy substance.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[ClH:15].Cl.[CH3:17][O:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][NH:24][C:25]([NH:27][C:28]([NH2:30])=[NH:29])=[NH:26])=[CH:21][CH:20]=1>C(O)C>[ClH:15].[NH2:30][C:28]1[NH:27][C:25]([NH:24][CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:32][CH:31]=2)=[N:26][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[N:29]=1
Reactant: COc1ccc(CNC(=N)NC(=N)N)cc1
Reactant: CCCCCCCCCCCCC=O
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCCCC1N=C(N)NC(NCc2ccc(OC)cc2)=N1

Procedure:
100 ml of ethanol, 9.2 ml (38.7 mmol) of 1-tridecanal and 0.8 ml of concentrated hydrochloric acid were added to 5.0 g (19.4 mmol) of N1-(4-methoxybenzyl)-biguanide hydrochloride, and the mixture was refluxed for 24 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. The first main fraction eluted with a mixture of chloroform and methanol (9:1.5) was recrystallized from 70% aqueous acetonitrile to obtain 3.0 g of colorless crystals (1) having a melting point of 162 to 164° C., and the second main eluate was recrystallized from 70% aqueous acetonitrile to obtain 1.3 g of colorless crystals (2) having a melting point of 182 to 184° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.Cl[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.N>O>[N:20]1[CH:21]=[CH:22][C:17]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=3)[CH2:6][CH2:5]2)=[CH:18][CH:19]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: Clc1ccncc1
Agent: Cl
Agent: N
Solvent: O
Product: COc1ccc(N2CCN(c3ccncc3)CC2)cc1
Yield: 31 %

Procedure:
4-(Piperazin-1-yl)anisole (4.24 g) and 4-chloropyridine hydrochloride (3.35 g) were intimately mixed and heated at 160°-170° C. (bath temperature) for 7 minutes. The solid obtained on cooling was dissolved in water (75 ml) and the solution basified with aqueous ammonia. The solid precipitate was extracted into ethyl acetate and the organic extract washed with water, filtered through phase separating paper (Whatman 1PS) and evaporated. The residue was recrystallised from ethanol to give 4-[4-(4-pyridyl)piperazin-1-yl]anisole (1.84 g) as a solid: m.p. 165°-167° C.; NMR (CDCl3) δ 8.3(2H,d); 6.86(4H,m); 6.71(2H,d); 3.78(3H,s); 3.46(4H,m); 3.2(4H,m).
Reaction SMILES: C([N:9]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11][N:10]1C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.Cl.O>C(O)CCC>[C:16]1([N:13]2[CH2:14][CH2:15][NH:9][NH:10][CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(c1ccccc1)N1CCN(c2ccccc2)CCN1C(=O)c1ccccc1
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: c1ccc(N2CCNNCC2)cc1
Reaction time: 72 h

Procedure:
A mixture of 1,2-dibenzoylhexahydro-5 phenyl-1H-1,2,5-triazepine (101.3 g), n-butanol (450 ml), 12N hydrochloric acid (915 ml) and water (915 ml) was mechanically stirred and heated under reflux on a steam bath overnight. Additional 12N hydrochloric acid (400 ml) and water (400 ml) were added and stirring and heating under reflux on a stea bath were continued for three days. n-Butanol (150 ml) was added and stirring and heating under reflux on a steam bath were continued for a further three days. After this time (7 days) the solid had dissolved. The mixture was extracted twice with ether and the aqueous solution was evaporated to smaller volume. Coevaporation with ethanol and concentrated hydrochloric acid caused crystallization of the titled product as the dihydrochloride salt; wt. 57.5 g (66%), mp=211°-218°.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([NH:13]C(=O)OCC1C=CC=CC=1)[CH:7]=2>[Pd].CO>[NH2:13][C:8]1[CH:7]=[C:6]2[C:11]([CH:12]=[C:3]([CH2:2][OH:1])[CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: O=C(Nc1ccc2cc(CO)cnc2c1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2cc(CO)cnc2c1
Reaction time: 1 h

Procedure:
A mixture of benzyl 3-(hydroxymethyl)quinolin-7-ylcarbamate (480 mg, 0.0016 mol), 10% Pd—C (50 mg), and MeOH (50 mL) was stirred under H2 (1 atm) for 1 h. The catalyst was filtered-off and the filtrate was concentrated to give the product as a yellow solid. LC-MS: 0.34 min, 175.1 (M+1).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[CH3:9][C:10]1[CH:18]=[C:17]([C:19]([F:28])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])[CH:16]=[C:15]([CH3:29])[C:11]=1[C:12](Cl)=[O:13]>O1CCCC1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[NH2:7][C:3]1[CH:2]=[C:1]([NH:8][C:12](=[O:13])[C:11]2[C:10]([CH3:9])=[CH:18][C:17]([C:19]([F:28])([C:20]([F:21])([F:22])[F:23])[C:24]([F:25])([F:26])[F:27])=[CH:16][C:15]=2[CH3:29])[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1C(=O)Cl
Reactant: Nc1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1C(=O)Nc1cccc(N)c1
Temperature: 70 °C
Reaction time: 48 h
Yield: 0.1 %

Procedure:
To a solution of benzene-1,3-diamine (4.48 g, 41.4 mmol) in anhydrous tetrahydrofuran (3 ml) under an atmosphere of nitrogen was added 2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzoyl chloride (4.40 g, 13.8 mmol) (Example I4) dissolved in anhydrous tetrahydrofuran (3 ml). The reaction mixture was stirred at 70° C. for 48 hours. Then the reaction mixture was diluted with ethyl acetate and aqueous sodium hydrogen carbonate (saturated). The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 3:1) to give N-(3-amino-phenyl)-2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzamide (3.4 mg, 61% yield). 1H-NMR (CDCl3, 400 MHz): 7.34 (t, 1H), 7.30 (s, 2H), 7.15 (t, 1H), 6.75 (d, 2H), 6.52 (d, 2H), 2.46 (s, 6H) ppm.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C3CCCCO3)=[CH:16][CH:15]=2)=O)=[N:10][CH:11]=1.[C:28]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=O)[CH2:29][CH3:30]>>[CH3:27][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][CH3:30])=[N:10][CH:11]=1
Reactant: CCC(=O)c1ccccc1
Reactant: CN(C)CCOc1ccc(C(=O)c2ccc(OC3CCCCO3)cc2)nc1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCN(C)C)cn1)c1ccccc1

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, (5-(2-(dimethylamino)ethoxy)pyridin-2-yl)(4-(tetrahydro-2H-pyran-2-yloxy) phenyl)methanone (1 eq) was reacted with propiophenone (2 eq) to give the desired product (Z/E=1/1). m/z=389[M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[CH2:20][OH:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CI.[C:26](=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[CH2:20][O:21][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(CO)c2cccc(OCc3ccccc3)c2n1
Reactant: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CI
Product: COCc1cc(C)nc2c(OCc3ccccc3)cccc12
Reaction time: 0.25 h

Procedure:
To a solution of 8-benzyloxy-4-hydroxymethyl-2-methylquinoline (148 mg) in N,N-dimethylformamide (1.5 ml) was added sodium hydroxide (60% in oil, 23.3 mg) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature. To the mixture was added methyl iodide (82.7 mg) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature and then overnight at ambient temperature. To the mixture was added saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water twice, dired over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (Ethyl acetate:n-hexane=1:3, V/V) to give 8-benzyloxy-4-methoxymethyl-2-methylquinoline (123 mg) as pale yellow solid.
Reaction SMILES: C(O[C:4](=[O:20])[CH2:5][C:6](=O)[CH2:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)C.[NH2:21][C:22]1[CH:26]=[CH:25][NH:24][N:23]=1>CCO>[OH:20][C:4]1[N:23]2[N:24]=[CH:25][CH:26]=[C:22]2[N:21]=[C:6]([CH2:7][CH:8]2[CH2:9][CH2:10][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13]2)[CH:5]=1
Reactant: CCOC(=O)CC(=O)CC1CCC(C(=O)OCC)CC1
Reactant: Nc1cc[nH]n1
Solvent: CCO
Product: CCOC(=O)C1CCC(Cc2cc(O)n3nccc3n2)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a 50 mL round-bottom flask containing ethyl 4-(4-ethoxy-2,4-dioxobutyl)cyclohexanecarboxylate (Int-4e, 2.33 g, 8.19 mmol) was added 3-amino-1H-pyrazole (681 mg, 8.19 mmol). The flask was heated via heat gun to ensure mixing of the oils, and then the reaction was shaken at 100° C. for 18 hours. After 18 hours, the resulting solid was taken up in EtOH and then the solvent was removed in vacuo to dry product. The product was then pumped dry on high vacuum overnight to further dry the product. The compound was taken on without further purification.