Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]2[NH:11][C:10]1=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:21][CH2:22][CH2:23][CH2:24][CH2:25]Br.C(Cl)(Cl)Cl>CN(C)C=O>[C:1]([N:9]1[CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]2[N:11]([CH2:25][CH2:24][CH2:23][CH2:22][Br:21])[C:10]1=[O:18])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC2CCCCC2N1C(=O)c1ccccc1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1C(=O)N(CCCCBr)C2CCCCC21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
To a solution of 3-benzoylperhydrobenzimidazol-2-one (2.7 9, 10.0 mmoles) in 50 ml of dimethylformamide was added 60% sodium hydride (400 mg, 10.0 mmoles), and the mixture was stirred at 60° C. for 30 minutes. To this mixture having been cooled to room temperature was further added 1,4-dibromobutane (10.8 g, 50.0 mmoles), and the resulting mixture was stirred at 60° C. for 4 hours. After chloroform was added to the reaction, insolubles were removed by filtration, the filtrate was washed with water, and the solvent was evaporated. The residue thus obtained was purified by chromatography on a silica gel column to give 1.5 g of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.C1C(=O)N([Br:30])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:30][CH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(CBr)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 26.3 %

Procedure:
A mixture of di-tert-butyl (6-methylpyridin-3-yl)imidodicarbonate (Compound 260D, 15 g, 49 mmol), NBS (8.2 g, 49 mmol) and AIBN (1.0 g) in CCl4 (200 mL) was stirred at 100° C. overnight. TLC showed the reaction was complete. The reaction mixture was concentrated and residue was purified by column chromatography to afford the desired compound (5.0 g, yield: 26%) as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ=1.41 (s, 18 H), 4.53 (s, 2 H), 7.44 (dd, J=2.4, 8.0 Hz, 1 H), 7.67 (d, J=8.4 Hz, 1 H), 8.33 (dd, J=2.4, 8.0 Hz, 1 H).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:36][C:37]1[N:41]2[C:42](=[O:51])[N:43]([CH:45]3[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]3)[CH2:44][C:40]2=[CH:39][N:38]=1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:36][C:37]1[N:41]2[C:42](=[O:51])[N:43]([CH:45]3[CH2:50][CH2:49][N:48]([C:10](=[O:12])[CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:47][CH2:46]3)[CH2:44][C:40]2=[CH:39][N:38]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Cc1ncc2n1C(=O)N(C1CCNCC1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ncc2n1C(=O)N(C1CCN(C(=O)CNC(=O)OC(C)(C)C)CC1)C2
Yield: 66 %

Procedure:
To a solution of Boc-glycine (0.44 g) and HOBt (0.58 g) in acetonitrile (15 ml) was added WSC (0.72 g), and the reaction mixture was mixed at room temperature for 15 minutes. Then, a solution of 5-methyl-2-(4-piperidinyl)-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one dihydrochloride (0.73 g), DBU (0.75 ml) and triethylamine (1.1 ml) in acetonitrile (5 ml) was added thereto. The reaction mixture was mixed at room temperature for 15 hours, the solvent was then distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified with basic silica gel column (ethyl acetate to ethyl acetate/methanol=5/1) to obtain the title compound as a colorless solid (0.62 g, 66%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=[O:13])[NH:3]1.[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.CCOC(C)=O>[CH2:17]([O:13][C:12](=[O:14])[CH2:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)CC1NC(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CC1c2ccccc2C(=O)N1Cc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(3-Oxo-2,3-dihydro-1H-isoindol-1-yl)-acetic acid (100 mg, 0.52 mmol) was dissolved in 2 mL dry DMF and stirred under N2 at 0° C. NaH (44 mg, 1.1 mmol) was added and stirring continued for 0.5 h. Benzyl bromide (0.13 mL, 1.1 mmol) was added, the mixture was warmed to room temperature and stirred for 3 h. The mixture was diluted with EtOAc. The organic phase was washed with 2×10 mL aq LiCl and 10 mL brine, then dried (MgSO4), filtered and evaporated. The title compound was purified by silica gel chromatography (102 mg, 53%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:18][CH2:19][CH2:20][Cl:21])=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>C1(C)C=CC=CC=1>[Cl:21][CH2:20][CH2:19][O:18][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:2](/[N:1]=[CH:24]/[N:25]([CH3:27])[CH3:26])=[N:3]2)=[CH:8][C:7]=1[O:16][CH3:17]
Reactant: COC(=O)c1cc2cc(OC)c(OCCCl)cc2nc1N
Reactant: COC(OC)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)c1cc2cc(OC)c(OCCCl)cc2nc1/N=C/N(C)C
Temperature: 25 °C
Yield: 64.7 %

Procedure:
A mixture of methyl 2-amino-7-[2-chloroethoxy]-6-methoxy-3-quinolinecarboxylate (5.00 g, 16.09 mmol) and 5.10 g of dimethylformamide dimethylacetal in 75 mL of toluene containing 50 mg of p-toluenesulfonic acid is heated at reflux for 10 minutes then cooled to room temperature. Diethyl ether is added and the solids are collected by filtration to provide 3.81 g of methyl 7-(2-chloroethoxy)-2-{[(IE)-(dimethylamino)methylidene]amino}-6-methoxy-3-quinolinecarboxylate as a pale yellow solid, mp 108-110° C.
Reaction SMILES: B(Br)(Br)Br.C([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:26]=[N:25][CH:24]=[C:23]([Cl:27])[C:20]=2[C:21]#[N:22])=[CH:15][CH:14]=1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:27][C:23]1[CH:24]=[N:25][CH:26]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=2)[C:20]=1[C:21]#[N:22]
Reactant: N#Cc1c(Cl)cncc1-c1ccc(OCc2ccccc2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1c(Cl)cncc1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 66.8 %

Procedure:
A 1 M dichloromethane solution of boron tribromide (13.39 mL, 13.39 mmol) was added to a solution of 3-(4-(benzyloxy)phenyl)-5-chloroisonicotinonitrile (2.147 g, 6.69 mmol) in dichloromethane (20 mL) in a room temperature water bath. The orange suspension was stirred at room temperature for 40 min, poured to a stirred solution of saturated sodium bicarbonate (300 mL), diluted with dichloromethane (150 mL) and the mixture stirred overnight. The two phases were separated. The aqueous phase was extracted with dichloromethane (2×100 mL). The combined extracts were washed with saturated sodium bicarbonate (50 mL), water (2×50 mL), brine (50 mL), dried (MgSO4) and concentrated. The residue was diluted with methanol (10 mL), toluene (10 mL) and hexanes (30 mL), stirred for 1 h and filtered. The solid was rinsed with 1:3 mixture of toluene/hexanes to give 3-chloro-5-(4-hydroxyphenyl)isonicotinonitrile as tan solid (1.03 g, 65% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 8.75 (1H, s), 8.71 (1H, s), 7.42-7.61 (2H, m), 6.87-7.05 (2H, m); MS (ES+) m/z: 231 (M+H); LC retention time: 3.223 min (analytical HPLC Method A).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:28])[NH:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25].[NH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34]>CCCCCC.C(OCC)(=O)C>[OH:34][CH2:33][C:32]([NH:31][C:5]([NH:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:28])([CH3:36])[CH3:35]
Reactant: CC(C)(N)CO
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1NC(=O)NC(C)(C)CO)C(c1ccc(C(C)C)cc1)CO2
Yield: 39 %

Procedure:
Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 138 and 2-amino-2-methyl-1-propanol, the title compound was synthesized in the same manner as in Example 143. Yield: 39%. Melting point: 157-158° C. (hexane-ethyl acetate).
Reaction SMILES: O[C:2](C(F)(F)F)=O.OC(C(F)(F)F)=O.[CH:15]12[O:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][N:17]([C:23]1[N:28]=[C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:26]=[C:25]([C:35]3[CH:40]=[CH:39][C:38]([NH:41][C:42]([NH:44][C:45]4[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=4)=[O:43])=[CH:37][CH:36]=3)[N:24]=1)[CH2:16]2.C=O>C(O)=O>[CH3:2][N:32]1[CH2:33][CH2:34][N:29]([C:27]2[N:28]=[C:23]([N:17]3[CH2:16][CH:15]4[O:22][CH:19]([CH2:20][CH2:21]4)[CH2:18]3)[N:24]=[C:25]([C:35]3[CH:36]=[CH:37][C:38]([NH:41][C:42]([NH:44][C:45]4[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=4)=[O:43])=[CH:39][CH:40]=3)[N:26]=2)[CH2:30][CH2:31]1
Reactant: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCNCC3)nc(N3CC4CCC(C3)O4)n2)cc1
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Solvent: O=CO
Product: CN1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1

Procedure:
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-2TFA (115 mg) in 1:1 98% formic acid and 37% formalin (4 mL) was heated at 75° C. for 90 minutes, then concentrated to dryness and purified on HPLC to give the title compound as its di-TFA salt; MS (ES+) 502.3 (M+H)+
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:39]=[CH:38][C:18]([C:19]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=3)=[O:29])=[CH:24][CH:23]=2)=[O:20])=[CH:17][CH:16]=1.[CH2:40]([O:52][C:53]1[CH:70]=[CH:69][C:56]([C:57]([O:59][C:60]2[CH:68]=[CH:67][C:63]([C:64](O)=[O:65])=[CH:62][CH:61]=2)=[O:58])=[CH:55][CH:54]=1)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CC(=O)OCC>[CH2:40]([O:52][C:53]1[CH:54]=[CH:55][C:56]([C:57]([O:59][C:60]2[CH:68]=[CH:67][C:63]([C:64]([O:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([O:30][C:28](=[O:29])[C:25]4[CH:24]=[CH:23][C:22]([O:21][C:19](=[O:20])[C:18]5[CH:38]=[CH:39][C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])=[CH:16][CH:17]=5)=[CH:27][CH:26]=4)[CH:32]=3)=[O:65])=[CH:62][CH:61]=2)=[O:58])=[CH:69][CH:70]=1)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)O)cc2)cc1
Reactant: O=C(Oc1ccc(C(=O)Oc2cccc(O)c2)cc1)c1ccc(OCCCCCCCCCCCCBr)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)Oc3cccc(OC(=O)c4ccc(OC(=O)c5ccc(OCCCCCCCCCCCCBr)cc5)cc4)c3)cc2)cc1

Procedure:
Synthesized as described for the preparation of compound BC1. Quantities: 25 (0.15 g, 0.25 mmol), 17 (0.11 g, 0.25 mmol), DMAP (0.03 g, 0.25 mmol), DCC (0.10 g, 0.5 mmol). Yield 0.18 g (72%). EA: Found: C, 69.39; H, 7.13. C58H69BrO10 requires C, 69.24; H, 6.91%. 1H NMR: δH (CDCl3; 300 MHz): 0.91 (3 H, t, 3J=6.8 Hz, CH3), 1.19-1.56 (34 H, m, CH2), 1.85 (6 H, m, O—CH2—CH2/Br—CH2—CH2), 3.43 (2 H, t, 3J=6.8 Hz, CH2Br), 4.08 (4 H, t, 3J=6.5 Hz, OCH2), 7.01 (2 H, d, 3J=8.8 Hz, Ar—H), 7.21 (3 H, m, Ar—H), 7.40 (4 H, d, 3J=8.6 Hz, Ar—H), 7.52 (1 H, t, 3J=8.1 Hz, Ar—H), 8.18 (4 H, d, 3J=8.8 Hz, Ar—H), 8.30 (4 H, d, 3J=8.6 Hz, Ar—H). 13C NMR: δC (CDCl3; 75 MHz): 14.5, 23.1, 26.4, 28.6, 29.2, 29.5, 29.75, 29.8, 29.85, 29.9, 29.95, 30.0, 32.3, 33.2, 34.4, 68.8, 114.7, 114.8, 116.2, 119.7, 121.4, 122.5, 127.0, 130.2, 132.2, 132.25, 132.3, 132.8, 151.8, 151.85, 155.9, 164.2, 164.5, 164.7. m/z (MALDI) 1028.00 (100%) and 1030.03 (97%) [M+Na]+, C58H69BrNaO10 requires 1027.40 (100%) and 1029.40 (97%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:26]1[CH:27]=[C:28]([C:32]2([C:35]#[N:36])[CH2:34][CH2:33]2)[CH:29]=[CH:30][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][O:5][C:26]1[CH:27]=[C:28]([C:32]2([C:35]#[N:36])[CH2:33][CH2:34]2)[CH:29]=[CH:30][CH:31]=1
Reactant: N#CC1(c2cccc(O)c2)CC1
Reactant: Cc1cccc(C)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cccc(C)c1COc1cccc(C2(C#N)CC2)c1
Reaction time: 16 h

Procedure:
A solution of 2,6-Dimethylbenzyl alcohol (2.81 g, 20.6 mmol) and diisopropyl azodicarboxylate (DIAD, 4.69 g, 23.2 mmol) in THF (20 ml) was added drop wise to a solution of 1-(3-hydroxyphenyl)cyclopropanecarbonitrile (Step B, 3.2 g, 20.1 mmol) and triphenylphosphine (5.37 g, 20.5 mmol) in THF (50 ml) at 0° C. under argon. The reaction mixture was stirred at the same temperature for 16 hours, diluted with ether and washed with water. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate, 9:1) to give the title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:17]=[CH:16][C:10]([CH2:11][O:12][CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=1.C(N(C(C)C)CC)(C)C.O>C(Cl)Cl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][O:12][CH2:13][CH2:14][O:15][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:16][CH:17]=1
Reactant: OCCOCc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of methanesulfonyl chloride (980 μL, 12.6 mmol) in dry DCM (10 mL) was slowly added to a cooled (0° C.) solution of 2-(4-chloro-benzyloxy)-ethanol (2.14 g, 11.46 mmol) and diisopropyethylamine (2.0 mL, 23 mmol) in dry DCM (10 mL). The reaction mixture was allowed to warm to RT overnight. Water was added and the organic layer was dried (MgSO4) and concentrated. The residue was purified by column chromatography over silica using a gradient of 0-20% diethyl ether/cyclohexane to afford the pure product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN1CCCCC1=O>[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: CN1CCCCC1=O
Product: O=[N+]([O-])c1cc(F)ccc1NC1CCN(Cc2ccccc2)CC1
Yield: 86.9 %

Procedure:
2,5-Difluoro-nitrobenzene (21.5 g), 1-benzyl-4-amino-piperidine (52.3 g) and N-methyl-piperidone (100 ml) were stirred at 100° C. for 3 h. After cooling the mixture was partitioned between water and ethyl acetate and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were extracted 5 times with water, and the solvent was evaporated in vacuo. The target compound was crystallized from methanol to yield 38.7 g of the title compound as orange crystals (mp. 86-87° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=O)[CH:13]=[C:12]3[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:33])=O>>[Cl:33][C:14]1[CH:13]=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)[CH:10]=2)[N:15]=1
Reactant: O=c1cc(-c2ccccc2)c2cc(C(c3ccc(F)cc3)n3ccnc3)ccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc(C(c2ccc3nc(Cl)cc(-c4ccccc4)c3c2)n2ccnc2)cc1
Yield: 99 %

Procedure:
A mixture of (±)-6-[(4-fluorophenyl)(1H-imidazol-1-yl)methyl]4-phenyl-2(1H)-quinolinone (0.0253 mol) in phosphoryl chloride (30 ml) was refluxed for 1 hour. The mixture was evaporated till dryness and the product was used without further purification, yielding 10.4 g (99%) of (±)-2-chloro-6-[(4-fluorophenyl)(1H-imidazol-1-yl)methyl]-4-phenyl-quinoline (interm. 1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].O1CCCC1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl.C(OCC)C.O>[CH3:27][S:28]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc([N+](=O)[O-])c(OS(C)(=O)=O)c1
Temperature: 0 °C

Procedure:
In a 1 liter round-bottomed flask were placed methyl 3-hydroxy-4-nitrobenzoate (21.7 g, 0.11 mole) and tetrahydrofuran (400 ml). To the resulting well-stirred mixture was added triethylamine (13.3 g, 0.132 mole) dropwise at -20° C. The reaction mixture was stirred at -20° C. for 10 minutes. Methanesulfonyl chloride (13.9 g, 0.121 mole) in methylene chloride (approximately 10 ml) was added slowly dropwise at such a rate as to keep the temperature at -20° C. After the addition was complete the reaction mixture was warmed up slowly to 0° C. and stirred at that temperature for 1 hour. The reaction mixture was poured into a mixture of water (500 ml) and ethyl ether (300 ml). The aqueous layer was separated and extracted with ethyl ether (2×300 ml). The combined ether layers were washed with water (2×250 ml), brine (1×250 ml) and dried over magnesium sulfate. The solvent was removed in the rotary evaporator and the resulting crude product triturated with hexane yielding 22.8 g of the expected methyl 3-methylsulfonyloxy-4-nitrobenzoate which was used as such in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:7]1)=[O:5])[CH3:2].[CH:17]1[C:30]2[C:21](=[CH:22][C:23]3[C:28]([C:29]=2[C:31](Cl)=[O:32])=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:20]=[CH:19][CH:18]=1>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]2[CH2:16][CH2:15][N:14]([C:31]([C:29]3[C:30]4[C:21]([CH:22]=[C:23]5[C:28]=3[CH:27]=[CH:26][CH:25]=[CH:24]5)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:32])[CH2:13]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1c2ccccc2cc2ccccc12
Reactant: CCOC(=O)[C@@H]1CCCN(C2CCNC2)C1
Product: CCOC(=O)[C@@H]1CCCN(C2CCN(C(=O)c3c4ccccc4cc4ccccc34)C2)C1
Yield: 100 %

Procedure:
The mixture of ethyl and isopropyl esters (1.23 g) was dissolved in anhydrous ethanol (˜50 mL) and dilute hydrochloric acid (2N, 4 mL) and 10% palladium on carbon (120 mg) was added. The suspension was shaken under hydrogen (48 psi) in a Parr shaker for 16 hr. Only a very small amount reduction occurred so the catalyst was filtered off and the solvent removed under vacuum. The residue was dissolved in glacial acetic acid, platinum (IV) oxide (100 mg) was added and the suspension shaken under 50 psi hydrogen at 60° C. overnight. The solvent was evaporated under vacuum, the residue dissolved in dichloromethane/methanol and the catalyst was filtered off though Celite®. The solvent was again evaporated and the residue partitioned between dilute hydrochloric acid and ethyl acetate (×3). The aqueous layer was made basic with 14% w/v sodium hydroxide and re-extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under vacuum. The product was purified by chromatography on silica gel eluting with 5%-10%-40%-methanol-dichloromethane to give (3R)-1-pyrrolidin-3-yl-piperidine-3-carboxylic acid ethyl ester (36.9 mg). This amine was reacted with anthracene-9-carbonyl chloride (Intermediate 3) by a procedure analogous to that described above for the preparation of Example 1 to give the title compound (70.1mg, 100%).
Reaction SMILES: [N:1]1([CH:6]2[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]2)[CH:5]=[N:4][CH:3]=[N:2]1.[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=2)=[CH:20][C:21]=1[NH2:22])=[O:16].C1([SiH3])C=CC=CC=1>C([Sn](Cl)(Cl)CCCC)CCC>[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=2)=[CH:20][C:21]=1[NH:22][CH:9]1[CH2:10][CH2:11][CH:6]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH2:7][CH2:8]1)=[O:16]
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N
Reactant: O=C1CCC(n2cncn2)CC1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Product: COC(=O)c1sc(C2=CCCCC2)cc1NC1CCC(n2cncn2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.6 %

Procedure:
A mixture of intermediate 1, 4-[1,2,4]triazol-1-yl-cyclohexanone (257 mg, 1.55 mmol) and 3-Amino-5-cyclohex-1-enyl-thiophene-2-carboxylic acid methyl ester (compound x, see Irina) (368 mg, 1.55 mmol) was treated by dibutyltin dichloride (24 mg, 0.078 mmol). The resulting mixture was stirred 5 min at room temperature and phenylsilane (210 μl, 1.70 mmol) was added. The reaction mixture was stirred at room temperature under nitrogen for 40 h. Solvent was removed and the crude was purified by silica gel column chromatography using a gradient from 50% EtOAc:hexanes to 100% EtOAc as eluent to give 5-cyclohex-1-enyl-3-(4-[1,2,4]triazol-1-yl-cyclohexylamino)-thiophene-2-carboxylic acid methyl ester (555 mg, 92%) as a yellow mixture of cis and trans isomers.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[N:20][N:21]([C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=3)[C:22]=2[OH:23])=[C:14]([CH3:33])[CH:13]=1)#[N:11].C(O)=O>>[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[N:20][N:21]([C:24]3[CH:32]=[CH:31][C:27]([C:28]([N:2]([CH3:1])[CH:3]4[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]4)=[O:29])=[CH:26][N:25]=3)[C:22]=2[OH:23])=[C:14]([CH3:33])[CH:13]=1)#[N:11]
Reactant: CNC1CCN(C)CC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Solvent: O=CO
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N(C)C3CCN(C)CC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 284 using N,1-dimethylpiperidin-4-amine and 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid to give a formic acid salt (42 mg, 0.088 mmol, 70.6%) as a white solid. MS: 431 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.71 (d, J=11.6 Hz, 2H) 1.78-1.95 (m, 2H) 2.35 (s, 3H) 2.78 (s, 3H) 2.92-3.83 (m, 7H) 4.34 (br. s., 1H) 7.43 (d, J=8.3 Hz, 1H) 7.48 (s, 1H) 7.76-7.88 (m, 2H) 8.06-8.11 (m, 1H) 8.38 (br. s., 1H) 8.43 (d, J=8.8 Hz, 1H).