Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[N:6]1[CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][C:18]#[N:19].[H][H]>[Ni].CO>[NH2:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][CH2:13][CH2:12][N:6]1[C@@H:5]([CH2:4][CH2:3][CH:2]([OH:1])[CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:10][CH2:9][CH2:8][C:7]1=[O:11]
Reactant: [H][H]
Reactant: N#CCOCCCCN1C(=O)CCC[C@@H]1CCC(O)Cc1ccccc1
Agent: [Ni]
Solvent: CO
Product: NCCOCCCCN1C(=O)CCC[C@@H]1CCC(O)Cc1ccccc1
Reaction time: 19 h
Yield: 65.6 %

Procedure:
Raney nickel (5 mg) was added to a solution of {4-[(R)-2-(3-hydroxy-4-phenyl-butyl)-6-oxo-piperidin-1-yl]-butoxy}-acetonitrile (10.5 mg, 0.029 mmol) in MeOH (1.5 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 19 h. The reaction mixture was filtered through celite, washing with MeOH, and the filtrate was concentrated in vacuo to afford 6.9 mg (65%) of the title compound.
Reaction SMILES: C1(S(O[CH2:11][CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH:16]=[CH:15][CH:14]=2)(=O)=O)C=CC=CC=1.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.[K].C(#N)C>O>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17]([CH:16]=[CH:15][CH:14]=[C:13]2[CH2:12][CH2:11][N:29]2[C:28](=[O:30])[C:27]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]3[C:25]2=[O:35])=[CH:18][CH:19]=1
Reactant: COc1ccc2cccc(CCOS(=O)(=O)c3ccccc3)c2c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CC#N
Product: COc1ccc2cccc(CCN3C(=O)c4ccccc4C3=O)c2c1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
The compound IV (14 g, 0.041 mol) produced as described above and potassium phthalimide (9.3 g, 0.050 mol) were added into a reaction vessel, and acetonitrile (150 ml) was added. The mixture was heated and refluxed for 4 hours. After cooling it to room temperature, 200 ml of water was added, and the mixture was stirred and filtered. The filter cake formed was washed with water and dried, to produce 11.5 g of N-[2-(7-methoxy-1-naphthyl)ethyl]phthalimide (II). The yield was 85%. The melting point was 160-161° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:24])[NH:20][C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:27]([F:30])([F:29])[F:28])[CH:4]=1.Br[CH2:32][CH2:33]Cl.[CH3:35][C@H:36]1[O:41][C@@H:40]([CH3:42])[CH2:39][NH:38][CH2:37]1>>[CH3:42][C@H:40]1[O:41][C@@H:36]([CH3:35])[CH2:37][N:38]([CH2:32][CH2:33][N:20]2[C:19](=[O:24])/[C:18](=[CH:17]/[C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([CH2:7][C:6]3[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:27]([F:30])([F:29])[F:28])[N:9]=[CH:10]4)/[S:22][C:21]2=[O:23])[CH2:39]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)NC4=O)ccc32)c(C(F)(F)F)c1
Reactant: ClCCBr
Product: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)N(CCN5C[C@@H](C)O[C@@H](C)C5)C4=O)ccc32)c(C(F)(F)F)c1

Procedure:
(5Z)-3-{2-[cis-2,6-Dimethylmorpholin-4-yl]ethyl}-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-methoxy-2-(trifluoromethyl)-benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 8), 1-bromo-2-chloroethane and cis-2,6-dimethylmorpholine following General Procedure G.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13](Cl)[N:12]=[C:11]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=3[CH3:23])[N:10]=2)=[CH:4][CH:3]=1.[CH3:24][S-:25].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]=[C:11]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=3[CH3:23])[N:12]=[C:13]([S:25][CH3:24])[N:14]=2)=[CH:4][CH:3]=1
Reactant: C[S-]
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Nc2ccc(Br)cc2)n1
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(Nc2ccc(Br)cc2)nc(-c2cc(Cl)ccc2C)n1
Reaction time: 24 h
Yield: 57 %

Procedure:
A mixture of the title compound of Example 20 (234 mg, 0.57 mmol), sodium thiomethoxide (50 mg, 0.71 mmol), and tetrahydrofuran (5 ml) was stirred for 24 hours. After concentrating under reduced pressure, the residue was dissolved in dichloromethane (25 ml). The solution was washed with water (25 ml) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with dichloromethane-hexane (1:1) to provide the title compound (137 mg, 57% yield). 1H NMR (DMSO-d6) 10.42 (s, 1H), 7.88 (s, 1H), 7.70 (s, 2H), 7.45-7.55 (m, 3H), 7.38 (m, 1H), 2.55 (s, 3H), 2.50 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](N)[C:5]2[CH:11]=[C:10]([CH:12]=[CH:13][C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1.[O:23]1CCOCC1>[OH-].[Na+]>[NH2:1][C:2]1[N:3]=[C:4]([OH:23])[C:5]2[CH:11]=[C:10]([CH:12]=[CH:13][C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: C1COCCO1
Reactant: Nc1nc(N)c2cc(C=Cc3cc(Cl)cc(Cl)c3)cnc2n1
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(O)c2cc(C=Cc3cc(Cl)cc(Cl)c3)cnc2n1
Temperature: 24 °C

Procedure:
A suspension of 0.4 g (1.2 mM) of 2,4-diamino-6-[2-(3,5-dichlorophenyl)ethenyl]pyrido[2,3-d]pyrimidine (prepared as described in Example 3), in 80 ml of 1N sodium hydroxide was heated at reflux for 24 hours. Since not all the starting material had dissolved, 10 ml of 5N sodium hydroxide and 25 ml of dioxane were added, and the mixture was heated at reflux for an additional 24 hours. The reaction mixture was cooled to 24° C., filtered, and the filtrate was diluted with 30 ml of glacial acetic acid. The precipitate which formed was collected by filtration, washed with 50 ml of water, and then with 50 ml of diethyl ether, and dried at 100° C. under vacuum to provide 160 mg of 2-amino-4-hydroxy-6-[2-(3,5-dichlorophenyl)ethenyl]pyrido-[2,3-d]pyrimidine.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]([CH:5]1[CH2:9][O:8][C:7](=[O:10])[NH:6]1)[CH3:4].[F:13][C:14]1[N:19]=[C:18](F)[CH:17]=[CH:16][N:15]=1.[H-].[Na+]>CN(C=O)C>[F:13][C:14]1[N:19]=[C:18]([N:6]2[CH:5]([CH:3]([CH3:4])[C:2]([F:1])([F:11])[F:12])[CH2:9][O:8][C:7]2=[O:10])[CH:17]=[CH:16][N:15]=1
Reactant: Fc1ccnc(F)n1
Reactant: CC(C1COC(=O)N1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C1COC(=O)N1c1ccnc(F)n1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.3 %

Procedure:
A solution of 4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one (270 mg, 1.474 mmol) and 2,4-difluoropyrimidine (171 mg, 1.474 mmol, 1 eq) in DMF (4 mL) was treated with NaH (60%, 88 mg, 2.212 mmol, 1.5 eq), then the resulting mixture was stirred at 0° C. for 10 minutes, then room temperature for 1 h. The reaction mixture was quenched with sat. Na2SO4 (15 mL) diluted with EtOAc (20 mL), washed and 4% aqueous NaCl (3×20 mL), dried over Na2SO4, concentrated in vacuo. Flash column chromatography (silica, 120 g, 15 m) 5% EtOAc/DCM to provide 3-(2-fluoropyrimidin-4-yl)-4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one (100 mg, white solid). 1H NMR (400 MHz, CDCl3) δ 8.55 (dd, J=5.8, 2.1 Hz, 1H), 8.20 (dd, J=5.8, 3.7 Hz, 1H), 5.04-4.84 (m, 1H), 4.68 (dd, J=9.5, 2.6 Hz, 1H), 4.54 (t, J=9.2 Hz, 1H), 3.34 (ddddd, J=13.3, 9.3, 7.1, 3.9, 1.6 Hz, 1H), 1.29 (d, J=7.3 Hz, 3H). MS 279.0631 m/z.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[N:18][C:19]([CH3:23])=[C:20](Br)[CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[N:18][C:19]([CH3:23])=[C:20]([C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=5)[CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccccc1
Temperature: 80 °C

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-bromo-6-methylpyridin-3-yl)cyclopropanecarboxamide (38 mg, 0.10 mmol) was dissolved in 1 mL of N,N-dimethylformamide (DMF) containing 0.2 mL of a 2M aqueous solution of potassium carbonate and 12 mg of Fibre-Cat 1007. The reaction mixture was then heated to 80° C. for 16 hours. The resulting material was cooled to room temperature, filtered, and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield the pure product. ESI-MS m/z calc. 372.2, found 373.2 (M+1)+. Retention time 1.80 minutes.
Reaction SMILES: CS(OC[C@H]1OC1)(=O)=O.[CH3:10][O:11][C:12]1[C:21]2[N:20]=[C:19]([NH2:22])[N:18]3[CH2:23][CH2:24][N:25]=[C:17]3[C:16]=2[CH:15]=[CH:14][C:13]=1[O:26][CH2:27][C@H:28]1[CH2:30][O:29]1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.[CH3:37][C:38]1[C:43]([C:44](O)=[O:45])=[CH:42][CH:41]=[CH:40][N:39]=1>CO.C(Cl)Cl.CO>[OH:29][C@@H:28]([CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[CH2:27][O:26][C:13]1[CH:14]=[CH:15][C:16]2[C:17]3[N:18]([CH2:23][CH2:24][N:25]=3)[C:19]([NH:22][C:44]([C:43]3[C:38]([CH3:37])=[N:39][CH:40]=[CH:41][CH:42]=3)=[O:45])=[N:20][C:21]=2[C:12]=1[O:11][CH3:10]
Reactant: COc1c(OC[C@H]2CO2)ccc2c1N=C(N)N1CCN=C21
Reactant: C1COCCN1
Reactant: Cc1ncccc1C(=O)O
Agent: CS(=O)(=O)OC[C@@H]1CO1
Solvent: CO
Solvent: ClCCl
Product: COc1c(OC[C@@H](O)CN2CCOCC2)ccc2c1N=C(NC(=O)c1cccnc1C)N1CCN=C21

Procedure:
Prepared using (S)-glycidyl methanesulfonate (Intermediate H, Step 1) in place of (R)-glycidyl methanesulfonate (Intermediate F, Step 1), and morpholine in place of piperidine in Step 1, and 2-methyl-3-pyridinecarboxylic acid in place of nicotinic acid in Step 2 (0.059 g, 56%): TLC (9:1 CH2Cl2/MeOH+1% NH4OH in MeOH)Rf 0.44; HPLC ret. time 0.81 min.; 1H NMR (DMSO-d6+1 drop TFA-d) δ 2.99 (s, 3H), 3.09-3.40 (m, 4H), 3.48 (br d, J=12.1 Hz, 2H), 3.63-3.83 (m, 2H), 3.89-4.01 (m, 2H), 4.02 (s, 3H), 4.18-4.29 (m, 4H), 4.38-4.46 (m, 1H), 4.46-4.55 (m, 2H), 7.50 (d, J=9.0 Hz, 1H), 7.96 (dd, J=6.2, 7.5 Hz, 1H), 8.05 (d, J=9.0 Hz, 1H), 8.91 (d, J=5.5 Hz, 1H), 9.06 (br d, J=8.3 Hz, 1H); mass spectrum m/z 495 ((M+1)+, 2.3%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[O:10][C@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1)([O-])=O.CCO>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[O:10][C@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ccncc2[N+](=O)[O-])C1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ccncc2N)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.3 %

Procedure:
Pd on C, (10%, wet, Degussa) (1 g, 0.9397 mmol) was added to a stirred solution of tert-butyl (3S)-3-[(3-nitro-4-pyridyl)oxy]piperidine-1-carboxylate (2.65 g, 8.196 mmol) in EtOAc (30 mL)/EtOH (15 mL). The reaction was placed under an atmosphere of hydrogen and stirred at ambient temperature for 16 hours. The catalyst was removed by filtration through a pad of celite and the filtrate concentrated in vacuo to give the sub-title compound as an off-white solid (2.46 g, >100% Yield). MS (2ES+) 587.3.
Reaction SMILES: N[C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[N:6]=1.[Na+].[Br-:21].N(OC(C)(C)C)=O>C(#N)C.O>[Br:21][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[N:6]=1
Reactant: [Br-]
Reactant: Nc1nc(CON2C(=O)c3ccccc3C2=O)cs1
Agent: CC(C)(C)ON=O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1OCc1csc(Br)n1
Temperature: 65 °C
Reaction time: 2 h
Yield: 29.5 %

Procedure:
To a suspension of 2-[(2-amino-1,3-thiazol-4-yl)methoxy]-1H-isoindole-1,3(2H)-dione (4.13 g, 15 mmol), NaBr (3.10 g, 30 mmol) and CuBr (2.15 g, 15 mmol) in acetonitrile (150 mL) at 40° C. under nitrogen atmosphere was added tert-butyl nitrite (2.32 mL, 19.5 mmol) dropwise over 30-40 min. After the addition was complete, heating was maintained towards an internal temp of 60-70° C., and the suspension was stirred at this temperature for 2 h. After cooling down, the mixture was diluted with water, and extracted with ethyl acetate. The combined organic layers (200 mL) were washed with aq HCl (1M, 50 mL), then with brine (50 mL) and dried (MgSO4). After concentration on the rotary evaporator, the residue was purified on silica gel to afford 2-[(2-bromo-1,3-thiazol-4-yl)methoxy]-1H-isoindole-1,3(2H)-dione [1.50 g, yield 28%; HPLC/MS: m/z=339 (M+H); log P(HCOOH)=2.39].
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:35][C:36]3[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[C:39]([NH2:46])=[C:38]([Cl:47])[CH:37]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@H:28]4[C:32]([OH:34])=[O:33])[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:48]=[CH:49][CH:50]=[CH:51][C:4]=2[NH:3]1.O[CH2:53][C:54]([N:56]([CH3:58])[CH3:57])=[O:55]>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:35][C:36]3[CH:41]=[C:40]([C:42]([F:43])([F:45])[F:44])[C:39]([NH2:46])=[C:38]([Cl:47])[CH:37]=3)[C:19]([N:21]3[CH2:22][CH2:23][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@H:28]4[C:32]([O:34][CH2:53][C:54](=[O:55])[N:56]([CH3:58])[CH3:57])=[O:33])[CH2:25][CH2:26]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:48]=[CH:49][CH:50]=[CH:51][C:4]=2[NH:3]1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC[C@H]3C(=O)O)CC2)cc1C(F)(F)F
Reactant: CN(C)C(=O)CO
Product: CN(C)C(=O)COC(=O)[C@@H]1CCCN1C1CCN(C(=O)[C@@H](Cc2cc(Cl)c(N)c(C(F)(F)F)c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CC1

Procedure:
Prepared analogously to Example 9.2 from 70 mg (0.10 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-((S)-2-carboxy-pyrrolidin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 11 mg (0.11 mmol) 2-hydroxy-N,N-dimethyl-acetamide.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11].C(N(CC)CC)C.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>ClCCl>[CH:19]1([C:22]([O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[O:23])[CH2:21][CH2:20]1
Reactant: COCCOCCOCCO
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOCCOCCOC(=O)C1CC1
Temperature: 0 °C

Procedure:
Triethylene glycol monomethyl ether (1.1 eq, 5.26 mmol, 0.84 ml) and triethylamine (1.1 eq, 5.26 mmol, 0.73 ml) were taken in a 10 ml round bottom flask and dichloromethane (3 ml) was added. This mixture was cooled to 0° C. and then cyclopropanecarbonyl chloride (4.78 mmol, 0.5 g, 0.43 ml) was added in a dropwise fashion maintaining the temperature at 0° C. with constant stirring.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH:23]([CH3:25])[CH3:24])[CH:17]=1)[C:10]([CH3:27])([CH3:26])[CH2:9]2)=[O:5])[CH3:2].[O-:28][C:29]#[N:30].[Na+]>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH:23]([CH3:24])[CH3:25])[C:29]([NH2:30])=[O:28])[CH:17]=1)[C:10]([CH3:26])([CH3:27])[CH2:9]2)=[O:5])[CH3:2]
Reactant: N#C[O-]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)C)c1)N2
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N(C(N)=O)C(C)C)c1)N2
Temperature: 40 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
To a solution of 2-(3-isopropylamino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (310 mg, 0.85 mmol) in acetic acid (2 mL) and water (2 mL) was added a solution of sodium cyanate (110 mg, 1.7 mmol) in water (2 mL) dropwise at 40° C. The reaction mixture was stirred at 40° C. for 4 h. Then the reaction mixture was extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[3-(1-isopropyl-ureido)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (347 mg, 100%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C24H31N3O3 (M+H)+: 410.53, observed: 410.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.Cl.[OH:20][CH:21]1[CH2:24][NH:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:8][C:6]1[N:7]=[C:2]([N:23]2[CH2:24][CH:21]([OH:20])[CH2:22]2)[N:3]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:5]=1
Reactant: OC1CNC1
Reactant: COc1ccc(CNc2nc(Cl)nc(Cl)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(CNc2nc(Cl)nc(N3CC(O)C3)n2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 93 %

Procedure:
A 1.47 g (5.16 mmol) portion of 2,4-dichloro-6-(4-methoxybenzylamino)-1,3,5-triazine was suspended in 100 ml of ethanol, mixed with 568 mg (5.18 mmol) of 3-hydroxyazetidine hydrochloride and 1.43 g of potassium carbonate and stirred at room temperature for 7 hours. After evaporation of the solvent under a reduced pressure, water was added to the residue and the resulting precipitate was collected by filtration to obtain 1.54 g (93%) of the title compound as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[NH:23][N:22]=C(C2C=CC(OC3C=CC=CC=3)=CC=2)[C:20]=1[C:37]#[N:38]>>[NH2:18][C:19]1[NH:23][N:22]=[C:13]([C:12]2[CH:16]=[CH:17][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[C:20]=1[C:37]#[N:38]
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Product: N#Cc1c(-c2ccc(OCc3ccccc3)cc2)n[nH]c1N

Procedure:
The desired product was prepared from 4-(benzyloxy)benzoic acid according to the procedures similar to those (step 1 to 3) for 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile under appropriate conditions recognized by one of ordinary skill in the art. 1H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 7.72 (d, J=8.8 Hz, 2H), 7.50-7.44 (m, 2H), 7.44-7.37 (m, 2H), 7.36-7.32 (m, 1H), 7.11 (d, J=7.2 Hz, 2H), 6.39 (br s, 2H) and 5.16 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]([N:20]=C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl>C(OCC)C>[ClH:1].[Cl:1][C:2]1[C:3]([CH:12]([NH2:20])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: FC(F)(F)c1cnc(C(Cc2ccccc2)N=C(c2ccccc2)c2ccccc2)c(Cl)c1
Agent: Cl
Solvent: CCOCC
Product: NC(Cc1ccccc1)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product from stage b) (1.29 g) in diethyl ether (5 ml) was added 1 M hydrochloric acid (10 ml) at room temperature and the solution was stirred at room temperature for 2 hours. The mixture was filtered to give a solid, which was washed with water (15 ml) then ether (15 ml). Drying in vacuo gave the title product. Water was removed from the aqueous phase by azeotropic distillation with toluene (×3), to give further quantities of the title product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(Cl)nc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(N2CCCNCC2)cn1

Procedure:
A mixture of 1-(6-chloro-3-pyridyl)-4-tert-butoxycarbonyl homopiperazine (1.7 g, 5.5 mmol), trifluoro acetic acid (4.5 ml, 55 mmol) and dichloromethane at room temperature for 1 h. The mixture was evaporated. Chromatography on silica gel with a mixture of petroleum:ethyl acetate (1:1) gave the title compound as free base. The corresponding salt was obtained by addition of a diethyl ether and methanol mixture (9:1) saturated with fumaric acid. Mp 165-167° C. Yield 0.72 g, 40%.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:17][Mg]Cl.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1.O>[CH3:17][C:5]1[C:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:8][C:7]=2[CH:15]=[CH:16][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2sc3ccccc3c2c1
Reactant: C[Mg]Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1c([N+](=O)[O-])ccc2sc3ccccc3c12
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a stirred suspension of 2-nitrodibenzothiophene (2.20 g, 9.61 mmol) in dry THF (100 ml) at −15° C. was slowly added methyl magnesium chloride (3 M solution in THF; 9.6 ml, 29 mmol). After stirring at this temperature for 5.5 h, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (6.98 g, 30.75 mmol) was added portion wise, keeping the temperature below −10° C. The mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with water and extracted into DCM. The organic layers were further washed with water, dried and purified by chromatography (eluent—50% DCM /isohexane) to give the title compound as a yellow solid. NMR: 8.52 (m, 1H), 8.12 (m, 2H), 7.94 (d, 1H), 7.61 (m, 2H), 2.92 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.[NH:20]=[N+:21]=[N-:22]>C1C=CC=CC=1>[CH:8]1([N:7]2[C:5]([CH2:4][CH2:3][CH2:2][Cl:1])=[N:22][N:21]=[N:20]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: [N-]=[N+]=N
Reactant: O=C(CCCCl)NC1CCCCC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: ClCCCc1nnnn1C1CCCCC1
Reaction time: 2 h

Procedure:
Into 200 ml of dried benzene, 30.6 g of N-γ-chlorobutyrylcyclohexylamine was added. While the inside temperature is kept below 20° C. by ice-cooling the outside of the reaction vessel, 30 g of PCl5 was added under stirring condition. After completion of the addition, the stirring is continued for 2 hours at a room temperature, then the reaction mixture is concentrated to a half volume thereof by using an evaporator with a bath temperature of below 50° C. To the concentrated reaction mixture was added dropwise 140 ml of benzene containing 10% of HN3 under stirring condition for 90 minutes while keeping the inside temperature below 15° C. After the addition operation, the reaction mixture is allowed to stand overnight at room temperature. Then the reaction mixture is refluxed for 3 hours with stirring and is concentrated. The thus obtained concentrate is extracted with 200 ml of chloroform. The chloroform layer is washed with 5% NaHCO3 aqueous solution and with water and dried with Na2SO4. After removal of the drying agent, the mother liquor is concentrated and the residue thus obtained is recrystallized from water-containing isopropanol to obtain 28 g of 1-cyclohexyl-5-γ-chloropropyltetrazole in the form of colorless needle like crystals. Melting point: 82°-85° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([O:10][CH3:11])[CH:3]=1.[N:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.O1CCN(C2C=CC(O)=CC=2)CC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:12]2[CH:17]=[CH:16][C:15](=[O:18])[CH:14]=[CH:13]2)=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: Oc1ccncc1
Reactant: COc1cc(Cl)ccc1CO
Agent: Oc1ccc(N2CCOCC2)cc1
Product: COc1cc(Cl)ccc1Cn1ccc(=O)cc1

Procedure:
The title compound was prepared by substituting (4-chloro-2-methoxy-phenyl)-methanol and pyridin-4-ol for Example 204A and 4-morpholinophenol, respectively, in Example 297A. MS (ESI) m/e 250 (M+H)+.