Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH3:9])[CH3:2].Br[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20]>>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][CH2:12][CH2:11][CH2:9][C:8]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cnccc1C
Reactant: Clc1ccccc1CCCBr
Product: CCc1cnccc1CCCCc1ccccc1Cl
Yield: 39.2 %

Procedure:
1.83 g (15.1 mmol) of 3-ethyl-4-methylpyridine and 3.53 g (15.1 mmol) of 1-bromo-3-(2-chlorophenyl)-propane were reacted in the same manner as in Example 26. The reaction product was purified to obtain 1.62 g of the desired compound (yield: 39.1%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([S:10](Cl)(=[O:12])=[O:11])[C:7]([O:14][CH3:15])=[CH:6][C:5]=1[O:16][CH2:17][CH3:18].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([S:10]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)(=[O:12])=[O:11])[C:7]([O:14][CH3:15])=[CH:6][C:5]=1[O:16][CH2:17][CH3:18]
Reactant: CCOc1cc(OC)c(S(=O)(=O)Cl)cc1C(=O)OC
Reactant: C1CCNC1
Product: CCOc1cc(OC)c(S(=O)(=O)N2CCCC2)cc1C(=O)OC

Procedure:
In a manner analogous to the method described in example 33, 5-chlorosulfonyl-2-ethoxy-4-methoxy-benzoic acid methyl ester was reacted with pyrrolidine to give the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([C:9]2([CH:15]=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:19][NH2:20]>>[CH3:19][NH:20][CH2:15][C:9]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=CC1(c2cccc(C(F)(F)F)c2)CCCCC1
Reactant: CN
Product: CNCC1(c2cccc(C(F)(F)F)c2)CCCCC1
Yield: 36.9 %

Procedure:
The title compound was prepared from 1-(3-(trifluoromethyl)phenyl)cyclohexane-carbaldehyde (116 mg, 0.5 mmol) and methylamine (2.0 M in THF, 2.5 ml, 5.0 mmol) according to General Procedure H2.The crude product was purified by silica gel column chromatography (MeOH/CH2Cl2, MeOH from 0% to 15%) to give N-methyl-1-(1-(3-(trifluoromethyl)phenyl)cyclohexyl)methanamine (50 mg, 45%). 1H NMR (CDCl3): δ 1.28-1.52 (m 4H), 1.54-1.60 (m, 2H), 1.69-1.76 (m, 2H), 2.12-2.18 (m, 2H), 2.29 (s, 3H), 2.66 (s, 2H), 7.45-7.48 (m, 2H), 7.56-7.59 (m, 1H), 7.61 (s, 1H). 13C NMR (CDCl3) δ 22.3, 26.7, 34.6, 37.4, 42.6, 64.2, 123.0, 123.9, 127.9, 129.1, 130.8, 131.1, 146.7.ESI MS m/z 271.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.O1CCCC1.[CH:22]1([Na])[CH:26]=[CH:25][CH:24]=[CH:23]1.Cl>O.C(OCC)C>[C:11]1([CH3:14])[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:15]=[CH:16][C:2]([CH3:1])=[CH:3][CH:4]=2)=[C:25]2[CH:24]=[CH:23][CH:22]=[CH:26]2)=[CH:9][CH:10]=1
Reactant: Cc1ccc(C(=O)c2ccc(C)cc2)cc1
Reactant: [Na]C1C=CC=C1
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(C(=C2C=CC=C2)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 74.5 %

Procedure:
A 200 ml two-necked flask equipped with a dropping funnel, a magnetic stirrer and a three-way cock, was purged thoroughly with nitrogen. Into the flask, 4,4′-dimethylbenzophenone 6.72 g (31.9 mmol) was introduced, and dehydrated tetrahydrofuran 30 ml was further added. With cooling in an ice bath, 2 mol/L tetrahydrofuran solution of cyclopentadienyl sodium, 19.0 ml (38.0 mmol), was dropwise added to the flask. The contents were stirred at room temperature in a nitrogen atmosphere for 6 days to obtain a solution. With the flask cooled in an ice bath, 1 N hydrochloric acid aqueous solution 100 ml and diethyl ether 100 ml were gradually added in this order. The resulting two-phase solution was poured into a 300 ml separation funnel, and the funnel was shaken several times so that the water phase was removed. The obtained organic phase was washed twice with water 100 ml and once with a saturated salt solution 100 ml, and dried over anhydrous magnesium sulfate. The solution was filtered to remove solids, and the solvent of the filtrate was distilled away to obtain a red oily matter 9.40 g. The oily matter was subjected to silica gel chromatography to obtain 6.15 g of 6,6-di-p-tolyl fulvene as a red solid (23.8 mmol, 74.5% yield). Identification of the 6,6-di-p-tolyl fulvene was made by 1H NMR, the results being given below:
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:6]=1)(=[O:3])[CH3:2].[I:23](O)(=O)=O.II>C(O)C>[C:1]([NH:4][C:5]1[N:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=[C:7]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[C:6]=1[I:23])(=[O:3])[CH3:2]
Reactant: [O-][I+2]([O-])O
Reactant: CCOC(=O)Cn1nc(-c2ccc(F)cc2)cc1NC(C)=O
Agent: II
Solvent: CCO
Product: CCOC(=O)Cn1nc(-c2ccc(F)cc2)c(I)c1NC(C)=O
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 397.9 %

Procedure:
To a solution of ethyl 2-(5-acetamido-3-(4-fluorophenyl)-1H-pyrazol-1-yl)acetate (1.1 g, 3.7 mmol) in ethanol (33 mL) were added iodic acid (170 mg, 0.95 mmol) and iodine (480 mg, 1.9 mmol). The reaction was stirred for 90 min at 60° C. The reaction mixture was concentrated in vacuo and the residue was dissolved in CH2Cl2 and washed with a 2 N Na2SO3 solution. The organic phase was dried over MgSO4, filtered and evaporated to give ethyl 2-(5-acetamido-3-(4-fluorophenyl)-4-iodo-1H-pyrazol-1-yl)acetate as a white solid (1.63 g), which was used as such in the subsequent step.
Reaction SMILES: C(C[C@@H:4]1[CH2:10][CH:9]2[N:11](C(OC(C)(C)C)=O)[CH:5]1[CH2:6][O:7][CH2:8]2)#N.[C:19]([OH:22])(=[O:21])[CH3:20]>Cl>[CH:9]12[NH:11][CH:5]([C@H:4]([CH2:20][C:19]([OH:22])=[O:21])[CH2:10]1)[CH2:6][O:7][CH2:8]2
Reactant: CC(C)(C)OC(=O)N1C2COCC1[C@H](CC#N)C2
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)C[C@@H]1CC2COCC1N2
Yield: 99 %

Procedure:
A solution of tert-butyl (6S)-6-(cyanomethyl)-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate 64b (180 mg, 0.71 mmol) in Conc. HCl (5 mL) and acetic acid (1 mL) was stirred at 100° C. for 4 h. Then the mixture concentrated in vacuo to afford 2-[(6S)-3-oxa-8-azabicyclo[3.2.1]octan-6-yl]acetic acid 64c (121 mg, 99%) which was used for next step without further purification. MS: calc'd (MH+) 172, measured (MH+) 172.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1COCC1>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][S:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1)[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CSc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.8 %

Procedure:
To a suspension of sodium hydride (60% in oil, 1.71 g, 42.8 mmol) in THF (40 mL), 4-methoxybenzenethiol (5.0 g, 35.7 mmol) was added dropwise at room temperature over a period of 10 min. The mixture was stirred at room temperature under N2 for 10 min and then cooled to 0° C. Ethyl bromoacetate (4.0 mL, 36 mmol) was added dropwise at 0° C. over a period of 10 min. The reaction mixture was stirred at room temperature for 30 min and then quenched with saturated ammonium chloride. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (1:9 ethyl acetate/hexanes) to provide (4-methoxy-phenylsulfanyl)-acetic acid ethyl ester (7.9 g, 98%) as colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.42 (d, J=6.6 Hz, 2H), 6.84 (d, J=6.6 Hz, 2H), 4.11 (q, J=7.1 Hz, 2H), 3.80 (s, 3H), 3.51 (s, 2H), 1.21 (t, J=7.1 Hz, 3H); ESI MS m/z 227 [(M+H)+, calcd for C11H15O3S, 227.0].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:9]([C:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH:12]=3)=[CH:10][C:3]=12.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:26])=[O:25])[C:9]([C:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH:12]=3)=[CH:10][C:3]=12.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]
Reactant: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(Br)ccnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2c(C3=CCNCC3)cc3c(Br)ccnc32)cc1

Procedure:
A mixture of Example 5C (8 g, 15.02 mmol) and trifluoroacetic acid (11.58 mL, 150 mmol) in dichloromethane (100 mL) was stirred at 20° C. for 12 hours and the mixture was concentrated to provide the title compound as a trifluoroacetic acid salt. MS (CI) m/z 432 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:30])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[CH:18]=4)[NH:13][C:12]=3[C:11]([C:27]([NH2:29])=[O:28])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1.N1C=CC=CC=1>ClCCl>[CH3:30][C:3]1[C:2]([NH:1][C:36](=[O:37])[C:35]2[CH:39]=[CH:40][C:32]([CH3:31])=[CH:33][CH:34]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[CH:18]=3)[NH:13][C:12]=2[C:11]([C:27]([NH2:29])=[O:28])=[N:10][CH:9]=1
Reactant: Cc1c(N)cccc1-c1cnc(C(N)=O)c2[nH]c3ccc(N4CCOCC4)cc3c12
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2cccc(-c3cnc(C(N)=O)c4[nH]c5ccc(N6CCOCC6)cc5c34)c2C)cc1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 52.1 %

Procedure:
To a solution of 4-(3-amino-2-methylphenyl)-6-morpholino-9H-pyrido[3,4-b]indole-1-carboxamide (0.0287 g, 0.071 mmol) and 4-methylbenzoyl chloride (0.013 g, 0.086 mmol) in dichloromethane (0.953 mL) under nitrogen was added pyridine (0.012 mL, 0.143 mmol). The vial was sealed and stirred at 40° C. After 15 min, the reaction was cooled to room temperature and concentrated in vacuo. It was diluted with MeOH (1 mL) and purified by reverse phase HPLC. The appropriate fractions were combined, basified with NaHCO3 (solid), and concentrated in vacuo. It was extracted with CH2Cl2 (3×). The organic layers were combined, dried over Na2SO4, and concentrated in vacuo to give the desired product (0.0192 g, 0.037 mmol, 51.7% yield) as a light yellow solid. LC/MS (M+H)=520.25; 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (s, 1H), 10.00 (s, 1H), 8.31 (d, J=2.2 Hz, 1H), 8.15 (s, 1H), 7.92 (s, 1H), 7.90 (s, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.70 (d, J=8.80 Hz, 1H), 7.55 (d, J=7.0 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.35 (s, 1H), 7.33 (s, 1H), 7.25-7.32 (m, 1H), 6.53 (d, J=2.2 Hz, 1H), 3.68 (m, 4H), 2.80-2.91 (m, 4H), 2.38 (s, 3H), 1.94 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)=[CH:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2]>C(OCC)(=O)C.C1COCC1>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:18][CH:19]=1)#[N:24]
Reactant: COC(=O)C=C(C=Cc1ccc(C#N)cc1)c1cccc(C#N)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CC(CCc1ccc(C#N)cc1)c1cccc(C#N)c1
Reaction time: 1 h
Yield: 57.4 %

Procedure:
Part C. The methyl 3-(3-cyanophenyl)-5-(4-cyanophenyl)-2,4-pentadienoate (5) (0.328 gm, 1.04 mmol) was dissolved in ethyl acetate/THF (1:1) and was degassed with N2. A catalytic amount of 10% Pd on carbon was added and the flask was placed on a Parr shaker for 1 hour at 45 p.s.i. The contents of the flask are filtered through Celite and the filtrate was concentrated under vacuum. The residue was chromatographed on silica gel eluting ethyl acetate:hexanes (25:75, v:v) to give methyl 4-(cyano)-beta-[3-(cyano)phenyl]benzene pentanoate as an oil 0.190 gm (57%). MS: (M+NH4)+ 336; 1H NMR (CDCl3): 1.95 (m, 1H), 2.05 (m, 1H), 2.55 (m, 2H), 2.65 (ddd, 2H), 3.15 (m, 1H), 3.60 (s, 3H), 7.20 (d, 2H), 7.45 (d, 2H), 7.50 (s, 1H), 7.55 (m, 3H).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:15]2[CH2:18][C@@H:17]([OH:19])[C@@H:16]2[CH2:20][CH3:21])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl.C(OCC)(=O)C>[CH3:28][S:29]([O:19][C@@H:17]1[CH2:18][N:15]([CH:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:16]1[CH2:20][CH3:21])(=[O:31])=[O:30]
Reactant: CC[C@H]1[C@H](O)CN1C(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H]1[C@H](OS(C)(=O)=O)CN1C(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 90.9 %

Procedure:
Triethylamine (0.94 mL, 6.74 mmol) was added to a solution of trans(±)-1-(Diphenylmethyl)-2-ethylazetidin-3-ol obtained in Example (234b) (1.20 g, 4.49 mmol) in dichloromethane (8 mL). Then, a solution of methanesulfonyl chloride (0.45 mL, 5.83 mmol) in dichloromethane (1.5 mL) was added dropwise at room temperature, followed by stirring for four hours. The reaction solution was diluted with ethyl acetate, washed with water and brine, and then dried over anhydrous magnesium sulfate. Following filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=5/1) to obtain 1.41 g of the title compound as a pale yellow oily substance (91%).
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:21][C:22]4[CH:23]=[C:24]([N:28]5[CH2:29][CH2:30][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[CH2:32][CH2:33]5)[CH:25]=[CH:26][CH:27]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: CC(C)(O)CN1CCN(c2cccc(N)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CC(C)(O)CN1CCN(c2cccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)c2)CC1

Procedure:
1-(4-{3-[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperazin-1-yl)-2-methyl-propan-2-ol was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.3249 mmol) and 1-[4-(3-amino-phenyl)-piperazin-1-yl]-2-methyl-propan-2-ol (89.0 mg, 0.357 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (36.0 mg, 0.0658 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.117 g, 68%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=6.1 Hz, 1H), 8.25 (d, J=8.4 Hz, 2H), 8.07 (d, J=8.4 Hz, 2H), 7.66 (d, J=7.4 Hz, 1H), 7.37 (s, 1H), 7.22 (t, J=8.2 Hz, 1H), 7.02 (t, J=7.0 Hz, 1H), 6.96 (dd, J=8.1, 1.3 Hz, 1H), 6.88 (s, 1H), 6.59 (dd, J=8.1, 1.7 Hz, 1H), 3.29-3.23 (m, 4H), 3.10 (s, 3H), 2.87-2.81 (m, 4H), 2.42 (s, 2H), 1.22 (s, 6H). MS=521 (MH)+.
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH2:8][CH:7]=[C:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:14])=[NH:13])[CH2:5][CH2:4]1>CO.[Pd]>[ClH:1].[ClH:1].[NH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:14])=[NH:13])[CH2:5][CH2:4]1
Reactant: N=C(N)c1cccc(C2=CCNCC2)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: N=C(N)c1cccc(C2CCNCC2)c1
Reaction time: 8 h
Yield: 188 %

Procedure:
3-(1,2,3,6-Tetrahydropyridin-4-yl)benzamidine dihydrochloride (1.0 g, 5.0 mmol) is dissolved in methanol (50 ml) treated with 5% Pd on carbon and stirred overnight under an atmosphere of hydrogen gas. The reaction mixture is filtered; the filtrate is concentrated to give 3-piperidin-4ylbenzamidine dihydrochloride as a white foam (1.30 g, 4.7 mmol). 1H NMR (DMSO) δ 9.40 (s, 2H), 9.2 (br, 4H), 7.67 (br, 2H), 7.56 (br, 2H), 3.4 (br, 2H), 3.0 (m, 3H), 2.7 (br, 4H). Ion spray MS M++1: 204.
Reaction SMILES: [CH2:1]1[C@H:6]2[C:7]3[N:13]([CH2:14][C@@H:2]1[CH2:3][NH:4][CH2:5]2)[C:11](=[O:12])[CH:10]=[CH:9][CH:8]=3.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]1[C@H:6]2[C:7]3[N:13]([CH2:14][C@@H:2]1[CH2:3][N:4]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:5]2)[C:11](=[O:12])[CH:10]=[CH:9][CH:8]=3
Reactant: O=c1cccc2n1C[C@@H]1CNC[C@H]2C1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=c1cccc2n1C[C@H]1C[C@@H]2CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
To a 25 ml round bottom flask was added 0.510 gm (2.68 mmol) cytisine in 10 ml of 1,2-dichloroethane. The above solution was treated with 0.272 ml (2.68 mmol) benzaldehyde, 153 μl acetic acid and 0.852 gm (4.02 mmol) sodium triacetoxyborohydride. The reaction mixture was stirred at room temperature for 2 hours and was then partitioned between methylene chloride and 1 N HCl (aq). The organic phase was washed with brine, dried and the solvent evaporated in vacuo to a solid. Chromatography on silica gel eluting with 1% methanol in methylene chloride afforded 434 mg (58%) of the title product which was used in the next step. 1H NMR (CDCl3, 250 MHz) δ 7.28 (dd, 1H), 7.15 (m, 3H), 6.98 (m, 2H), 6.98 (m, 2H), 6.52 (d, 1H), 5.92 (d, 1H), 4.10 (d, 1H), 3.88 (dd, 1H), 3.40 (dd, 2H), 2.88 (m, 3H), 2.39 (br.s, 1H), 2.3 (dd, 2H), 1.82 (dd, 2H) ppm.
Reaction SMILES: [ClH:1].[C:2]([C:5]1[S:9][C:8]2[CH2:10][CH:11]([C:14]([O:16]CC)=[O:15])[CH2:12][CH2:13][C:7]=2[CH:6]=1)(=[NH:4])[NH2:3]>Cl>[ClH:1].[C:2]([CH:5]1[S:9][C:8]2[CH2:10][CH:11]([C:14]([OH:16])=[O:15])[CH2:12][CH2:13][C:7]=2[CH2:6]1)(=[NH:3])[NH2:4]
Reactant: CCOC(=O)C1CCc2cc(C(=N)N)sc2C1
Agent: Cl
Product: N=C(N)C1CC2=C(CC(C(=O)O)CC2)S1
Temperature: 70 °C
Reaction time: 9 h
Yield: 91.8 %

Procedure:
A mixture of 2-amidino-6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene hydrochloride (1.15 g), and 6 N HCl (10 ml) was stirred at 70° C. for 9 hours. The resulting precipitate was washed with Et2O to give 2-amidino-6-carboxy-4,3,6,7-tetrahydrobenzo[b]thiophene hydrochloride (0.96 g).
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[CH:16]1[C:33]2[C:20](=[CH:21][C:22]3[C:31]([CH:32]=2)=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=3)[CH:19]=[CH:18][CH:17]=1>ClC1C=CC=CC=1Cl>[CH:19]1[C:20]2[C:33](=[C:32]([CH:9]=[O:10])[C:31]3[C:22]([CH:21]=2)=[CH:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=3)[CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc2cc3cc4ccccc4cc3cc2c1
Reactant: CN(C=O)c1ccccc1
Solvent: Clc1ccccc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c2ccccc2cc2cc3ccccc3cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 31 %

Procedure:
To a 3-necked RB flask equipped with overhead mechanical stirrer, condenser, addition funnel and N2 inlet line with bubbler was added N-methylformanilide (Aldrich, 89.21 g, 0.66 mol, 81 mL) and o-dichlorobenzene (Aldrich, 200 mL). The mixture was cooled to 10° with an ice bath. Phosphorus oxychloride (Aldrich, 101.21 g, 0.66 mol, 60 mL) was then added dropwise to the solution not allowing the reaction temperature to rise above 10°. The reaction mixture was then allowed to warm to RT. Solid naphthacene (Cambridge Chemical, Inc., 50 g, 0.22 mol) was then added in five portions over 5 min. The reaction mixture was warmed slowly to 80° (the mixture turned from purple to an almost black color). The reaction was stirred at 80° for 12 h, cooled, poured into ice water (2 L) and stirred an additional 12 h at RT. The mixture was then filtered. The organic layer in the filtrate was dried (Na2SO4) and applied to a plug of SiO2 (500 g) and eluted first with PhCH3 followed by CH2Cl2. The appropriate fractions were combined and the solvent removed by rotary evaporation. Recrystallization (CH2Cl2 /EtOAc) gave 17.5 g (31.1% yield) of naphthacene-5-carbaldehyde, mp 163°-164° (lit. 164°, N. P. Buu-Hoi et al., Recueil 76, 674 (1957)), (C,H). The solid from the filtration of the crude reaction mixture was washed with a large volume of CH3OH (5×200 mL), dissolved in THF (4 L) and passed through a plug of SiO2 (500 g) using an additional 2 L of THF as eluting solvent. The solvent was reduced to a volume of 300 mL and then diluted to 800 mL with EtOAc. The solvent volume was reduced to 250 mL. After filtration and drying, 10.90 g (17.4% yield) of naphthacene-5,11-dicarbaldehyde, mp 247°-250°, (C,H) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:43](OC(=O)C)(=[O:45])[CH3:44].N1C=CC=CC=1>O1CCCC1>[C:14]([O:13][C:11]([NH:10][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:31][CH2:32][N:33]([C:36]4[CH:41]=[CH:40][C:39]([NH:42][C:43](=[O:45])[CH3:44])=[CH:38][N:37]=4)[CH2:34][CH2:35]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:12])([CH3:16])([CH3:17])[CH3:15]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCN(c4ccc(N)cn4)CC3)cc2C1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(N2CCC(COc3ccc4c(c3)CN(C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC4)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N,N′-di-tert-butoxycarbonyl-7-[1-(5-aminopyridin-2-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (100 mg) in tetrahydrofuran (1.5 ml) were added acetic anhydride (0.017 ml) and pyridine (0.017 ml), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:acetone=2:1). The obtained residue was dissolved in methanol and treated with active charcoal, and dried under reduced pressure to give the title compound (75 mg).