Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.[CH:31]1([NH2:34])[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:31]1([NH:34][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([N:16]3[CH2:17][CH2:18][N:13]([CH2:12][C:9]4[CH:10]=[N:11][C:5]5[N:4]6[CH2:28][CH2:29][CH2:30][C@H:3]6[C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)[CH2:14][CH2:15]3)=[N:20][CH:21]=2)[CH2:33][CH2:32]1
Reactant: NC1CC1
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
(S)-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinic acid (87 mg, 0.213 mmol) and cyclopropanamine (18.24 mg, 0.319 mmol) were suspended in DMF (1 ml) and treated with DIPEA (0.186 ml, 1.065 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (162 mg, 0.426 mmol). The reaction mixture was stirred at room temperature for 3 h and purified using HPLC (10-95% acetonitrile in water, NH4HCO3 buffered) to afford (S)-N-cyclopropyl-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinamide (70.3 mg, 0.157 mmol, 73.7% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.49-0.56 (m, 2H) 0.62-0.70 (m, 2H) 1.82-2.02 (m, 3H) 2.11-2.22 (m, 1H) 2.40 (t, J=4.93 Hz, 4H) 2.78 (tq, J=7.34, 3.86 Hz, 1H) 3.34 (br. s., 2H) 3.36-3.44 (m, 1H) 3.49-3.64 (m, 5H) 3.94-4.03 (m, 1H) 6.81 (d, J=8.59 Hz, 1H) 6.98 (d, J=1.77 Hz, 1H) 7.61 (d, J=1.77 Hz, 1H) 7.90 (dd, J=9.09, 2.53 Hz, 1H) 8.20 (d, J=4.04 Hz, 1H) 8.54 (d, J=1.77 Hz, 1H) 10.44 (s, 1H); [M+H] calc'd for C24H29N7O2, 448; found, 448.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:15]([Cu])#[N:16].CO.ClCCl>CN(C=O)C>[C:15]([C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6])#[N:16]
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: N#C[Cu]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(C(=O)O)cc(C(F)(F)F)c1
Temperature: 150 °C
Reaction time: 15.5 h

Procedure:
In a 3-neck 100 mL round-bottomed flask, 3-bromo-5-(trifluoromethyl)benzoic acid (10.0, 1.0 eq.) was dissolved in DMF (100 mL, 10 Vol). CuCN was added at RT and the reaction was stirred at 150° C. for 15-16 hr. Reaction completion was monitored on TLC using MeOH:dichloromethane (1:9) mobile phase. Reaction mixture was quenched into the ice-water slurry (1000 mL) and filtered over celite. Compound was extracted in the ethyl acetate (250 mL×3). Organic layer was washed with water (150 mL) followed by drying using anhydrous sodium sulphate. Organic layer was concentrated under reduced pressure. Then again the crude was dissolved in ethyl acetate and extracted with (250 mL×3). Combined aqueous layer was again acidified with dil HCl (350 mL) to get pH 3. Then aqueous layer was extracted with ethyl acetate (250 mL×3). This combined organic layer was washed with water (150 mL) followed by drying using anhydrous sodium sulphate. Organic layer was concentrated under reduced pressure to afford 6.0 g of crude compound, Yield (75.4%). This crude material was directly used for next step without purification; Mass: (ES−) 214.14 (M−1).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH2:12]C=O)[CH2:8][CH2:9][C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([CH:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:23][CH3:24])=[O:22].[C:45]1(C)C=CC=CC=1>>[C:10]([CH2:9][CH2:8][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:12][CH:45]=[CH:25][C:21]([O:23][CH3:24])=[O:22])#[N:11]
Reactant: N#CCCC(CC=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1
Product: COC(=O)C=CCC(CCC#N)(c1ccccc1)c1ccccc1
Yield: 69 %

Procedure:
A mixture of 4,4-diphenyl-5-formylpentanonitrile (1.87 g, 7.1 mmol) and (carbomethoxymethylene)triphenyl phosphorane (2.85 g. 8.5 mmol) in toluene (50 mL) was heated under reflux for three days. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography to give the desired product as a colorless oil (1.56 g 69%): MS showed (M+H)+ c 320: 1H-NMR (CDCl3, δ): 1.97-2.0(m. 2H), 2.44-2.51 (m. 2H), 3.00 (dd, 2H, J=1.4, 7.4 Hz), 3.68 (s, 3H), 5.82 (dt, 1H, J=l.4. 15.6 Hz), 6.52 (dt, 1H. J=7.3, 15.6 Hz), 7.10-7.55 (m, 4H), 7.21-7.35 (m, 6H); Anal. Calcd for C,,H21NO2 : C. 78.97; H. 6.63; N, 4.39; Found: C, 78.68; H, 6.85; N. 4.27.
Reaction SMILES: [C:1]([C:9]1[CH:26]=[CH:25][C:12]([C:13]([N:15]2[CH2:21][CH2:20][C:19]3[CH:22]=[CH:23][O:24][C:18]=3[CH2:17][CH2:16]2)=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][NH:28][CH3:29].[CH2:30]=O>C(O)(=O)C>[CH3:27][N:28]([CH2:30][C:23]1[O:24][C:18]2[CH2:17][CH2:16][N:15]([C:13](=[O:14])[C:12]3[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:26][CH:25]=3)[CH2:21][CH2:20][C:19]=2[CH:22]=1)[CH3:29]
Reactant: CNC
Reactant: O=C(c1ccccc1)c1ccc(C(=O)N2CCc3ccoc3CC2)cc1
Reactant: C=O
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(C(=O)c1ccc(C(=O)c3ccccc3)cc1)CC2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.179 g (0.518 mmol) of 6-(4-benzoylbenzoyl)-5,6,7,8-tetrahydro-4H-furo[2,3-d]azepine in 20 ml of acetic acid, 56 mg (0.62 mmol) of 50% aqueous dimethylamine and 50 mg (0.62 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 30 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: CN(C)C=O.ClC1C=CC=C([N+]([O-])=O)C=1S[C:17]1[N:18]([CH2:25][C@:26]([OH:51])([CH3:50])[CH2:27][N:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][CH:38]=[CH:39][C:40]3[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=3)=[O:35])[CH2:30][CH2:29]2)[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[N:21]=1.CC(C)([O-])C.[Na+].O>C(OCC)(=O)C>[CH3:50][C@@:26]1([CH2:27][N:28]2[CH2:29][CH2:30][N:31]([C:34]([O:36][CH2:37][CH:38]=[CH:39][C:40]3[CH:45]=[CH:44][C:43]([C:46]([F:47])([F:49])[F:48])=[CH:42][CH:41]=3)=[O:35])[CH2:32][CH2:33]2)[O:51][C:17]2=[N:21][C:20]([N+:22]([O-:24])=[O:23])=[CH:19][N:18]2[CH2:25]1
Reactant: C[C@](O)(CN1CCN(C(=O)OCC=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Sc1c(Cl)cccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]1(CN2CCN(C(=O)OCC=Cc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Reaction time: 0.5 h
Yield: 49.7 %

Procedure:
To N,N-dimethylformamide (0.9 ml) solution of 3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-{3-[2-(2-chloro-6-nitrophenylthio)-4-nitroimidazol-1-yl]-2-hydroxy-2-methylpropyl}piperazin-1-carboxylate (89 mg) was added sodium tert-butoxide (16 mg) at 0° C., and stirred at the same temperature for 30 minutes. To the reaction mixture was added water and ethyl acetate, the organic layer was taken by separation. The ethyl acetate layer was washed with an aqueous solution of 5% potassium carbonate, water, and an aqueous solution being saturated with sodium chloride, then dried over anhydrous sodium sulfate. The residue obtained by removal of the solvent by distillation was purified by use of a thin layer chromatography (eluent: dichloromethane/ethyl acetate/methanol=15/15/1), there was obtained 3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-carboxylate (32 mg, yield: 51%) as pale yellow amorphous product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[CH:4][CH:3]=1.Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:23]1([CH2:22][CH2:21][O:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:16](=[O:17])[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]3=[O:18])=[CH:6][CH:7]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: ClCCN1CCCCC1
Reactant: O=C1c2ccccc2C(=O)N1c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1c1ccc(OCCN2CCCCC2)cc1
Temperature: 85 °C
Reaction time: 72 h
Yield: 25.7 %

Procedure:
To a 50 mL vial which contained a solution of 2-(4-Hydroxy-phenyl)-isoindole-1,3-dione (239 mg, 1 mmol) and 1-(2-chloroethyl) piperidine hydrochloride (390 mg, 2 mmol) in DMF (15 mL) was added K2CO3 (600 mg, 4.5 mmol) at rt. The reaction mixture was heated to 85° C. and stirred at 85° C. for 72 h. After cooled to rt, the reaction mixture was poured into 50 mL ice-water mixture and then was extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (3×30 mL), brine (30 mL) and dried over Na2SO4. After concentrated in vacuo, the residue was purified by a column chromatography on silica gel to yield the title product, (90 mg, 28%); LCMS; 97%, ESI+; Calcd: 350.4; Found m/z: 351.6 (M+1); 1HNMR (400 MHz, CDCl3) δ 1.40-1.68 (m, 6H), 2.52 (br, 4H), 2.80 (t, J=6.0 Hz, 2H), 4.15 (t, J=6.0 Hz, 2H), 7.02 (d, J=9.2 Hz, 2H), 7.32 (d, J=9.2 Hz, 2H), 7.77-7.79 (m, 2H), 7.84-7.96 (M, 2H).
Reaction SMILES: CS(OCC[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@@H:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[NH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.[CH2:42](N(CC)CC)[CH3:43]>>[F:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C@H:20]1[C:19]2[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=2[C:17]2[N:16]=[C:15]([NH:14][C:11]3[CH:12]=[CH:13][CH:8]=[C:9]([CH2:42][CH2:43][N:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)[CH:10]=3)[N:24]=[CH:23][C:22]=2[CH2:21]1
Reactant: C1CNCCN1
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccccc2F)C3)cc1
Product: Fc1ccccc1[C@@H]1Cc2cnc(Nc3cccc(CCN4CCNCC4)c3)nc2-c2ccccc21

Procedure:
This was synthesized by using (R)-4-(6-(2-fluorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, piperazine and triethylamine as described in general procedure 6 to afford the desired product. Yellow solid (46%). M.p.=165-167° C. 1H NMR 400 MHz (DMSO-d6) δ 9.82 (s, 1H), 9.71 (s, 1H), 7.83 (s, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.61 (t, J=7.2 Hz, 1H), 7.48 (t, J=7.6 Hz, 1H), 7.33-7.22 (m, 3H), 7.08-7.02 (m, 2H), 7.91 (d, J=7.6 Hz, 1H), 6.11 (t, J=7.6 Hz, 1H), 4.68 (t, J=6.8 Hz, 1H), 3.79 (br, 2H), 3.56-3.38 (m, 7H), 3.19-3.09 (m, 4H), 2.93 (t, J=16.4 Hz, 2H). LCMS m/e 480 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:29])[O:11][C:12]2[C:17]([C:18]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[CH:16][CH:15]=[C:14]([O:27][CH3:28])[CH:13]=2.[Br:30][CH2:31][CH2:32]Br.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl.O>CC(C)=O>[Br:30][CH2:31][CH2:32][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([O:27][CH3:28])=[CH:15][CH:16]=3)[O:11][C:10](=[O:29])[C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:21][CH:22]=1
Reactant: BrCCBr
Reactant: COc1ccc2c(Cc3ccc(O)cc3)c(-c3ccc(Cl)cc3Cl)c(=O)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(Cc3ccc(OCCBr)cc3)c(-c3ccc(Cl)cc3Cl)c(=O)oc2c1
Reaction time: 48 h
Yield: 60.5 %

Procedure:
A mixture of 3-(2,4-dichlorophenyl)-4-(4-hydroxybenzyl)-7-methoxy-chromen-2-one (6.4 g, 15.0 mmol), 1,2-dibromoethane (12.9 mL, 149.8 mmol) and K2CO3 (4.14 g, 30 mmol) in acetone (65 mL) was stirred at reflux temperature for 20.5 h. An additional portion of K2CO3 (241.6 mg, 1.75 mmol) and 1,2-dibromoethane (3.2 mL, 37.5 mmol) was added at that time and once more 7.5 h later. Heating was continued for an additional 20 h, for a total reaction time of 48 h. The resultant mixture was cooled to room temperature and poured into CH2Cl2/H2O. The layers were separated, and the aqueous phase was extracted with CH2Cl2 (2×). The combined organic layers were washed with brine (2×) and dried (MgSO4), and the solvent was removed in vacuo. The resultant residue was purified using flash chromatography (300 g silica gel, 4.5:1:1→4:1:1→3:1:1 hexanes:CH2Cl2:AcOEt) to provide the title compound as a white solid (4.851 g, 61%) in addition to recovered starting material (2.054 g, 32%). 1H NMR (300 MHz, CDCl3) δ 7.50 (d, J=2.0 Hz, 1H), 7.44 (d, J=9.0 Hz, 1H), 7.26 (dd, J=2.0, 8.0 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 6.98–6.91 (m, 2H), 6.88 (d, J=2.0 Hz, 1H), 6.79–6.74 (m, 3H), 4.23 (t, J=6.5 Hz, 2H), 4.04 (d, J=15.5 Hz, 1H), 3.87 (s, 3H), 3.78 (d, J=15.5 Hz, 1H), 3.61 (t, J=6.5 Hz, 2H); MS (ESI) m/z 532.7 (M+H)+; HPLC tR 8.38 min.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[N:10]=[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)=[N:13][N:12]2[CH:31]=1.[OH-].[Na+].C(N(CC)CC)C.Cl[C:42]([O:44][CH3:45])=[O:43]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:26][O:25][C:23]1[CH:24]=[C:19]([CH:20]=[C:21]([O:29][CH3:30])[C:22]=1[O:27][CH3:28])[CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]2[N:12]([CH:31]=[C:9]([NH:8][C:42](=[O:43])[O:44][CH3:45])[N:10]=2)[N:13]=1
Reactant: COc1cc(COc2ccc3nc(N)cn3n2)cc(OC)c1OC
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1cn2nc(OCc3cc(OC)c(OC)c(OC)c3)ccc2n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 22.9 %

Procedure:
The product of stage (a) (1.0 g, 3.03 mmol) was suspended in dichloromethane and shaken with dilute sodium hydroxide solution. The organic phase was dried (Na2SO4) and evaporated to give a brown oil which was dissolved in dichloromethane and treated, with stirring, with triethylamine (0.42 ml, 3.03 mmol), methyl chloroformate (0.23 ml, 3.03 mmol) and 4-dimethylaminopyridine (18 mg, 0.3 mmol). The mixture was stirred at ambient temperature for 17 h then heated under reflux for 2 h and evaporated in vacuo. The resulting solid was partioned between chloroform and water, the organic phase was separated, dried (Na2SO4) and evaporated to give a solid which was chromatographed on SiO2 eluting with 2% methanol-chloroform. The product was recrystallised from DMF-H2O to give the title compound (0.27 g), mp. 210°-212°, NMR identical to the product of Example 1.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][O:4][CH2:5][C:6](O)=[O:7].S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl>[F:1][C:2]([F:10])([F:9])[CH2:3][O:4][CH2:5][C:6]([Cl:13])=[O:7]
Reactant: O=C(O)COCC(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(Cl)COCC(F)(F)F
Yield: 54.6 %

Procedure:
To a 3-neck 500 ml round-bottom flask equipped with a magnetic stirrer, reflux condenser and addition funnel was added (2,2,2-trifluoroethoxy)acetic acid (30.90 g, 0.196 moles) and 250 ml of chloroform under nitrogen. Thionyl chloride (30.20 g, 0.250 moles) was added dropwise and the solution refluxed for 2 hours. The mixture was then concentrated by distillation of the chloroform and excess thionyl chloride. The remaining yellow oil was distilled in vacuo to give 18.9 g of the product as a colorless oil, bp 40°-48° C./20 mm.
Reaction SMILES: C(ON=[C:6]([C:15]1[CH:16]=[C:17]([N:21]2[C:25]3[CH:26]=[CH:27][C:28]([C:30](=[O:32])[CH3:31])=[CH:29][C:24]=3[N:23]=[CH:22]2)[CH:18]=[CH:19][CH:20]=1)[O:7]C1CCN(C)CC1)(C)C.C[O:34][C:35](OC)(C)[CH3:36].[CH3:40][N:41]([CH:43]=O)[CH3:42]>>[CH3:42][N:41]([CH3:40])[CH:43]=[CH:31][C:30]([C:28]1[CH:27]=[CH:26][C:25]2[N:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([C:6]([O:34][CH2:35][CH3:36])=[O:7])[CH:16]=3)[CH:22]=[N:23][C:24]=2[CH:29]=1)=[O:32]
Reactant: COC(C)(C)OC
Reactant: CN(C)C=O
Reactant: CC(=O)c1ccc2c(c1)ncn2-c1cccc(C(=NOC(C)C)OC2CCN(C)CC2)c1
Product: CCOC(=O)c1cccc(-n2cnc3cc(C(=O)C=CN(C)C)ccc32)c1
Temperature: 120 °C
Yield: 62 %

Procedure:
To a suspension of 5-acetyl-1-(3-(methoxycarbonyl)phenyl)benzimidazole (prepared in analogy with Example 26) (0.6 g, 2.04 mmol) in anhydrous DMF (5 ml) was added dimethylformaldehyde dimethylacetal (0.43 ml, 3.24 mmol) and the mixture was heated to 120° C. under a stream of nitrogen overnight. The cooled mixture was poured into ice-water (25 ml) and the precipitate was filtered off and purified by column-chromatography on silica gel using a mixture of ethyl acetate and methanol (9:1 v/v) as the eluent to yield 5-(3-dimethylaminopropenoyl)-1-(3-(ethoxycarbonyl)phenyl)-benzimidazole (0.44 g, 62%).
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].N1C2C=CC=C[C:29]=2N=N1.C[Mg]Br>C(O)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([CH:4]([C:3]2[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[C:9]([CH3:10])[C:2]=2[CH3:1])[CH3:29])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(C=O)c(C)c1C
Agent: C[Mg]Br
Solvent: CCO
Product: COc1ccc(C(C)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2,3-dimethyl 4-methoxy benzaldehyde (1 g, 3.05 mmol), 1 equivalent of piperazine-1-carboxylic acid tert-butyl ester (0.57 g, 3.05 mmol), 1 equivalent of benzotriazole in ethanol was stirred at room temperature for 30 minutes. The solvent was removed and the reaction was dried under vacuum. The reaction mixture was then dissolved in anhydrous THF(20 ml) under N2 at −78° C. Then 3 equivalents (3.05 ml) of methyl magnesium bromide (3M in THF) was added to the solution slowly. The reaction mixture was kept at this temperature for 2 hours and warmed up to room temperature for overnight. The mixture was washed with 2N NaOH and water and extracted with ethyl acetate (2×30 ml). The combined organic layers were dried over MgSO4. After removal of organic solvent, the residue was purified by a flash column on silica gel eluted with 1:1 EtOAC:Hexane first, then with 10% MeOH(NH3) in dichloromethane. 4-[1-(4-methoxy-2,3-dimethyl-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester was obtained as a yellow oil (0.59 g, 56%). Analysis H1 NMR (400 MHz, CDCl3): 7.21 (1H, d), 6.68 (1H, d), 3.8 (3H, s), 3.58 (1H, q), 3.38 (3H, m), 2.45 (2H, m), 2.37 (2H, m), 2.24 (3H, s), 2.18 (3H, s), 1.43 (9H, s), 1.24 (3H, d). MS (LC-MS): Calculated for C20H32N2O3 348.48. Found 349.29 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH3:27])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Yield: 84 %

Procedure:
A suspension of 6.90 g of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 4, 10.4 g of potassium carbonate, and 2.3 mL of methyl iodide in 40 mL of DMF is stirred at 90° C. for 4 hours, then cooled and diluted with 350 mL of water. The resulting solid is filtered, washed well with water, and dried under vacuum. Flash chromatography of the solid on silica using 3-5% methanol in dichloromethane provides 6.02 g of the title compound as a solid.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[H-].[Na+].C(O)(=O)C.C([O:19][C:20]1[C:21]([CH2:30]O)=[CH:22][C:23]2[O:28][CH2:27][CH2:26][CH2:25][C:24]=2[CH:29]=1)(=O)C>CN(C)C=O>[OH:19][C:20]1[C:21]([CH2:30][S:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH2:4][OH:5])=[CH:22][C:23]2[O:28][CH2:27][CH2:26][CH2:25][C:24]=2[CH:29]=1
Reactant: CC(=O)Oc1cc2c(cc1CO)OCCC2
Reactant: OCc1ccccc1S
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: OCc1ccccc1SCc1cc2c(cc1O)CCCO2
Reaction time: 0.5 h

Procedure:
To a solution of o-mercaptobenzylalcohol (289 mg, 2.06 mmol) in dry dimethylformamide (3 mL) was added sodium hydride (60% dispersion in mineral oil, 83 mg, 2.07 mmol) portionwise and the mixture allowed to stir for 30 minutes. To the resulting solution was added dropwise a solution of 6-acetoxy-7-hydroxymethyl-3,4-dihydrobenzopyran acetate (543 mg, 2.06 mmol) in dry dimethylformamide and the mixture allowed to stir at room temperature under nitrogen for three hours, heated to 50° for 30 minutes, then allowed to cool and stir overnight. The reaction was quenched with 2.5N sodium hydroxide (2 mL) and after stirring for 30 minutes, the mixture was poured into water (75 mL). The aqueous mixture was neutralized with 2N hydrochloric acid (2.5 mL), extracted with ether (2×100 mL) and the ether extract washed with brine (3×100 mL), dried (Na2SO4) and concentrated. The crude product was purified by preparative HPLC (2:1 hexane/ethyl acetate as eluant) to afford 6-hydroxy-7-(2-hydroxymethylphenyl)thiomethyl-3,4-dihydrobenzopyran as a pale off-white solid, m.p. 140°-141° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: Cn1nc(Cl)cc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(Cl)cc(Nc2ccc(C3CCNCC3)cn2)c1=O
Reaction time: 18 h
Yield: 79.7 %

Procedure:
To tert-butyl 4-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)piperidine-1-carboxylate (782 mg, 1.86 mmol, Eq: 1.00) in DCM (20 ml) was added TFA (2.12 g, 1.43 ml, 18.6 mmol, Eq: 10). The reaction mixture stirred under nitrogen for 18 h. Concentrated in vacuo to give 6-chloro-2-methyl-4-(5-(piperidin-4-yl)pyridin-2-ylamino)pyridazin-3(2H)-one (474 mg, 80%). LC/MS-ESI observed [M+H]+ 320.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1)([O-:5])=[O:4].Br[C:16](Br)([CH2:19][CH3:20])[CH2:17][CH3:18]>CS(C)=O.C1COCC1.CCOC(C)=O>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2([C:13]#[N:14])[CH2:20][CH2:19][CH2:16][CH2:17][CH2:18]2)=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: N#CCc1ccc([N+](=O)[O-])cc1
Reactant: CCC(Br)(Br)CC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#CC1(c2ccc([N+](=O)[O-])cc2)CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 51.5 %

Procedure:
A slurry of NaH (711 mg, 29.6 mmol) in DMSO (10 mL) and THF (3 mL) was treated portionwise slowly with (4-nitro-phenyl)-acetonitrile (2.00 g, 12.3 mmol) and stirred at RT for 5 min until H2 evolution ceased. A solution of dibromopentane (2.02 mL, 14.8 mmol) in THF (10 mL) was added to the slurry over 10 min. The mixture was stirred at RT for an additional 5 min, placed in an oil bath at RT, slowly warmed to 70° C., and stirred at 70° C. for 1 h. The cooled mixture was diluted with EtOAc (250 mL) and washed with water (3×100 mL) and brine (2×100 mL). The combined aqueous layers were extracted with EtOAc (1×100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 10% EtOAc-hexane afforded the title compound (1.46 g, 51%) as a tan solid. 1H-NMR (CDCl3; 400 MHz): δ 8.26 (d, 2H, J=8.4 Hz), 7.69 (d, 2H, J=8.4 Hz), 2.21-2.13 (m, 2H), 1.98-1.74 (m, 8H).