Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O)=[O:3].CCN(C(C)C)C(C)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>ClCCCl>[O:4]1[C@H:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]2[NH:11][C:2]1=[O:3]
Reactant: O=C(Cl)Oc1ccccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C1N[C@H]2CCCC[C@@H]2O1
Yield: 75 %

Procedure:
The (1S,2S)-2-Aminocyclohexanole (750 mg, 6.51 mmol) and the 2-Nitrophenyl chloroformate (1378 mg, 6.84 mmol) were stirred in DCE (15 mL) with DIEA (2.39 mL, 13.68 mmol) in a sealed vial at 90° C. for 1 h. The reaction mixture was given into a separating funnel with 50 mL EtOAc and 50 mL saturated NaHCO3 solution. The aqueous layer was washed with 50 mL EtOAc. The organic layers were combined and washed with 50 mL H2O, 50 mL brine, dried with Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (hexane/EtOAc: 7:3→3:7) to give the title compound (770 mg, 5.13 mmol). tR: 0.69 min (LC-MS 1); 1H NMR (400 MHz, <dmso>) δ ppm 1.19-1.44 (m, 3H) 1.45-1.61 (m, 1H) 1.65 (d, J=9.77 Hz, 1H) 1.76 (d, J=11.34 Hz, 1H) 1.82-1.93 (m, 1H) 1.93-2.10 (m, 1H) 3.03-3.23 (m, 1H) 3.74 (td, J=11.34, 3.52 Hz, 1H) 7.53 (br. s., 1H)
Reaction SMILES: [CH3:1][O:2][C@H:3]([C@@H:8]([CH3:16])[C@@H:9]([O:14][CH3:15])/[CH:10]=[CH:11]/[CH:12]=[CH2:13])[C@@H:4]([CH3:7])[CH2:5][OH:6].C[N+]1([O-])CCOCC1>ClCCl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH3:1][O:2][C@H:3]([C@@H:8]([CH3:16])[C@@H:9]([O:14][CH3:15])/[CH:10]=[CH:11]/[CH:12]=[CH2:13])[C@@H:4]([CH3:7])[CH:5]=[O:6]
Reactant: C=C/C=C/[C@H](OC)[C@H](C)[C@@H](OC)[C@@H](C)CO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: C=C/C=C/[C@H](OC)[C@H](C)[C@@H](OC)[C@@H](C)C=O
Reaction time: 3 h
Yield: 93 %

Procedure:
To (E)-(2S,3S,4S,5S)-3,5-Dimethoxy-2,4-dimethyl-nona-6,8-dien-1-ol (1.3 g, 5.70 mmol) in anhydrous dichloromethane (58 ml) at room temperature and under an atmosphere of nitrogen was added activated 4A molecular sieves (1.3 g), N-methylmorpholine-N-oxide (2.0 g, 17.1 mmol) and TPAP (100 mg, 0.29 mmol). The reaction was stirred for 3 hours and filtered through a SiO2 pad, and the pad washed well with diethyl ether. The filtrate was concentrated in vacuo to afford the product as a clear oil (1.2 g, 93%). 1H NMR (300 MHz, CDCl3) δ 9.83 (d, J=2.7 Hz, 1H), 6.40 (dt, J=16.8 Hz, 10.2 Hz, 1H), 6.24 (dd, J=15.2 Hz, 10.6 Hz, 1H), 5.45 (dd, J=15.2 Hz, 8.8 Hz, 1H), 5.26 (dd, J=16.4 Hz, 1.3 Hz, 1H), 5.14 (dd, J=10.2 Hz, 1.6 Hz, 1H), 3.87 (dd, J=9.1 Hz, 2.4 Hz, 1H), 3.41 (m, 1H), 3.43 (s, 3H), 3.26 (s, 3H), 2.62 (m, 1H), 1.70 (m, 1H), 1.00 (d, J=7.1 Hz, 3H), 0.82 (d, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]2[CH2:13][C@H:12]([S:14][C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][N:10]2[C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=2)=[O:35])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:54][S:55](Cl)(=[O:57])=[O:56]>ClCCl>[CH3:54][S:55]([O:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]2[CH2:13][C@H:12]([S:14][C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:11][N:10]2[C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=2)=[O:35])[CH2:4][CH2:3]1)(=[O:57])=[O:56]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN1CCN(O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)ON1CCN(C[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-2-[(4-hydroxypiperizin-1-yl)methyl]-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (5.4 g) and triethylamine (1.54 ml) in dichloromethane (60 ml) was added methanesulfonyl chloride (0.72 ml) under ice-cooling and the mixture was stirred under the same condition for 1 hour. The reaction mixture was washed successively with aqueous sodium hydrogen carbonate and aqueous sodium chloride, dried over magnesium sulfate, and evaporated in vacuo to give (2S,4S)-2-[(4-methanesulfonyloxypiperizin-1-yl)methyl]-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (6.06 g).
Reaction SMILES: [F:1]/[C:2](=[C:5](/[C:7]1[CH:16]=[C:15]2[C:10]([C:11]([CH3:22])([CH3:21])[CH2:12][CH:13]=[C:14]2[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:9][C:8]=1[O:23][CH2:24][CH3:25])\[CH3:6])/[CH2:3][OH:4].C[N+]1([O-])CCOCC1.ClCCl>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1]/[C:2](=[C:5](/[C:7]1[CH:16]=[C:15]2[C:10]([C:11]([CH3:22])([CH3:21])[CH2:12][CH:13]=[C:14]2[C:17]([CH3:19])([CH3:18])[CH3:20])=[CH:9][C:8]=1[O:23][CH2:24][CH3:25])\[CH3:6])/[CH:3]=[O:4]
Reactant: CCOc1cc2c(cc1/C(C)=C(/F)CO)C(C(C)(C)C)=CCC2(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: CCOc1cc2c(cc1/C(C)=C(/F)C=O)C(C(C)(C)C)=CCC2(C)C

Procedure:
As described in General Procedure H-1, (2E)-2-fluoro-3-(4,4-dimethyl-6-ethoxy-1-tert-butyl-3,4-dihydronaphthalen-7-yl)-2-butenol (Compound A-55, 0.023 g, 0.066 mmol), tetrapropylammonium perruthenate (0.012 g, 0.038 mmol) and 4-methylmorpholine N-oxide (0.022 g, 0.19 mmol) were reacted in acetonitrile (0.2 mL) and dichloromethane (1 mL) to produce the title compound as an oil.
Reaction SMILES: [OH-].[Na+].[CH:3]([C:15]1[CH:16]=[N:17][N:18]([CH:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([O:23]CC)=[O:22])[CH:19]=1)=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C(O)C>[CH:3]([C:15]1[CH:16]=[N:17][N:18]([CH:20]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:21]([OH:23])=[O:22])[CH:19]=1)=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCC=Cc1cnn(C(C(=O)OCC)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCC=Cc1cnn(C(C(=O)O)c2ccccc2)c1
Reaction time: 1 h
Yield: 105.2 %

Procedure:
Solid NaOH (6.72 g, 168 mmol) was added to a solution of ethyl (±)-4-(1-dodecenyl)-α-phenyl-1H-pyrazole-1-acetate (44.41 g, 112 mmol) in 500 mL 95% ethanol. The resulting yellow solution was stirred for 1 hour and then concentrated in vacuo. The residue was partitioned between water and ether, the aqueous layer was acidified with concentrated HCl and extracted with ethyl acetate. The ethyl acetate layer was dried over MgSO4, filtered, and concentrated to give a yellow oil (43.4 g) used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[C:29]([C:30](Cl)=[O:31])=[C:28]([CH3:33])[O:27][N:26]=1>>[CH3:16][N:15]([CH3:17])[C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:13][CH2:12][CH:11]([NH:14][C:30]([C:29]2[C:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[Cl:18])=[N:26][O:27][C:28]=2[CH3:33])=[O:31])[CH2:10][CH2:9]1
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)Cl
Reactant: CN(C)C1(c2cccc(F)c2)CCC(N)CC1
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)NC1CCC(c2cccc(F)c2)(N(C)C)CC1

Procedure:
As described for Example 118, the polar diastereoisomer of 1-(3-fluorophenyl)-N,N-dimethylcyclohexane-1,4-diamine (350 mg) was reacted with 400 mg 3-(2-chlorophenyl)-5-methylisoxazole-4-carbonylchloride and worked up in a similar manner. The resultant crude product (590 mg) was chromatographed on silica gel (4.0×15 cm) with ethyl acetate/n-hexane/methanol (V:V=1:1:1). 440 mg of the polar diastereoisomer of 3-(2-chlorophenyl)-5-methylisoxazole-4-carboxylic acid [4-dimethylamino-4-(3-fluorophenyl)cyclohexyl]amide were obtained which, dissolved in 90 ml 2-butanone, were converted overnight into the corresponding hydrochloride by adding 17 μl water and 120 μl chlorotrimethylsilane (460 mg of white solid, Mp. 209-211° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH3:21])[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].CO.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH3:21])[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: CCc1c(C(=O)OC)cc(Cl)cc1N(C)C1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1c(C(=O)O)cc(Cl)cc1N(C)C1CCOCC1
Temperature: 50 °C
Reaction time: 27 h
Yield: 97.6 %

Procedure:
To a solution of methyl 5-chloro-2-ethyl-3-[methyl(oxan-4-yl)amino]benzoate (334 mg, 1.07 mmol) in THF (11 ml) was added 4M NaOH (10.7 ml). The reaction mixture was stirred at 50° C. for 27 hours. MeOH (5 ml) was added to the reaction mixture and this was stirred for a further 21 hours at 50° C. The reaction mixture was acidified to pH 2-3 with 6M HCl and extracted with DCM (5×10 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give 311 mg of the title compound as an orange oil that solidified upon standing. The material was taken through the next step without further purification. LC-MS 79%, 2.01 min (3 minute LC-MS method), m/z=298.0/300.0, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.72 (d, J=2.1 Hz, 1H), 7.37-7.27 (m, 1H), 4.00 (brd, J=11.1 Hz, 2H), 3.36 (td, J=11.6, 2.0 Hz, 2H), 3.11 (q, J=7.4 Hz, 2H), 2.94 (t, J=10.6 Hz, 1H), 2.64 (s, 3H), 1.78-1.56 (m, 4H), 1.15 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=1)[CH3:2].OS(O)(=O)=O.[CH3:18]O>>[CH2:1]([NH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:18])=[O:9])=[CH:6][N:5]=1)[CH3:2]
Reactant: CCNc1ccc(C(=O)O)cn1
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCNc1ccc(C(=O)OC)cn1
Yield: 84 %

Procedure:
A suspension of 6-(ethylamino)nicotinic acid (50 g, 0.3 mol) in methanol (500 ml) was treated with concentrated H2SO4 (30 ml). The reaction was heated at reflux for 18 hours. The reaction mixture was then evaporated, poured into ice water (1 L) and adjusted to pH 8 with solid sodium hydrogen carbonate (foaming). The aqueous mixture was extracted with ethyl acetate (3×300 ml) and the organic layers combined, dried (MgSO4) and evaporated to give methyl 6-(ethylamino)nicotinoate as an off-white solid (45.5 g, 84%).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Cl[CH2:22][C:23](=[O:25])[CH3:24]>>[CH2:22]([N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19])[C:23]([CH3:24])=[O:25]
Reactant: CC(=O)CCl
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: CC(=O)Cn1c(Oc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Yield: 45 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and chloroacetone were reacted by the same way with the example 1 to obtain the titled compound (155 mg, yield: 45%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([Cl:7])=[CH:4][CH:3]=1.[CH2:8]([OH:11])[C:9]#[CH:10]>N1CCCCC1.CCOC(C)=O.CCOCC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[Cl:7][C:5]1[S:6][C:2]([C:10]#[C:9][CH2:8][OH:11])=[CH:3][CH:4]=1
Reactant: C#CCO
Reactant: Clc1ccc(Br)s1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: OCC#Cc1ccc(Cl)s1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 9.1 %

Procedure:
Nitrogen (g) is bubbled through a solution of 5-bromo-2-chloro-thiophene (1.00 g, 5.06 mmol) in 8 mL of piperidine. After 5 min, propargyl alcohol (0.32 mL, 5.56 mmol), tetrakis(triphenylphosphine) palladium(0) (0.06 g) and CuI (catalytic amount) are added to the solution. The mixture is heated at 80° C. for 1 h in a sealed glass vessel. At this time, the mixture is cooled and diluted with EtOAc/Et2O. The organic layer is washed 3N HCl, water, saturated NaHCO3 solution and saturated NaCl solution. The organic layer is dried, filtered and concentrated. The crude residue is purified via flash column chromatography eluting with a gradient of 10% EtOAc/hexanes to 20% EtOAc/hexanes to give the title compound (0.8 g, 0.46 mmol) as an oil. 1H NMR (DMSO-d6, 300 MHz) δ6.99 (d, 1H), 6.80 (d, 1H), 4.49 (s, 2H), 1.90 (bs, 1H). EI MS, [M]+=172, 174 (Cl pattern).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:16][S:17][CH2:18][C:19]([N:21]3[C@@H:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:24][O:23][C:22]3=[O:32])=[O:20])[O:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37](/[N:40]=[CH:41]/[C:42]2[CH:56]=[CH:55][C:45]([O:46][CH2:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[CH:44][CH:43]=2)=[CH:36][CH:35]=1.C(N(C(C)C)C(C)C)C.[NH4+].[Cl-]>C(Cl)Cl.[Cl-].[Na+].O.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].Cl[Ti](Cl)(Cl)Cl.C(O)(C)C>[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([NH:40][C@@H:41]([C:42]2[CH:43]=[CH:44][C:45]([O:46][CH2:47][C:48]([O:50][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:49])=[CH:55][CH:56]=2)[C@@H:18]([S:17][CH2:16][C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[O:9][CH2:10][C:11]([CH3:14])([CH3:15])[CH2:12][O:13]2)[C:19](=[O:20])[N:21]2[C@@H:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:24][O:23][C:22]2=[O:32])=[CH:38][CH:39]=1
Reactant: CC1(C)COC(CSCC(=O)N2C(=O)OC[C@@H]2c2ccccc2)(c2ccc(Cl)cc2)OC1
Reactant: CC(C)(C)OC(=O)COc1ccc(/C=N/c2ccc(Cl)cc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: ClCCl
Solvent: O
Solvent: CC(C)O
Product: CC1(C)COC(CS[C@@H](C(=O)N2C(=O)OC[C@@H]2c2ccccc2)[C@@H](Nc2ccc(Cl)cc2)c2ccc(OCC(=O)OC(C)(C)C)cc2)(c2ccc(Cl)cc2)OC1
Temperature: -40 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
Tetraisopropyl orthotitanate (0.23 ml, 0.77 mmol) was added to a solution of TiCl4 (1M in CH2Cl2, 2.25 ml, 2.25 mmol) in CH2Cl2 (22 ml) at 0° C. under inert atmosphere. The mixture was stirred for ten minutes. (4S)-3-[({[2-(4-Chlorophenyl)-5,5-dimethyl-1,3-dioxan-2-yl]methyl}thio)acetyl]-4-phenyl-1,3-oxazolidin-2-one (1.44 g, 3.03 mmol) in dry CH2Cl2 (25 ml) was added dropwise over 45 minutes and the mixture was stirred for ten minutes. tert-Butyl (4-{(E)-[(4-chlorophenyl)imino]methyl}phenoxy)acetate (2.09 g, 6.04 mmol) in dry CH2Cl2 (25 ml) was added dropwise over 80 minutes. The mixture was cooled to −40° C. and stirred for 20 minutes. Ethyl diisopropyl amine (1.03 ml, 6.02 mmol) was added dropwise over 40 minutes and the mixture was stirred at −40° C. for ten minutes. The mixture was cooled to −78° C. and isopropanol (80 ml) was added. The temperature was allowed to reach room temperature over three hours. NH4Cl (10%, 80 ml) was added and the mixture was stirred for 35 minutes. Brine (200 ml) was added and the mixture was extracted twice with 400 ml diethyl ether. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. Purification by flash-chromatography (10%-20% EtOAc in hexane) afforded 1.69 g (65%) of the title compound as a white solid. 1H-NMR (CDCl3, 200 MHz): δ 0.65 (s, 3H), 1.3 (s, 3H), 1.5 (s, 9H), 2.6-2.9 (m, 2H), 3.4 (m, 4H), 4.2 (m, 1H), 4.5 (s, 2H), 4.64-8 (m, 2H), 5.3 (m, 1H), 5.7 (d, 1H), 6.4 (m, 2H), 6.7-7.4 (m, 15H).
Reaction SMILES: Cl.[OH:2][C:3]1[C:8]([C:9]2[NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([C:27]([NH2:29])=[NH:28])=[CH:26][C:20]=2[N:19]=1>CO.O=[Pt]=O>[OH:2][C:3]1[C:8]([C:9]2[NH:17][C:12]3[CH2:13][NH:14][CH2:15][CH2:16][C:11]=3[N:10]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([C:27]([NH2:29])=[NH:28])=[CH:26][C:20]=2[N:19]=1
Reactant: N=C(N)c1ccc2[nH]c(-c3cccc(-c4nc5cnccc5[nH]4)c3O)nc2c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: N=C(N)c1ccc2[nH]c(-c3cccc(-c4nc5c([nH]4)CNCC5)c3O)nc2c1
Reaction time: 15 h
Yield: 19.8 %

Procedure:
PtO2 (20 mg) and concentrated hydrochloric acid (5 mL) was added to a solution of 2-[2-Hydroxy-3-(1H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-1H-benzoimidazole-5-carboxamidine (Example 120, Table 2) (100 mg, 0.27 mmol) in MeOH (20 mL). The mixture was hydrogenated at 50 psi in a Parr apparatus for 12-18 h. After the hydrogenation was completed, the catalyst was filtered and the filtrate was concentrated to dryness. HPLC purification (2-50% acetonitrile/60 minutes) followed by lyophilization afforded 2-[2-Hydroxy-3-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-1H-benzoimidazole-5-carboxamidine 75 as pale yellow powder (20 mg, 20% yield) (Example 296, Table 2a).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:24])=[C:13]([F:23])[CH:14]=2)[N:9]=1.[CH3:25][NH:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:18]([C:17]1[C:8]([N:26]([CH3:25])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([F:23])=[C:12]([F:24])[CH:11]=2)=[O:19])[CH3:22]
Reactant: CCOC(=O)CCNC
Reactant: CCOC(=O)c1cc2cc(F)c(F)cc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCN(C)c1nc2cc(F)c(F)cc2cc1C(=O)OCC
Temperature: 90 °C
Reaction time: 4 h
Yield: 96.8 %

Procedure:
56.2 g of sodium carbonate are added to a solution of 72 g of 2-chloro-3-ethoxycarbonyl-6,7-difluoroquinoline and 45.1 g of N-methyl-N-(β-ethoxycarbonylethyl)amine in 750 cm3 of toluene. The suspension obtained is heated to approximately 90° C. and then stirred for 4 hours at this temperature. The reaction mixture is then cooled to approximately 20° C. and thereafter washed with 3 times 400 cm3 of water. The organic phase is concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C. 94 g of 3-ethoxycarbonyl-6,7-difluoro-2-[N-methyl-N-(β-ethoxycarbonylethyl)amino]quinoline are obtained in the form of an oil, which is used without further purification for the subsequent steps.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:15]=[CH:14][S:13][CH:12]=1.[C:16](Cl)(=[O:18])[CH3:17]>ClCCl>[S:13]1[CH:14]=[CH:15][C:11]([CH2:10][NH:9][C:16](=[O:18])[CH3:17])=[CH:12]1
Reactant: NCc1ccsc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccsc1
Temperature: -5 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
Triethylamine (0.46 g, 4.4 mmol) was added dropwise to a stirred suspension of 3-(aminomethyl)thiophene hydrochloride (0.6 g, 4 mmol) in dry dichloromethane (20 ml) maintained under nitrogen at -5° C. After 15 minutes acetyl chloride (0.31 g, 4 mmol) was added dropwise to the solution which was then stirred for 3 hours at -5° C. After this time the reaction mixture was washed sequentially with dilute HCl (50 ml, 0.5M) and dilute NaOH (50 ml, 0.5 m). The organic layer was separated, dried with magnesium sulphate, and the solvent removed in vacuo to yield the crude product which was recrystallised from hexane to give N-(3-thienylmethyl)acetamide (0.52 g, 85%) M.p. 46°-47° C. (Found: C, 53.5; H, 6.2; N. 8.7, S, 20.4. Calculated for C7H9NOS: C, 54.2; H, 5.8, N, 9.0; S, 20.7 (%); IR (Nujol): 3250, 1650 cm-1 ; EI m/e Intensity (%): 155 (37, M+), 112 (55, C4H3S.CH2NH+), 97 (29, C4H3S.CH2+). 83 (12, C4H3S); δH(CDCl3) 7.00-7.29 (3H, m), 6.26 (1H, br,s), 4.41 (2H, d), 1.93 (3H, s); δC(CDCl3): 23.1, 38.7, 122.2, 126.3, 127.3, 139.8, 170.0 ppm.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[C:28]3[CH2:30][NH:31][CH2:32][CH2:33][C:27]3=[N:26][C:25]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:20][CH2:19]1)[C:12]#[N:13].C=O.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:19][CH2:20][N:21]([C:24]2[N:29]=[C:28]3[CH2:30][N:31]([CH3:2])[CH2:32][CH2:33][C:27]3=[N:26][C:25]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:22][CH2:23]1)[C:12]#[N:13].[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CNCC2
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CN(C)CC2
Temperature: 23 °C
Reaction time: 2 h

Procedure:
To a solution of 3-fluoro-4-((1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrile TFA salt (20.7 mg, 0.039 mmol) and formaldehyde (3.2 μL, 0.043 mmol) in MeOH (0.5 mL) was added DIPEA (0.014 mL, 0.079 mmol) and sodium triacetoxyborohydride (16.7 mg, 0.079 mmol) at 23° C. The mixture was stirred at 23° C. for 2 hr and then concentrated via rotary evaporation. The crude material was diluted with DMSO, filtered, rinsed with DMSO, and purified by with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm was used, using a 30% to 40% ACN gradient to give the title compound as a TFA salt (5.3 mg, 25%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6, mixture of rotamers) δ ppm 1.16-1.24 (m, 6H), 1.87-1.96 (m, 2H), 2.08-2.16 (m, 2H), 2.74-2.85 (m, 0.9H), 2.85-2.92 (m, 1.1H), 2.95 (br s, 1.3H), 2.96 br s, 1.7H), 2.97-3.00 (m, 1H), 3.25-3.42 (m, 3H), 3.65-3.71 (m, 1H), 4.12-4.19 (m, 2H), 4.25-4.31 (m, 1H), 4.82-4.88 (m, 1H), 5.89 (d, J=8.3 Hz, 1H), 7.50 (t, J=8.6 Hz, 1H), 7.66-7.71 (m, 1H), 7.87 (dd, J=11.4, 2.0 Hz, 1H), 9.96 (br s, 1H); ESI-MS m/z [M+H]+ 425.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:15][C:16]([CH2:18]Cl)=[O:17]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][C:16](=[O:17])[CH2:18][N:11]3[CH2:10][CH2:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:13][CH2:12]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=C(CCl)CCl
Solvent: CC(C)=O
Product: O=C(CN1CCN(c2ccc(F)cc2)CC1)CN1CCN(c2ccc(F)cc2)CC1

Procedure:
To a solution of 1-(4-fluorophenyl)piperazine (12 g) in acetone (40 ml) kept at reflux temperature a solution of 1,3-dichloroacetone (1.3 g) in acetone (10 ml) was added dropwise. The mixture was refluxed for another 2 hours. Acetone was evaporated in vacuo. The remaining viscous oil was subjected to column chromatography on silica gel (eluted with ethyl acetate/ethanol/triethylamine 80:20:4). The title compound 13a crystallized from diethyl ether. Yield 0.6 g. Mp 106°-107° C. 1H NMR (CDCl3) δ2.70 (t,8H), 3.15 (t,8H), 3.45 (s, 4H), 6.85-7.00 (m,8H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:18]([F:19])=[C:17](F)[CH:16]=[C:15]2[C:10]=1[C:11](=[O:27])[C:12]([C:24]([OH:26])=[O:25])=[CH:13][N:14]2[CH:21]1[CH2:23][CH2:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH:32]1[CH3:37])(=[O:30])[CH3:29]>N1C=CC=CC=1>[C:28]([N:31]1[CH2:36][CH2:35][N:34]([C:17]2[CH:16]=[C:15]3[C:10]([C:11](=[O:27])[C:12]([C:24]([OH:26])=[O:25])=[CH:13][N:14]3[CH:21]3[CH2:23][CH2:22]3)=[C:9]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:18]=2[F:19])[CH2:33][CH:32]1[CH3:37])(=[O:30])[CH3:29]
Reactant: CC(=O)N1CCNCC1C
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)c(NCc3ccccc3)c2c1=O
Solvent: c1ccncc1
Product: CC(=O)N1CCN(c2cc3c(c(NCc4ccccc4)c2F)c(=O)c(C(=O)O)cn3C2CC2)CC1C

Procedure:
A mixture of 5-benzylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-acetyl-2-methylpiperazine and pyridine was heated under reflux. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with chloroform. The extract was dried and chloroform was evaporated. Ethanol was added to the residue, and the crystals were collected by filtration to give 7-(4-acetyl-3-methyl-1-piperazinyl)-5-benzylamino-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. It was recrystallized from ethanol/diisopropyl ether. m.p. 235°-236° C.