Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3](CC)CC)C.ClC(OCC)=O.[C:14]([CH2:17][N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH:20]([NH:28][C:29]([C:31]2[NH:35][C:34]3[S:36][C:37]([Cl:39])=[CH:38][C:33]=3[CH:32]=2)=[O:30])[C:19]1=[O:40])([OH:16])=O.N>C1COCC1.CCOC(C)=O.O>[Cl:39][C:37]1[S:36][C:34]2[NH:35][C:31]([C:29]([NH:28][CH:20]3[CH2:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:18]([CH2:17][C:14](=[O:16])[NH2:3])[C:19]3=[O:40])=[O:30])=[CH:32][C:33]=2[CH:38]=1
Reactant: O=C(O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Reaction time: 1 h
Yield: 55.6 %

Procedure:
Triethylamine (38 μL, 0.27 mmol) then ethyl chloroformate (26.1 μL, 0.27 mmol) were added to N-[1-(carboxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 2; 100 mg, 0.25 mmol) in anhydrous THF (2 mL) at 0° C. followed by stirring for 1 h. Concentrated aqueous NH3 (1 mL) was added and the reaction was stirred for a further 1 h. Water (20 mL) and EtOAc (40 mL) were added and the organic layer was separated, washed with 1M HCl (20 mL) and the organic layer was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (MeOH:DCM 1:19) to afford the title compound (56 mg, 56%) as a white solid.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][C:10](=[O:21])[CH:11]([CH:16]([CH3:20])[C:17]([CH3:19])=O)[C:12](OC)=O.C(I)C>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C.O>[CH2:12]([CH:11]1[C:10](=[O:21])[C:9]([O:8][CH3:7])=[C:17]([CH3:19])[CH:16]1[CH3:20])[CH3:1]
Reactant: COCC(=O)C(C(=O)OC)C(C)C(C)=O
Reactant: O=C([O-])[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCI
Product: CCC1C(=O)C(OC)=C(C)C1C
Temperature: 60 °C
Reaction time: 1.67 h
Yield: 14.3 %

Procedure:
22.80 g (165 mmol) of potassium carbonate and 0.69 g (3 mmol) of benzyltriethylammonium chloride are suspended in 150 ml of acetonitrile. While stirring 32.42 g (150 mmol) of methyl 4-methoxy-2-(1-methylacetonyl)-acetoacetate are added thereto and the mixture is heated to 60° C. 28.08 g (180 mmol) of ethyl iodide are added thereto within 100 minutes and the mixture is stirred at 60° C. for a further 90 hours. The suspension is then poured into a solution of 10.35 g (75 mmol) of potassium carbonate in 450 ml of water and heated at reflux temperature for 30 hours. The cooled reaction solution is extracted 3 times with 300 ml of CH2Cl2. The combined organic phases are dried over magnesium sulphate and concentrated on a rotary evaporator. The crude product is distilled at 20 mbar/97°-99° C. and gives 3.61 g (14.3%) of 5-ethyl-2-methoxy-3,4-dimethyl-2-cyclopenten-1-one.
Reaction SMILES: [Na].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].[O-]CC.[Na+].Br[CH:16]([CH3:20])[C:17](=[O:19])[CH3:18]>C(O)C>[CH2:9]([O:8][C:2]([CH:3]([CH:16]([CH3:20])[C:17](=[O:19])[CH3:18])[C:4](=[O:5])[CH3:6])=[O:7])[CH3:10]
Reactant: CC(=O)C(C)Br
Reactant: CCOC(=O)CC(C)=O
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C(C)=O)C(C)C(C)=O
Reaction time: 0.5 h

Procedure:
7.3 G., 0.317 mol of sodium was dissolved in 125 ml. of absolute ethanol. 87.0 G. (0.669 mol) of ethyl acetoacetate were added to the resulting solution of sodium ethoxide in the cold. The reaction mixture was heated to reflux and 48.6 g. (0.322 mol) of freshly distilled 3-bromo-2-butanone were added dropwise with stirring over a period of 30 min. Refluxing was continued until the mixture tested neutral to pH paper (~1.5 hrs.). The precipitated sodium bromide was filtered off the cold solution and most of the ethanol was removed on an evaporator. The mixture was filtered again and distilled. The 3-ethoxycarbonyl-4-methylhexane-2,4-dione fraction which boiled at 131°-137° C./18 mm. was collected.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C1(OC)C=CC=CC=1.N(CC1C=CC(OC)=CC=1)=[N+]=[N-].[F:25][C:26]1[C:27](=[O:46])[NH:28][C:29](=[O:45])[N:30]([C@H:32]2[C@@H:35]([CH2:36][O:37]CC3C=CC=CC=3)[CH2:34][CH2:33]2)[CH:31]=1>CO>[F:25][C:26]1[C:27](=[O:46])[NH:28][C:29](=[O:45])[N:30]([C@H:32]2[C@@H:35]([CH2:36][OH:37])[CH2:34][CH2:33]2)[CH:31]=1
Reactant: O=c1[nH]c(=O)n([C@@H]2CC[C@@H]2COCc2ccccc2)cc1F
Agent: COc1ccc(CN=[N+]=[N-])cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: CO
Product: O=c1[nH]c(=O)n([C@@H]2CC[C@@H]2CO)cc1F
Temperature: 0 °C

Procedure:
In a 25 mL flask with AlCl3 (1.93 g, 14.4 mmol) inside, dry anisole 5 mL was added under argon to give a light yellow solution. In another flask with N3-PMB-5-fluoro-1-[cis-4-(benzyloxymethyl)cyclobutyl]uracil (0.66 g, 1.44 mmol) inside, dry anisole 5 mL was added, after which time AlCl3 solution was added to it ver slowly at room temperature. After addition finishes, the mixture was cooled to 0° C. and dry MeOH was added slowly to give a colorless solution at the end. Then the solvents were removed and the product was purified by silica gel flash chromatography (CH2Cl2: MeOH=20:1 to CH2Cl2: MeOH=10:1) to give a white solid (0.26 g, 74%, Rf=0.11 (CH2Cl2: MeOH=20:1)). 1H NMR (CD3OD, 400 MHz): δ IR (neat) νmax 3402, 3064, 2934, 1694, 1473, 1369, 1244, 1041, 1005, 913, 784, 706.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]=[C:40]=[O:41]>CO.CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH:30][C:40]([NH:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[O:32][CH3:31])=[O:41])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Reactant: COc1ccccc1N=C=O
Solvent: CC#N
Solvent: CO
Product: COc1ccccc1NC(=O)Nc1nc2nc(NCCCN3CCN(C)CC3)ncc2cc1-c1c(Cl)cccc1Cl

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 0.334 of 2-methoxyphenyl isocyanate according to the general procedure of Example 37 to give 0.9232 g of 1-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-(2-methoxy-phenyl)-urea, ESMS (20/80 MeOH/CH3CN+0.1% AcOH): M+ +H=595; mp 152.5-154° C.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[OH2:6].[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([CH:24]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[C:25]#N)[CH:22]=3)[N:17]3[N:34]=[N:35][N:36]=[C:16]3[CH:15]=2)[CH:11]=[CH:12][CH:13]=1>C(O)(=O)C>[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([CH:24]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[C:25]([OH:2])=[O:6])[CH:22]=3)[N:17]3[N:34]=[N:35][N:36]=[C:16]3[CH:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: O
Reactant: N#CC(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc1nnnn12
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(O)C(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc1nnnn12
Temperature: 0 °C
Yield: 91 %

Procedure:
Sulfuric acid (25 ml) was added slowly to H2O (25 ml). Acetic acid (25 ml) was added. Intermediate (59) (0.0190 mol) was added portionwise. The mixture was stirred and refluxed for 18 hours then cooled, poured out into ice water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated till dryness. The residue (8.9 g) was taken up in EtOAc. The organic layer was separated, washed several times with water, dried (MgSO4), filtered and the solvent was evaporated till dryness, yielding 7.8 g (91%) of 5-(3-chlorophenyl)-α-(4-chlorophenyl)-tetrazolo[1,5-a]quinoline-7-acetic acid, MS (ESI) m/z:449, 451, 453 (MH+) (intermediate 60).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[C:26]5[CH2:27][CH2:28][NH:29][CH2:30][C:25]=5[S:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.Br[CH2:32]/[CH:33]=[CH:34]/[C:35]([OH:37])=O.Cl.[O:39]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[O:39]1[CH2:45][CH2:44][CH2:43][N:42]([CH2:32]/[CH:33]=[CH:34]/[C:35]([N:29]2[CH2:28][CH2:27][C:26]3[C:19]4[C:18]([NH:17][C:13]5[CH:12]=[C:11]6[C:16](=[CH:15][CH:14]=5)[N:8]([CH2:7][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[N:9]=[CH:10]6)=[N:23][CH:22]=[N:21][C:20]=4[S:24][C:25]=3[CH2:30]2)=[O:37])[CH2:41][CH2:40]1
Reactant: C1CNCCOC1
Reactant: c1ccc(Cn2ncc3cc(Nc4ncnc5sc6c(c45)CCNC6)ccc32)nc1
Reactant: O=C(O)/C=C/CBr
Agent: Cl
Product: O=C(/C=C/CN1CCCOCC1)N1CCc2c(sc3ncnc(Nc4ccc5c(cnn5Cc5ccccn5)c4)c23)C1

Procedure:
The title compound was synthesized in analogy to Example 130 from N-[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-amine from Example 62A (100 mg, 0.24 mmol), (2E)-4-bromobut-2-enoic acid (75 mg, 0.36 mmol) and 1,4-oxazepane hydrochloride (53 mg, 0.39 mmol) to yield 62 mg (42%).
Reaction SMILES: [Br:1][C:2]1[C:6]([Br:7])=[C:5]([Br:8])[NH:4][N:3]=1.[OH-].[Na+].S(OC)(O[CH3:15])(=O)=O>>[Br:1][C:2]1[C:6]([Br:7])=[C:5]([Br:8])[N:4]([CH3:15])[N:3]=1
Reactant: COS(=O)(=O)OC
Reactant: Brc1n[nH]c(Br)c1Br
Agent: [Na+]
Agent: [OH-]
Product: Cn1nc(Br)c(Br)c1Br
Reaction time: 0.17 h

Procedure:
To 3,4,5-tribromopyrazole (4.5 g, 0.15 mole) in 3N aqueous sodium hydroxide (6 g, 0.15 mole) is added at room temperature with stirring dimethyl sulfate (19 g, 0.15 mole). After 10 minutes a solid separates out. An additional gram of dimethyl sulfate is added and the mixture is stirred for 3 days, filtered and the precipitate water washed and air dried to yield 33 g (73%), mp 85°C. to 86°C. Crystallization from cyclohexane yields desired solid product whose melting point ranges from about 90°C. to 91°C.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:22])[CH2:12][CH2:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)C.[OH-].[K+].Cl>C1COCC1.O>[O:21]=[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:13][CH2:12][C:11]([C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:23])=[O:3])=[CH:6][CH:7]=1)=[O:22]
Reactant: CCOC(=O)c1ccc(C(=O)CCC(=O)c2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(C(=O)CCC(=O)c2ccccc2)cc1
Temperature: 0 °C
Yield: 45.8 %

Procedure:
To a solution of 6.17 g 4-(4-oxo-4-phenyl-butyryl)-benzoic acid ethyl ester from Step 1 in 100 mL THF was added a solution of 3.86 g (69 mmol) potassium hydroxide in 110 mL water. The reaction was heated to reflux for 4.5 hr and allowed to cool. The reaction was transferred to an Ehrlenmeyer flask and cooled to 0° C. in an ice bath. Concentrated hydrochloric acid was added dropwise until a solid precipitated. The solid was collected by filtration and dried to afford 2.59 g (9.1 mmol) 4-(4-oxo-4-phenyl-butyryl)-benzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14](=[O:27])[CH2:15][S:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]1[O:13][CH2:12]1.C(O)=[O:29]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14](=[O:27])[CH2:15][S:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]([OH:13])[CH2:12][OH:29]
Reactant: COc1cc(C(=O)CSc2ccnc3ccccc23)ccc1OCC1CO1
Reactant: O=CO
Solvent: O
Product: COc1cc(C(=O)CSc2ccnc3ccccc23)ccc1OCC(O)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
4-[2-[3-Methoxy-4-(2,3-epoxypropoxy)phenyl]-2-oxoethylthio]quinoline (Compound 57; 2.0 g, 5.25 mmol) was added at 0° C. to the mixture of formic acid (40 ml) and water (4 ml), and stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was added with an ice-cooled aqueous solution of 40% sodium hydroxide (7.0 ml) and stirred at 0° C. for 30 minutes. The solvent was removed under reduced pressure and the residue was chromatographed by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain 1.4 g of the titled compound (67.0%). Melting Point: 177° C. (decomp.)
Reaction SMILES: [H-].[Na+].[CH3:3]N(C=O)C.[Cl:8][C:9]1[CH:34]=[CH:33][C:12]2[NH:13][C:14]([CH2:16][N:17]([CH3:32])[C:18](=[O:31])[CH2:19][N:20]3[C:24]4[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=4[S:22][C:21]3=[O:30])=[N:15][C:11]=2[CH:10]=1.CI>O>[ClH:8].[Cl:8][C:9]1[CH:34]=[CH:33][C:12]2[N:13]([CH3:3])[C:14]([CH2:16][N:17]([CH3:32])[C:18](=[O:31])[CH2:19][N:20]3[C:24]4[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=4[S:22][C:21]3=[O:30])=[N:15][C:11]=2[CH:10]=1
Reactant: CN(C)C=O
Reactant: CN(Cc1nc2cc(Cl)ccc2[nH]1)C(=O)Cn1c(=O)sc2ccc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CN(Cc1nc2cc(Cl)ccc2n1C)C(=O)Cn1c(=O)sc2ccc(Cl)cc21
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen gas flow, to a mixture of NaH (55% in oil, 35 mg) and DMF (4 mL) was added a mixture of N-[(5-chloro-1H-benzimidazol-2-yl)methyl]-2-(5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)-N-methylacetamide (335 mg) and DMF (10 mL) under ice-cooling, followed by stirring at room temperature for 30 minutes. The reaction mixture was ice-cooled and methyl iodide (55 μL) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was added to water, followed by extraction with EtOAc. The organic layer was washed with brine and dried over Na2SO4, and then concentrated under reduced pressure. To the residue was added chloroform. The resulting solid was collected and then washed with chloroform. To a mixture of the obtained solid and MeOH (3 mL) was added 4 M hydrogen chloride/EtOAc (300 μL), followed by stirring at room temperature. The reaction mixture was concentrated under reduced pressure, and to the residue was added EtOAc. The resulting solid was collected and then washed with EtOAc to obtain N-[(5-chloro-1-methyl-1H-benzimidazol-2-yl)methyl]-2-(5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)-N-methylacetamide hydrochloride (60 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B(O)O)[CH:5]=[CH:4][N:3]=1.Cl[C:12]1[CH:20]=[CH:19][N:18]2[C:14](=[N:15][C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=32)[N:13]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:12]2[CH:20]=[CH:19][N:18]3[C:14](=[N:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=43)[N:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccn2c(n1)nc1ccccc12
Reactant: OB(O)c1ccnc(F)c1
Product: Fc1cc(-c2ccn3c(n2)nc2ccccc23)ccn1

Procedure:
General experimental procedure (A) for Suzuki coupling with 2-fluoropyridin-4-ylboronic acid was followed. Reaction was performed on a 40 mg scale of 2-chloropyrimido[1,2-a]benzimidazole. The residue was purified by HPLC (acetonitrile/water) to give 6.2 mg (12%) of T732 as a white solid. 1H NMR (CD3OD): δ 9.91 (1H, d, J=7.2 Hz), 8.47-8.53 (2H, m, overlapped), 8.39 (PH, d, J=7.2 Hz), 8.25 (1H, m), 8.04 (1H, m), 7.95 (1H, d, J=8.4 Hz), 7.89 (1H, m), 7.76 (1H, m); MS: 265 (M+H+).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:31])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)[CH:19]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][I:33]>CN(C=O)C>[I-:33].[CH3:32][N+:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:31])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)[CH:19]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CI
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CN4CCCCC4)cc3)c2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(C[N+]4(C)CCCCC4)cc3)c2)cc1
Product: [I-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.4 %

Procedure:
In DMF (4ml) was dissolved (E)-N-[4-(piperidino-methyl)-phenyl]-3-(4-methylphenyl)cinnamamide (0.41g), and to the mixture was added methyl iodide (0.43g). The mixture was stirred at room temperature for 20 hours and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give (E)-1-methyl-1-[4-(3-(4-methyl-phenyl)cinnamamido)benzyl]-piperidinium iodide (Compound 72) (0.51g) as pale yellow crystals.
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]([C:8]2[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=2)=O)[CH2:3][CH2:2]1.Cl.[CH2:18]([NH:25][NH2:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:18]([N:25]1[C:6]([C:8]2[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=2)=[CH:5][C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(C(=O)C#CC2CC2)s1
Reactant: NNCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cc(C3CC3)nn2Cc2ccccc2)s1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Methyl 5-(3-cyclopropylpropioloyl)thiophene-2-carboxylate (100 mg, 0.427 mmol) was dissolved in N,N-dimethylformamide (2 mL), and the solution was cooled to 0° C. Benzylhydrazine hydrochloride (74.5 mg, 0.470 mmol) was added followed by potassium carbonate (77 mg, 0.555 mmol). The mixture was stirred at 0° C. until the ice bath melted and was stirred overnight at room temperature. The solution was partitioned between water and ethyl acetate. The organic extract was dried with sodium sulfate, filtered, concentrated and purified by normal phase chromatography to afford the title compound.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].Cl.[NH2:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([O:28][CH3:29])[CH:20]=3)=[O:18])=[N:15][CH:16]=2)[CH:13]=1>N1C=CC=CC=1.Cl>[CH3:29][O:28][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[N+:25]([O-:27])=[O:26])[C:17]([C:14]1[N:12]2[CH:13]=[C:8]([NH:7][S:1]([CH3:4])(=[O:3])=[O:2])[CH:9]=[CH:10][C:11]2=[CH:16][N:15]=1)=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)c2ncc3ccc(N)cn23)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(C(=O)c2ncc3ccc(NS(C)(=O)=O)cn23)ccc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 18 h
Yield: 91.6 %

Procedure:
0.107 ml (1.38 mmol) of mesyl chloride is added to 0.40 g (1.15 mmol) of (6-aminoimidazo[1,5-a]pyridin-3-yl) (3-methoxy-4-nitrophenyl)methanone hydrochloride in 10 ml of pyridine cooled to 5° C. and the mixture is allowed to return to ambient temperature and is stirred for 18 hours. The medium is taken up in 130 ml of 1N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous sodium chloride solution, then dried over sodium sulfate and concentrated under reduced pressure. The residue is taken up in isopropyl ether, filtered off, washed with isopropyl ether and then dried. 411 mg of a yellow solid are obtained. Melting point: 249° C.; 1H NMR (d6-DMSO): 3.14 (3H, s), 4.02 (3H, s), 7.39 (1H, d), 7.94 (1H, s), 8.02-8.11 (3H, m), 8.13 (1H, s), 9.88 (1H, s)
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][N:11](C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26]CCCl.ClC(OC(Cl)C)=O>CO>[ClH:26].[CH2:1]([O:8][CH:9]1[CH2:10][NH:11][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reactant: ClCCCl
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Product: Cl
Product: c1ccc(COC2CNC2)cc1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
A 16 mL vial was charged with 3-(benzyloxy)-1-(diphenylmethyl)azetidine (103 mg, 0.31 mmol; which may be prepared as described in Step 1) and 1,2-dichloroethane (1.4 mL). 1-Chloroethyl chloroformate (45 μL, 0.41 mmol) was added and the reaction mixture was stirred at 70° C. for 1.5 h. After cooling to room temperature, methanol (1.4 mL) was added and the reaction mixture was stirred at 70° C. for 1.5 h. The reaction mixture was cooled and concentrated to dryness. The residue was purified on column chromatography (eluent: Pentane/NH3 7N in MeOH, 98/2) to give the title compound (57 mg, 92%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:20]#[N:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].S(=O)(=O)(O)[OH:25]>O.C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:20]([NH2:21])=[O:25])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: N#CC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)C1(c2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 60 °C
Yield: 83.9 %

Procedure:
A mixture of 3 kg of commercial 1-benzyl-4-cyano-4-phenylpiperidine, 6 l of water, 8.98 l of toluene and 1.35 kg of an aqueous 35% sodium hydroxide solution is heated under nitrogen at 60° C. and the aqueous phase is separated out by settling at this temperature. The toluene phase is dried by azeotropic distillation and the solution thus obtained containing the 1-benzyl-4-cyano-4-phenylpiperidine base is added to a mixture of 2.83 kg of 95% sulfuric acid, 1.73 kg of glacial acetic acid and 3 l of toluene. The mixture thus obtained is heated for 6 hours, the heating is then stopped, the mixture is cooled to 60° C. and 3 l of water are added at this temperature. The mixture is allowed to cool to room temperature (about 20° C.) and is then poured into 8.65 l of 30% sodium hydroxide and 6.75 l of water. The temperature rises gradually to 75° C. The phases are separated by settling while hot and the organic phase is washed with water and dried azeotropically. The toluene solution is concentrated to half its volume and then cooled gradually to 60° C. and the crystallization is initiated. The crystallization is completed by cooling to 0° C. over 2 hours. The precipitate thus obtained is filtered off, washed and dried under vacuum at 60° C. 2.68 kg of 1-benzyl-4-phenyl-4-piperidinecarboxamide are thus obtained;
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]([O:15]C(=O)C)[CH:12]=[C:11]2[C:6]=1[C:7](=[O:29])[C:8]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=[C:9]([CH2:19]Br)[O:10]2)(=O)C.[CH3:30][NH:31][CH3:32].[ClH:33]>C(Cl)(Cl)Cl>[ClH:33].[CH3:30][N:31]([CH2:19][C:9]1[O:10][C:11]2[C:6]([C:7](=[O:29])[C:8]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=[C:5]([OH:4])[CH:14]=[C:13]([OH:15])[CH:12]=2)[CH3:32]
Reactant: CNC
Reactant: COc1ccc(-c2c(CBr)oc3cc(OC(C)=O)cc(OC(C)=O)c3c2=O)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2c(CN(C)C)oc3cc(O)cc(O)c3c2=O)cc1
Reaction time: 1 h

Procedure:
To a solution of 5,7-diacetoxy-4'-methoxy-2-bromomethylisoflavone (500 mg) in 5 ml chloroform, was added 240 mg of 50% aqueous solution of dimethylamine at room temperature with stirring. After one hour, the solid which separated out was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform). To the liquid thus obtained was added ethanolic solution of hydrogen chloride, the solvent was distilled off, and the solid which separated out was recrystallized from ethanol, giving 150 mg of 2-(dimethylaminomethyl)-5,7-dihydroxy-4'-methoxyisoflavone hydrochloride.