Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].N1C=CC=CC=1.[C:16](Cl)(=[O:20])[CH2:17][CH2:18][CH3:19].N#N>O.C(Cl)Cl>[C:16]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1)(=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: O=Cc1cccc(O)c1
Reactant: CCCC(=O)Cl
Agent: N#N
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)Oc1cccc(C=O)c1
Reaction time: 20 h
Yield: 74.9 %

Procedure:
To a 250 mL dry round bottom flask were added 3-hydroxybenzaldehyde (5.0 g, 41.0 mmol), anhydrous CH2Cl2 (50 mL). The solution was cooled in an ice-water bath, then pyridine (6.64 mL, 82.0 mmol) was added. To the resulting solution, butyryl chloride (5.15 mL, 49.2 mmol) was added slowly under stirring and N2. The mixture was first stirred at 0° C. for 2 hours, then at room temperature for 20 hours. To the reaction mixture, water (80 mL) was added and the CH2Cl2 layer was separated. The aqueous layer was extracted continually with CH2Cl2 (50 mL×3). The combined CH2Cl2 solution was dried over Na2SO4. After removal of the solvent, the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give 3-formylphenyl butyrate (5.9 g) as colorless oil. Yield: 75%. 1H NMR (CDCl3, 300 MHz): δ=9.96 (s, 1H), 7.72 (t of d, J=1.2, 7.5 Hz, 1H), 7.60 (t, J=2.4 Hz, 1H), 7.52 (t, J=8.1 Hz, 1H), 7.36-7.32 (m, 1H), 2.56 (t, J=7.5 Hz, 2H), 1.78 (sextet, J=7.2 Hz, 2H), 1.04 (t, J=7.5 Hz, 3H). 13C NMR (CDCl3, 75.5 MHz): δ=191.2, 171.7, 151.3, 137.7, 130.1, 127.8, 127.2, 122.2, 36.0, 18.3, 13.5.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH:16]C(C)(C)C)(=[O:15])=[O:14])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:14])=[O:15])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1ccccc1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCCc1ccccc1S(N)(=O)=O
Reaction time: 21 h
Yield: 81.9 %

Procedure:
The product from Example 5 (13.8 g) was added in portions to 75 ml of trifluoroacetic acid at room temperature and the resulting solution was stirred for 21 hours. Removal of the trifluoroacetic acid in vacuo gave a light orange oil which crystallized upon addition of diethyl ether. Filtration and air drying yielded 9.18 g of pure 2-[2-(acetyloxy)ethyl]benzenesulfonamide as a white powder, m.p. 116°-117.5° C.
Reaction SMILES: O[N:2]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.C(N(CC)C(C)C)(C)C.C(OC([N:38]1[CH2:42][CH2:41][CH:40]([C:43]2[CH:48]=[CH:47][C:46]([NH:49][C:50]3[N:55]=[C:54]([CH2:56][CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=4[CH2:64][C:65]([O-:67])=O)[C:53]([C:68]([F:71])([F:70])[F:69])=[CH:52][N:51]=3)=[CH:45][CH:44]=2)[CH2:39]1)=O)(C)(C)C.[Li+].C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[NH:38]1[CH2:42][CH2:41][CH:40]([C:43]2[CH:44]=[CH:45][C:46]([NH:49][C:50]3[N:55]=[C:54]([CH2:56][CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=4[CH2:64][C:65]([NH2:2])=[O:67])[C:53]([C:68]([F:71])([F:70])[F:69])=[CH:52][N:51]=3)=[CH:47][CH:48]=2)[CH2:39]1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)[O-])n3)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 23 h
Yield: 75.3 %

Procedure:
1-Hydroxybenzotriazole (38.0 mg, 0.28 mmol), EDCI (50.0 mg, 0.32 mmol) and N,N-diisopropylethylamine (187 uL, 1.08 mmol) were added to a solution of lithium 2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I140) (124 mg, 0.215 mmol) in dry THF (6 mL) and dry DMF (1 mL) under an atmosphere of nitrogen. Ammonium carbonate (101 mg, 1.08 mmol) was added in one portion to the stirred reaction mixture after 10 minutes and the reaction was stirred at room temperature for 23 hours. The volatiles were removed in vacuo and the residual solution was diluted with EtOAc (65 mL) and washed with saturated NaHCO3 (65 mL). The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL) and dried over MgSO4. The solvent was removed in vacuo to afford a pale yellow oil. The crude material was purified by column chromatography on silica gel (0-80% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I141) (76 mg, 62%) as a white solid; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.02 (s, 1H), 7.56 (d, J=7.4 Hz, 2H), 7.29-7.20 (m, 4H, obscured by solvent), 5.36 (d, J=21.2 Hz, 2H), 3.89-3.76 (m, 1H), 3.66-3.51 (m, 2H), 3.45-3.27 (m, 4H), 3.15-3.04 (m, 4H), 2.29-2.25 (m, 1H), 2.01-1.94 (m, 1H), 1.49 (s, 9H). LCMS Method C: rt 6.37 min; m/z 570.1 [M+H]+, 568.2 [M−H]−.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1>CO.[Pd]>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: C1=C(c2nccs2)CCC2(C1)OCCO2
Agent: [Pd]
Solvent: CO
Product: c1csc(C2CCC3(CC2)OCCO3)n1
Yield: 94.1 %

Procedure:
To a Parr hydrogenation bottle was added 2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3-thiazole (0.22 g, 0.99 mmol), dissolved in methanol (15 mL), followed by the addition of 10% Pd/C (0.08 g). This mixture was hydrogenated at 50 psi overnight. After the catalyst was filtered and washed with methanol, the filtrate was concentrated in vacuo to give 0.21 g of 2-(1,4-dioxaspiro[4.5]dec-8-yl)-1,3-thiazole in 95% yield. MS (EI) calcd: (M+1)+=226.1; found: 225.9.
Reaction SMILES: [C:1]1([C@@H:7]([CH3:11])[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:32])[C:18]=1[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)=[O:21]>>[Cl:32][C:17]1[CH:16]=[N:15][CH:14]=[C:13]([Cl:12])[C:18]=1/[CH:19]=[C:20](\[O:21][C:8](=[O:9])[C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:11])/[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1
Reactant: C[C@@H](C(=O)Cl)c1ccccc1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC
Product: COc1ccc(/C(=C/c2c(Cl)cncc2Cl)OC(=O)[C@H](C)c2ccccc2)cc1OC
Yield: 21 %

Procedure:
The compound was obtained starting from 2-(R)-phenyl-propionyl chloride and 2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl) -ethanone, following the procedure of Example 7 (0.22 g, 0.48 mmol, 21% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3][CH2:2]1.[CH:34](OC(=O)C)=[O:35]>>[CH:34]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:5][CH2:6]1)=[O:35]
Reactant: CC(=O)OC=O
Reactant: O=C(NCC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: O=CN1CCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (piperidin-4-ylmethyl)-amide (example A144) and acetic formic anhydride the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[C:5]#[N:6].[H][H].CCCCCC.C(OCC)(=O)C>[Pd].C(O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6]
Reactant: N#Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#Cc1ccc(N)c(O)c1
Reaction time: 1 h

Procedure:
A parr bottle was charged with palladium on activated carbon (5%, 0.204 g). A solution of 3-hydroxy-4-nitrobenzonitrile (1.36 g, 0.00829 mol) in 41 ml of ethanol was added. The reaction mixture was placed under 25 psi of hydrogen gas and shaken for 1 hour. TLC (1:1 hexane:ethyl acetate) shows that no starting material remained. The mixture was filtered through Celite® and evaporated to yield 3-hydroxy-4-aminobenzonitrile, 1.08 g (0.00806 mol, 97%).
Reaction SMILES: [C:1]([C:3](=[C:6]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=1)SC)[C:4]#[N:5])#[N:2].O.[NH2:20][NH2:21]>CO>[NH2:2][C:1]1[NH:21][N:20]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5]
Reactant: CCOc1ccc(NC(SC)=C(C#N)C#N)cc1
Reactant: NN
Solvent: CO
Solvent: O
Product: CCOc1ccc(Nc2n[nH]c(N)c2C#N)cc1

Procedure:
A mixture of 21.5 g (82.9 mmol) of 2-cyano-3-(4-ethoxy-phenylamino)-3-methylmercapto-acrylonitrile, 4.31 ml (87 mmol) of hydrazine hydrate and 110 ml of methanol is heated under reflux for 7 hours and then concentrated by evaporation in vacuo. Recrystallization of the residue from ethyl acetate/hexane yields the title compound; m.p. 166-167° C.
Reaction SMILES: C[O:2][CH:3]1[CH2:35][C:7]2[NH:8][C:9]([C:11]3[C:12]([CH3:34])=[CH:13][C:14]([CH3:33])=[C:15]([CH:32]=3)[C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])=[N:10][C:6]=2[CH2:5][CH2:4]1.C(#N)C.Cl[Si](Cl)(Cl)Cl.[I-].[Na+]>ClCCl>[OH:2][CH:3]1[CH2:35][C:7]2[NH:8][C:9]([C:11]3[C:12]([CH3:34])=[CH:13][C:14]([CH3:33])=[C:15]([CH:32]=3)[C:16]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]4[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=4)[CH2:22][CH2:23]3)=[O:17])=[N:10][C:6]=2[CH2:5][CH2:4]1
Reactant: COC1CCc2nc(-c3cc(C(=O)N4CCC(c5ccc(C#N)cc5)CC4)c(C)cc3C)[nH]c2C1
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc(C)c(-c2nc3c([nH]2)CC(O)CC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 20 °C
Reaction time: 8 h
Yield: 9.2 %

Procedure:
Into around-bottom flask, was placed a solution of 4-(1-(5-(6-methoxy-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile (compound 459, 80 mg, 0.17 mmol, 1.0 equiv) in a solvent mixture of acetonitrile and dichloromethane (10/10 mL). Tetrachlorosilane (32 mg, 0.19 mmol, 1.1 equiv) and sodium iodide (28 mg, 0.19 mmol, 1.1 equiv) were added to the reaction and the resulting mixture was stirred overnight at 20° C. The reaction was quenched with aqueous sodium bicarbonate (10 mL) and the aqueous was extracted with ethyl acetate (3×10 mL). The combined organics was dried (Na2SO4), filtered and concentrated in vacuo and the residue was purified by silica gel chromatography with ethyl acetate as the eluent to obtain the title compound as a yellow solid (7.1 mg, 9%). m/z (ES+) 455 (M+H)+.
Reaction SMILES: [N+]([O-])([O-])=O.[Na+].[CH:6]([NH:8][C:9]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](N)[CH:12]=1)=[O:7].O.[OH-].[NH4+].[ClH:28]>S(=O)(=O)(O)O.C(O)(=O)C>[CH:6]([NH:8][C:9]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:28])[CH:12]=1)=[O:7]
Reactant: CC(Cc1cccc(N)c1)(NC=O)c1ccccc1
Reactant: Cl
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: CC(Cc1cccc(Cl)c1)(NC=O)c1ccccc1
Reaction time: 2.5 h

Procedure:
To a solution of N-formyl-l-(3-nitrophenyl)-2-phenyl-2-propylamine (5.0g, 0.017mol) in methanol (200 ml) was added 10% Pd/C catalyst (0.5g) and the mixture hydrogenated at 50 psi in a Parr apparatus for 3 hours. The catalyst was removed by filtration and the solvent evaporated to a white solid, 4.6 g. This solid was recrystallised from isopropanol (50 ml) to give 2.6 g of N-formyl-1-(3-aminophenyl)-2-phenyl-2-propylamine, mp 114°-115° C. To a stirred solution of sodium nitrate (2.0 g,0.03 mol) in sulphuric acid (15 ml) at 0° C. under nitrogen was added dropwise a solution of N-formyl-1-(3-aminophenyl)-2-phenyl-2-propylamine (7.0 g, 0.027 mol) in acetic acid (75 ml) and the solution was stirred 2.5 hours at a temperature less than 20° C. The above mixture was added to a solution of cuprous chloride (5.3 g, 0.054 mol) in concentrated HCl (50 ml) at 15° C., and the resulting solution was stirred at that temperature for 1 hour. The reaction mixture was poured into water (500 ml), basified with concentrated ammonium hydroxide, and extracted with chloroform (3×200 ml). The combined chloroform extracts were dried over magnesium sulphate and the solvent evaporated to a solid, 7.5 g. Thissolid was recrystallised from isopropanol (20 ml) to provide 3.2 g of N-formyl-1-(3-chlorophenyl)-2-phenyl-2-propylamine, mp 108°-109° C.
Reaction SMILES: C([NH:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[CH2:15][CH2:14]1)=[O:11])(=O)C1C=CC=CC=1>[OH-].[Na+]>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[CH2:19][N:16]1[CH2:17][CH2:18][CH:13]([NH:12][C:10]([NH2:9])=[O:11])[CH2:14][CH2:15]1
Reactant: O=C(NC(=O)c1ccccc1)NC1CCN(Cc2ccc3ccccc3c2)CC1
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)NC1CCN(Cc2ccc3ccccc3c2)CC1

Procedure:
1-Benzoyl-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea (prepared according to Example 1) is hydrolysed by refluxing in 2N sodium hydroxide to give [1-(naphth-2-ylmethyl)piperid-4-yl]urea(m.p. 183°-5° C.). The product is acylated by reaction with 4-methoxybenzoyl chloride to give the title compound, m.p. of HCl, quarterhydrate=193°-193.5° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10][CH:9]1[C:17]([O-:19])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].Cl.[CH2:22]([NH2:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[CH2:22]([NH:24][C:17]([CH:9]1[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10]1)=[O:19])[CH3:23]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)N1c2ncccc2CC1C(=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)C1Cc2cccnc2N1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
In a 100 mL round-bottomed flask, lithium 1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (400 mg, 1.48 mmol, Eq: 1.00), ethanamine hydrochloride (145 mg, 1.78 mmol, Eq: 1.2) and HATU (675 mg, 1.78 mmol, Eq: 1.2) were combined in DMF (6 mL) to give a light yellow suspension. Triethylamine (0.45 mL, 3.2 mmol, Eq: 2.2) was added. The reaction was stirred overnight then diluted with ethyl acetate (30 mL) and saturated aqueous NaHCO3 (20 mL). The aqueous layer was separated, extracted with DCM (20 mL×2) and the combined organic layers were washed with 1 M aqueous NaOH (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was azeotroped with n-heptane (30 mL×3) to give tert-butyl 2-(ethylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (322 mg), m/z=292 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19](O)[CH2:20][OH:21].CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH3:16])[O:21][CH2:20][CH2:19][O:17]2)=[CH:11][C:10]=1[F:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCO
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(c2ccc(OCc3ccccc3)c(F)c2)OCCO1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 1-(4-(benzyloxy)-3-fluorophenyl)ethanone 22 (23.8 g, 97.5 mmol), ethylene glycol (16.4 mL, 293 mmol), p-TsOH (930 mg, 4.88 mmol) and toluene (400 mL) was stirred under reflux conditions for 4 days, azeotropically removing water with a Dean-Stark trap. The mixture was cooled to room temperature and quenched by addition of saturated sodium bicarbonate solution (200 mL). The aqueous phase was back-extracted with toluene (3×200 mL). The combined organic phases were washed with brine (200 mL), dried over sodium sulfate, filtered and the solvent removed under reduced pressure to give 28.7 g (103%) of crude 23 as a yellow solid. Crude 23 was used without further purification. 1H NMR (CDCl3) δ: 7.39 (m, 5H), 7.22 (dd, 1H), 7.16 (dd, 1H), 6.95 (t, 1H), 5.12 (s, 2H), 4.12 (dd, 2H), 3.77 (dd, 2H), 1.62 (s, 3H). LCMS m/z=289.1 (M+H).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.C(OC(=O)[NH:35][CH2:36][CH2:37][CH:38]=O)(C)(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C1COCC1>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)[CH2:38][CH2:37][CH2:36][NH2:35]
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Reactant: CC(C)(C)OC(=O)NCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a stirred solution of 2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzoimidazole-1-carboxylic acid tert-butyl ester (390 mg, 0.98 mmol), (3-oxo-propyl)-carbamic acid tert-butyl ester (170 mg, 0.98 mmol) from above and THF (9.8 mL) was added NaBH(OAc)3 (623 mg, 2.94 mmol) and the resulting mixture was stirred at room temperature for 1 hour. AcOH (56 μL, 0.98 mmol) was added and the mixture stirred at room temperature overnight. The mixture was concentrated under reduced pressure, diluted with CH2Cl2 (40 mL) and washed with 1N NaOH (10 mL). The aqueous was extracted with (2×20 mL) and the combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. A solution of the resulting orange foam in CH2Cl2 (4 mL) and TFA (4 mL) was stirred at room temperature for 2.5 hours. The mixture was concentrated under reduced pressure, partially dissolved in H2O (2 mL), basified with 1N NaOH and extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 100:7:1) afforded N1-(1H-benzoimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine (290 mg, 75% over 3 steps) as a white foam.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:23]([C:25]1[CH:26]=[C:27](Br)[CH:28]=[CH:29][CH:30]=1)[CH3:24].[C:32]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].CC(C)([O-])C.[Na+]>CCOCC.Cl[Pd]Cl.CCOC(C)=O.CCCCCC.C1(C)C=CC=CC=1>[C:32]([N:39]1[CH2:40][CH2:41][N:42]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH2:23][CH3:24])[CH:26]=2)[CH2:43][CH2:44]1)([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]
Reactant: CCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl[Pd]Cl
Agent: CC(C)(C)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCc1cccc(N2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 0.25 h

Procedure:
Into a 15 mL round-bottomed flask fitted with a reflux condensor, a magnetic stirring bar, and a nitrogen inlet was added 1 mL dry toluene followed by 0.016 g (0.09 mmol) PdCl2 and 0.055 g (0.18 mmol) tri-o-tolylphosphine. After stirring for 15 min, an additional 15 mL dry toluene was added followed by 0.33 g (1.8 mmol) 3-ethylbromobenzene, 0.41 g (2.2 mmol) 1-Boc-piperazine and 0.242 g (2.5 mmol) sodium t-butoxide. The reaction was heated to reflux for 18 hr, after which time TLC (20% EtOAc/Hexane) showed the formation of a new spot. The reaction was cooled, diluted with 50 mL of ether, filtered through a Celite pad, and extracted with 3×10 mL water and 1×15 mL brine. The organic phase was dried (Na2SO4), filtered and the solvent removed in vacuo to get the crude product, which was purified by passing through a 2" silica pad (1% to 4% EtOAc/Hexane) to yield 1-Boc-4-(3-ethylphenyl)piperazine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8][N:7](N)[C:6]=2[CH:15]=1.[C:16]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8][N:7]3[C:6]=2[C:15]=1[C:16]1[CH2:20][CH2:19][CH2:18][C:17]=13
Reactant: O=C1CCCC1
Reactant: CN1CCc2ccc(F)cc2N(N)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CCCO
Solvent: O
Product: CN1CCc2ccc(F)c3c4c(n(c23)CC1)CCC4
Temperature: 25 °C
Yield: 20.3 %

Procedure:
To a solution of 9-fluoro-4-methyl-3,4,5,6-tetrahydro-2H-benzo[e][1,4]diazocin-1-ylamine (4.0 g, 19.1 mmole) in 1-propanol (300 mL) was added cyclopentanone (14.3 ml, 169.6 mmole), followed by p-toluenesulfonic acid monohydrate (10.3 g, 53.3 mmole), and the resulting reaction mixture was refluxed for 30 hours. The reaction mixture was cooled to room temperature and solvent removed in vacuo to produce a brown residue. The residue was diluted with ethyl acetate (500 mL) and washed with saturated aqueous sodium bicarbonate (350 mL), saturated aqueous sodium chloride (350 mL), dried (sodium sulfate) and concentrated in vacuo. Purification by flash column chromatography (silica gel, ethyl acetate:hexanes 1:1) provided 1.0 g of the title compound. 70.5 mg of the free amine was treated with one equivalent of fumaric acid in ethanol to form a fumarate salt, mp 168-170° C. MS (ES) m/z 259.12 ([M+H]+).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]([CH2:11]Br)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:13][C:14]([NH2:16])=[S:15]>C(O)C>[OH:1][N:2]=[C:3]([C:9]1[N:13]=[C:14]([NH2:16])[S:15][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=NO)C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Product: CCOC(=O)C(=NO)c1csc(N)n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl 2-hydroxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (2.4 g) and thiourea (0.76 g) in ethanol (15 ml) was stirred for 1 hour at 60° C. Ethanol was distilled off under reduced pressure and water was added to the residue. The resultant mixture was adjusted to pH 1.0 and washed with ethyl acetate. The aqueous layer was adjusted to pH 4.5 with triethylamine and extracted with ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to column chromatography on silica gel using a mixture of ethyl acetate and benzene (1:3) as developing solvent. The eluates containing syn isomer were collected and concentrated to give ethyl 2-hydroxyimino-2-(2-amino-1, 3-thiazol-4-yl)acetate (syn isomer) (0.3 g).