Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:22]3[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[C:18]3[C:13](=[CH:14][C:15]([N:19]([CH3:21])[CH3:20])=[CH:16][CH:17]=3)[C:11](=[O:12])[O:10]2)=[CH:5][CH:4]=1.CC1C(N)=C(C)C(C)=C(C=1)C(C)(O)C1C=CC(N)=CC=1.CN(C)C1C=C(C=CC=1)C(O)=O>S(=O)(=O)(O)O>[CH3:30][N:28]([CH3:29])[C:25]1[CH:24]=[CH:23][C:22]([CH:9]([C:18]2[CH:17]=[CH:16][C:15]([N:19]([CH3:21])[CH3:20])=[CH:14][C:13]=2[C:11]([OH:12])=[O:10])[C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:31])=[CH:8][CH:7]=2)=[CH:27][CH:26]=1
Reactant: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3)OC(=O)c3cc(N(C)C)ccc32)cc1
Agent: CN(C)c1cccc(C(=O)O)c1
Agent: Cc1cc(C(C)(O)c2ccc(N)cc2)c(C)c(C)c1N
Agent: O=S(=O)(O)O
Product: CN(C)c1ccc(C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2C(=O)O)cc1

Procedure:
A process for preparing 3,3-bis(4-dimethylaminophenyl)-6-dimethylaminophthalide which comprises reacting one mole proportion of tetramethyl-4,4'-diaminobenzhydrol with from about 0.9 to about 1.2 mole proportions of 3-dimethylaminobenzoic acid in aqueous sulfuric acid at a temperature of 65°-100° C. to form 2-[4,4'-bis(dimethylamino)benzhydryl]-5-dimethylaminobenzoic acid, adding sodium hydroxide to the reaction mixture to form the sodium salt of the said benzoic acid therein, contacting the reaction mixture at a temperature of about 40°-90° C. with a solvent selected from a liquid aromatic hydrocarbon and a mixture of liquid aromatic hydrocarbon and a water-immiscible alkane, whereby impurities present in said solution are extracted therefrom; separating the organic extract phase from the aqueous reaction mixture phase, treating the reaction mixture phase with an inorganic oxidizing agent to oxidize the sodium salt of the 2-[4,4'-bis(dimethylamino)benzhydryl]-5-dimethylaminobenzoic acid to the 3,3-bis-(4-dimethylaminophenyl)-6-dimethylaminophthalide product and recovering said product from the reaction mixture.
Reaction SMILES: [C:1]([NH:3][C:4](=[O:7])[O:5][CH3:6])#[N:2].[C:8]1(N)[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14]>>[N:2]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:1]=1[NH:3][C:4]([O:5][CH3:6])=[O:7]
Reactant: COC(=O)NC#N
Reactant: Nc1ccccc1N
Product: COC(=O)Nc1nc2ccccc2[nH]1
Yield: 94 %

Procedure:
The salt of methyl cyanocarbamate with o-phenylenediamine (1.0 parts) is heated at 145°-50° C. for 10 minutes. This treatment gives 0.86 parts (94% yield) of 2-benzimidazolecarbamic acid, methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH2:11][O:12][CH2:13][C:14]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:10]=1)[C:5](O)=[O:6].[CH3:33][NH:34][CH3:35].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]([CH:8]=[C:4]([C:5](=[O:6])[N:34]([CH3:35])[CH3:33])[CH:3]=1)[CH2:11][O:12][CH2:13][C:14]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(C(=O)O)c2)(c2ccccc2)CC1
Reactant: CNC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cc(Br)cc(COCC2(c3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 1.5 h

Procedure:
A stirred solution of 3-bromo-5-(((1-(tert-butoxycarbonyl)-4-phenylpiperidin-4-yl)methoxy)methyl)benzoic acid (160 mg, 0.32 mmol) in dimethylformamide (5 mL) was cooled to 0° C. and sequentially treated with methylene chloride (2 mL), dimethylamine (1 N in tetrahydrofuran, 0.32 mL, 0.32 mmol), N,N-diisopropylethylamine (90 μL, 0.64 mmol), and PyBop® (0.21 g, 0.38 mmol). The solution was stirred for 1.5 h and concentrated. The product was purified by column chromatography (30% ethyl acetate/hexanes) to give 120 mg (70%). 1H-NMR (CDCl3, 500 MHz) δ 7.38-7.40 (m, 1H), 7.33-7.35 (m, 4H), 7.22-7.24 (m, 2H), 7.03 (s, 1H), 4.32 (s, 2H), 3.74-3.77 (m, 2H), 3.38 (s, 2H), 3.08 (s, 3H), 2.99-3.05 (m, 2H), 2.90 (s, 3H), 2.16-2.19 (m, 2H), 1.83-1.89 (m, 2H), 1.43 (s, 9H). Mass spec.: 533.24 (MH)+.
Reaction SMILES: [OH:1][C:2]1([C:6]2[S:7][C:8]([C:11]3[CH:12]=[C:13]([NH:18][C:19]4[N:24]=[C:23]([O:25][C:26]([CH3:35])([CH3:34])[C:27]([O:29]C(C)(C)C)=[O:28])[CH:22]=[CH:21][N:20]=4)[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:10]=2)[CH2:5][CH2:4][CH2:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:1][C:2]1([C:6]2[S:7][C:8]([C:11]3[CH:12]=[C:13]([NH:18][C:19]4[N:24]=[C:23]([O:25][C:26]([CH3:35])([CH3:34])[C:27]([OH:29])=[O:28])[CH:22]=[CH:21][N:20]=4)[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1cc(Nc2nccc(OC(C)(C)C(=O)OC(C)(C)C)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2nccc(OC(C)(C)C(=O)O)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To tert-butyl 2-{[2-({3-[2-(1-hydroxycyclobutyl)-1,3-thiazol-5-yl]-5-methylphenyl}amino)-pyrimidin-4-yl]oxy}-2-methylpropanoate (Example 94A-25, 140 mg, 0.28 mmol) in DCM (1 mL) was added of trifluoroacetic acid (220 μL, 2.8 mmol). The mixture was aged for 2 hours and additional trifluoroacetic acid (500 μL, 6.4 mmol) was added. The reaction was stirred overnight. The reaction was concentrated under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried, filtered and solvent removed under reduced pressure to afford 2-{[2-({3-[2-(1-hydroxycyclobutyl)-1,3-thiazol-5-yl]-5-methylphenyl}amino)pyrimidin-4-yl]oxy}-2-methylpropanoic acid (110 mg, 0.25 mmol, 88%) as pale yellow oil. MS ESI: [M+H]+ m/z 441.2. 1H NMR (600 MHz, DMSO-d6): δ 9.50 (s, 1H); 8.18 (d, J=6 Hz, 1H); 7.96 (s, 1H); 7.66 (s, 1H); 7.44 (s, 1H); 7.05 (s, 1H); 6.27 (d, J=6 Hz, 1H); 2.52-2.27 (m, 4H); 2.46 (s, 3H); 1.86 (s, 2H); 1.66 (s, 6H). rhSYK activity=++
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:17]=3[CH:18]=[CH:19][CH:20]=2)=[O:11])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>ClCCl>[CH3:37][S:38]([NH:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)[C:17]=3[CH:18]=[CH:19][CH:20]=2)=[O:11])=[CH:4][CH:3]=1)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cn1
Temperature: 0 °C

Procedure:
To a solution of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide (40.0 mg, 0.111 mmol) in dichloromethane (1.0 mL) was added DIEA (0.15 mL, 0.89 mmol). The solution was cooled to 0° C., treated with methanesulfonyl chloride (0.021 mL, 0.28 mmol), and gradually allowed to warm to room temperature. The solution was diluted CH2Cl2 (20 mL) and washed with saturated aqueous NH4Cl (3×10 mL), saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered and concentrated. The crude mixture was diluted with THF (0.5 mL) and a 1 M solution of TBAF in THF (1.0 mL, 1.0 mmol) was added. The solution was warmed at reflux for 6 hours. The solution was cooled to room temperature and quenched with saturated aqueous NH4Cl (15 mL), diluted with ethyl acetate (15 mL), and washed with NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of 0-10% MeOH in CH2Cl2 to afford the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH3:62])([CH3:61])[C:8]3[C:13]([O:14][C:15]=2[C:16]=1[CH2:17][C:18]([O:20]CC1C=CC=CC=1)=[O:19])=[C:12]([CH2:28][NH:29][C:30](=[O:58])[C@H:31]([CH3:57])[NH:32][C:33](=[O:56])[C@H:34]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=1)[NH:35][C:36](=[O:43])[C@H:37]([C@H:39]([CH2:41][CH3:42])[CH3:40])[NH2:38])[C:11]([O:59][CH3:60])=[CH:10][CH:9]=3>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH3:62])([CH3:61])[C:8]3[C:13]([O:14][C:15]=2[C:16]=1[CH2:17][C:18]([OH:20])=[O:19])=[C:12]([CH2:28][NH:29][C:30](=[O:58])[C@H:31]([CH3:57])[NH:32][C:33](=[O:56])[C@H:34]([CH2:44][C:45]1[CH:46]=[CH:47][C:48]([O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[CH:49][CH:50]=1)[NH:35][C:36](=[O:43])[C@H:37]([C@H:39]([CH2:41][CH3:42])[CH3:40])[NH2:38])[C:11]([O:59][CH3:60])=[CH:10][CH:9]=3
Reactant: CC[C@H](C)[C@H](N)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@@H](C)C(=O)NCc1c(OC)ccc2c1Oc1c(ccc(OC)c1CC(=O)OCc1ccccc1)C2(C)C
Agent: [Pd]
Solvent: CO
Product: CC[C@H](C)[C@H](N)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@@H](C)C(=O)NCc1c(OC)ccc2c1Oc1c(ccc(OC)c1CC(=O)O)C2(C)C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
A solution of 0.27 g of benzyl 3,6-dimethoxy-9,9-dimethyl-5-[(L-isoleucyl-O-tert-butyl-L-tyrosyl-L-alanyl)aminomethyl]xanthene-4-acetate in 15 ml of methanol was treated with 50 mg of palladium/charcoal (10%) and stirred under hydrogen for 3 hours. After filtering off the catalyst the solvent was removed and the residue was washed with ether. 0.24 g of 3,6-dimethoxy-9,9-dimethyl-5-[(L-isoleucyl-O-tert-butyl-L-tyrosyl-L-alanyl)aminomethyl]xanthene-4-acetic acid of m.p. 146°-149° was obtained; IR 1662, 1606, 1506, 1494 cm-1.
Reaction SMILES: [CH2:1]([N:8]([C:13]1[CH:18]=[N:17][N:16]([CH3:19])[C:15](=[O:20])[C:14]=1[Cl:21])[CH2:9][CH2:10][CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22]CCl.S(Cl)(Cl)=O>CN(C1C=CN=CC=1)C>[CH2:1]([N:8]([C:13]1[CH:18]=[N:17][N:16]([CH3:19])[C:15](=[O:20])[C:14]=1[Cl:21])[CH2:9][CH2:10][CH2:11][Cl:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ncc(N(CCCO)Cc2ccccc2)c(Cl)c1=O
Reactant: ClCCl
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: Cn1ncc(N(CCCCl)Cc2ccccc2)c(Cl)c1=O
Reaction time: 14 h
Yield: 91 %

Procedure:
To a solution of 10.00 g (32 mmol) of 5-[N-benzyl-N-(3-hydroxypropyl)amino]-4-chloro-2-methyl-3(2H)-pyridazinone in 100 ml of dichloromethane 3.5 ml (5.5 g, 46 mmol) of thionyl chloride are added dropwise while stirring. If necessary, a catalytic amount of 4-(N,N-dimethyl amino)pyridine is added to the solution. The reaction mixture is boiled for 14 hours, then cooled and evaporated. The evaporation residue is triturated with diethyl ether. The crystals are filtered off and washed with diethyl ether. In this way 9.50 g (95%) of the title compound are obtained with a melting point of 92-93° C.
Reaction SMILES: [CH:1]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]=1)=[CH:2][CH2:3][CH2:4][CH3:5].C([Li])CCC.[Cl:20][B:21](Cl)[N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24]>C(OCC)C>[Cl:20][B:21]([N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([CH:1]=[CH:2][CH2:3][CH2:4][CH3:5])=[CH:7]1
Reactant: CC(C)N(B(Cl)Cl)C(C)C
Reactant: CCCC=CC1=CCc2ccccc21
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC=CC1=CC(B(Cl)N(C(C)C)C(C)C)c2ccccc21
Temperature: -74 °C
Reaction time: 3 h

Procedure:
Metallocene MET-1, shown below, was synthesized by first reacting lithiated indene with 5-bromo-1-pentene. Pure 3-(1-pentenyl) indene was obtained via vacuum distillation as a pale yellow oil. One mole of 3-(1-pentenyl) indene was added to diethyl ether and cooled to −74° C., and one mole of n-butyllithium was added. The reaction mixture was stirred at 21° C. for 3 hr, then cooled again to −74° C., followed by the addition of a diethyl ether solution of dichloro(diisopropylamino) boron, and then stirred for 12 hr while warming to 21° C. The resulting yellow slurry was centrifuged, and the bright yellow solution was poured off and solvent removed under reduced pressure. Monochloro(diisopropylamino)-3-(1-pentenyl)indenylboron was obtained as a yellow oil. 1 mol of indene was added to diethyl ether and cooled to −74° C., then n-butyllithium was added and the solution was stirred at 20° C. for 3 hr. The solution was cooled to −74° C. and a diethyl ether solution of monochloro(diisopropylamino)-3-(1-pentenyl)indenylboron was added, resulting in an orange slurry, which was stirred at 20° C. for 12 hr. The reaction solution was filtered into a Schlenk-tube and the solvent was removed under reduced pressure, yielding Ligand-1 shown below.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[S:14][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:16][C:11]3=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.CCOCC>C(Cl)Cl>[CH3:27][O:28][C:29]1[CH:30]=[CH:31][C:32]([S:35]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[N:13]=[C:12]4[S:14][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:16][C:11]4=[CH:10][CH:9]=3)[CH:5]=[CH:6][CH:7]=2)(=[O:37])=[O:36])=[CH:33][CH:34]=1
Reactant: CC(=O)Nc1nc2ccc(-c3cccc(N)c3)nc2s1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Nc2cccc(-c3ccc4nc(NC(C)=O)sc4n3)c2)cc1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 38.2 %

Procedure:
N-(5-(3-aminophenyl)thiazolo[5,4-b]pyridin-2-yl)acetamide (102.6 mg, 0.361 mmol) was suspended in DCM (2.7 ml) and pyridine (0.050 ml, 0.61 mmol) and 4-methoxybenzene-1-sulfonyl chloride (107.2 mg, 0.519 mmol) were added. The reaction was stirred under nitrogen at room temperature for about 100 minutes. The, reaction was treated with Et2O and filtered. Solid washed with Et2O, MeOH, and Et2O, then collected and purified on HPLC (10% to 95% MeCN/water with 0.1% TFA over 30 minutes) to afford N-(5-(3-(4-methoxyphenylsulfonamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)acetamide (62.7 mg, 38% yield). MS (ESI pos. ion) m/z: 455. Calculated exact mass for C21H18N4O4S2 454.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C@@H:19]([NH:28][C:29](=[O:42])[CH2:30][C:31]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([CH3:33])[CH3:32])[C:18]2=[O:43])=[CH:12][CH:11]=1)=[C:2]=[O:3].[CH2:44]([CH2:46][NH2:47])[OH:45]>>[OH:45][CH2:44][CH2:46][NH:47][C:2]([NH:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[CH:12][C:13]([CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C@@H:19]([NH:28][C:29](=[O:42])[CH2:30][C:31]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([CH3:33])[CH3:32])[C:18]2=[O:43])=[CH:14][CH:15]=1)=[O:3]
Reactant: NCCO
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3N=C=O)cc2)C1=O)NC(=O)OC(C)(C)C
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3NC(=O)NCCO)cc2)C1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from N-[1-[[(2'-isocyanato)[1,1'-biphenyl]-4-yl]methyl]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-t-butoxycarbonylamino-3-methylbutanamide and ethanolamine by the procedure described in Example 6, Step A. FAB-MS: calculated for C36H45N5O6 643; found 666 (M+Na). 1H NMR (400 MHz, CDCl3): δ 1.29 (s, 3H), 1.31 (s, 3H), 1.38 (s, 9H), 1.90 (m, 1H), 2.5 (dd, 2H), 2.58 (m, 2H), 2.7 (m, 1H), 3.21 (t, 2H), 3.54 (m, 2H), 4.49 (m, 1H), 4.88 (d, 1H), 5.10 (d, 1H), 6.81 (d, 1H), 7.21 (m, 11H), 7.74 (d, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[O:13][CH3:14].[Cl-:16].[NH2:17][N+:18]1[CH:22]=[CH:21][N:20]([NH2:23])[C:19]=1[CH2:24][CH2:25][CH3:26]>C(O)(=O)C>[Cl-:16].[CH3:1][N:2]([CH3:15])[C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6]([CH:7]=[N:17][N+:18]2[CH:22]=[CH:21][N:20]([N:23]=[CH:7][C:6]3[CH:9]=[C:10]([O:11][CH3:12])[C:3]([N:2]([CH3:1])[CH3:15])=[C:4]([O:13][CH3:14])[CH:5]=3)[C:19]=2[CH2:24][CH2:25][CH3:26])=[CH:5][C:4]=1[O:13][CH3:14]
Reactant: COc1cc(C=O)cc(OC)c1N(C)C
Reactant: CCCc1n(N)cc[n+]1N
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCCc1n(N=Cc2cc(OC)c(N(C)C)c(OC)c2)cc[n+]1N=Cc1cc(OC)c(N(C)C)c(OC)c1
Reaction time: 16 h

Procedure:
1.43 g (6.8 mmol) of 4-dimethylamino-3,5-dimethoxy-benzaldehyde are added to a solution of 0.60 g (3.4 mmol) of 1,3-diamino-2-propyl-imidazolium chloride in 5 ml of glacial acetic acid. After leaving to stand for 16 hours the product is crystallized out by the addition of ether and then recrystallized from ethanol. There is obtained 1,3-bis[[4-(dimethylamino)-3,5-dimethoxybenzylidene]amino]-2-propylimidazolium chloride of melting point 218°-219°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO>[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][O:16][CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOCc2ccc(F)cc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Fc1ccc(COCCC2CCNCC2)cc1
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-[2-(4-fluorobenzyloxy)ethyl]piperidine (257 mg, 0.76 mmol) in MeOH (0.5 mL) was added 2N anhydrous HCl/ether (1.0 mL, 2.0 mmol). The reaction mixture was stirred overnight. After evaporation, the residue was dissolved in deionized water. EtOAc was used to wash the aqueous layer before the pH was altered to approx. 9-10. The aqueous layer was extracted three times with CH2Cl2, and the combined organic phases were dried over Na2SO4. After evaporation, 4-[2-(4-fluorobenzyloxy)ethyl]piperidine (150 mg, 83% yield) was obtained as a colorless oil.
Reaction SMILES: [Si:1]([O:18][C@H:19]1[C:24](=[CH2:25])[C@@H:23]([F:26])[CH2:22]/[C:21](=[CH:27]\[C:28](OCC)=[O:29])/[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl.C1(C)C=CC=CC=1>[Si:1]([O:18][C@H:19]1[C:24](=[CH2:25])[C@@H:23]([F:26])[CH2:22]/[C:21](=[CH:27]\[CH2:28][OH:29])/[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C1[C@@H](F)C/C(=C\C(=O)OCC)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=C1[C@@H](F)C/C(=C\CO)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 67.7 %

Procedure:
The compound of Example 13G (40 mg, 0.09 mmol) was dissolved in 1 mL of 1:1 dichloromethane/toluene and cooled to −78° C. Diisobutylaluminum hydride (1 M in hexanes, 0.36 mL) was added, and the mixture was stirred for 20 minutes. The reaction was quenched by the addition of water; the mixture was warmed to ambient temperature, and then acidified to pH˜2 by addition of concentrated HCl. The mixture was extracted with ethyl acetate; the organics were washed with brine and dried over Na2SO4. The solvents were removed in vacuo; the residue was purified by chromatography on an Analogix Intelliflash 280™, eluting with 17% ethyl acetate in hexanes to give the titled compound (25 mg, 68%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[N:20]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:25][C:21]1[N:20]=[N:19][CH:24]=[CH:23][CH:22]=1)=[O:9]
Reactant: Nc1cccnn1
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1cccnn1)c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Solid 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5, method C; 200 mg, 0.651 mmol) was added to a stirred suspension of CD (106 mg, 0.651 mmol) in THF (6 ml) under nitrogen at 20° C. The reaction mixture was stirred at room temperature for 10 min and pyridazin-3-amine (61.9 mg, 0.651 mmol) was added dropwise. After refluxing for 14 h, the reaction mixture was concentrated to obtain crude product. The crude product was purified by silica gel chromatography, eluting with hexane:ethyl acetate (4:1) to yield the title compound. 183 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(OCC)(=O)C.O>[CH2:23]([O:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([O:12][CH3:13])[CH:3]=[C:2]([F:1])[CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1cc(F)cc(O)c1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: COc1cc(F)cc(OCc2ccccc2)c1[N+](=O)[O-]
Yield: 98.8 %

Procedure:
A mixture of 5-fluoro-3-methoxy-2-nitrophenol(0.56 g), acetonitrile(5 mL), potassium carbonate(0.46 g) and benzyl bromide(0.56 g) was stirred at reflux for 2 h. The cooled mixture was treated with water and ethyl acetate and the organic phase was separated, washed with brine, dried and evaporated to dryness. The residue was purified by flash chromatography eluting with increasingly polar mixtures of ethyl acetate and hexane to give the product (0.82 g), (m/e278, MH+).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[C@H:8]([S:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:7][C:6]1=[O:29])=[N+]=[N-].[Cl-].[NH4+]>CO.[Zn]>[NH2:1][CH2:4][C@H:5]1[C@H:8]([S:9][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH:7][C:6]1=[O:29]
Reactant: [N-]=[N+]=NC[C@@H]1C(=O)N[C@H]1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: NC[C@@H]1C(=O)N[C@H]1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of trans 3-azidomethyl-4-tritylthio-2-azetidinone (10.0 g, 47.5 mmol) in dry methanol (500 ml) was added ammonium chloride (19.0 g) and zinc powder (1.0 g) and the suspension was stirred at room temperature for 5 h. The reaction mixture was filtered and evaporated. The residue was partitioned between 1N hydrochloric acid and benzene. The aqueous layer was basified with 1M sodium bicarbonate and extracted with methylene chloride. The extracts were washed with brine, dried (MgSO4) and evaporated in vacuo. The crude amine crystallized from ether, 14.05 g (79%); mp 139°-139.5° C.; Anal. calcd for C23H22N2OCl.1/4 CH2Cl2 : C 70.56, H 5.73, N 7.08; Found: C 70.68, H 5.94, N 7.27; ir (CHCl3) νmax : 3400 and 1760 cm-1 ; 1Hmr (CDCl3) δ: 7.35 (15H, m), 5.15 (1H, m), 4.3 (1H, bs), 2.7-3.5 (3H, m) and 1.3 ppm (2H, m).