Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:3]=12.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=1.[H-].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=4[C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:3]=12
Reactant: CCCc1nc2c(Cl)ccnc2[nH]1
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1nc2c(Cl)ccnc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
200 mg of the above-prepared 7-chloro-2-n-propyl-3H-imidazo[4,5-b]pyridine and 380 mg of methyl 2-(4-bromomethylphenyl)benzoate were dissolved in dimethylformamide, and 50 mg of sodium hydride was added to the solution. The mixture was stirred at room temperature for 20 min, and water was added thereto, followed by extraction with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was distilled off in vacuo. The residue was purified by silica gel chromatography (benzene:ethyl acetate=40:1→20:1) to prepare the intended product as a colorless oleaginous substance. The yield was 140 mg.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:19]([NH2:21])[CH3:20]>C(#N)C>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:21][CH2:19][CH3:20])=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCNCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 50 %

Procedure:
To a mixture of 0.34 g (2.0 mmol, 1.0 eq.) of 1-(chloromethyl)-4-nitrobenzene and 1.38 g (10 mmol, 5.0 eq.) of potassium carbonate in 20 mL of acetonitrile was added 0.33 g (4.0 mmol, 2.0 eq.) ethylamine hydrochloride. The reaction mixture was heated at reflux for 16 h. The reaction mixture was allowed to cool to room temperature, filtered and the solvent removed in vacuo to provide 0.18 g (1.0 mmol, 50%) of N-(4-nitrobenzyl)ethanamine (I-29).
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.CCN(CC)CC.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[NH2:1][C:2]1[S:10][C:5]2[CH2:6][N:7]([C:34]([NH:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:35])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1sc2c(c1C(=O)c1ccc(Cl)cc1)CCNC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1sc2c(c1C(=O)c1ccc(Cl)cc1)CCN(C(=O)Nc1ccccc1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-amino-3-(4-chlorobenzoyl)-4,5,6,7-tetrahydrothieno(2,3-c)pyridine) (1.02 mmol) in dry CH2Cl2 (20 mL), Et3N (1.2 eq) and phenylisocyanate (1.2 eq) were added. The mixture was stirred at room temperature for 4 hours, then was concentrated at reduced pressure and the residue purified by flash chromatography (EtOAc/light petroleum 3/7) to afford the desired compound as a solid (mp 216-217 ° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][CH:13]([CH3:15])[CH3:14])[CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.[CH2:31]([O:33][C:34](=[O:43])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40](Cl)=[O:41])[CH3:32]>ClCCl>[CH2:31]([O:33][C:34](=[O:43])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40](=[O:41])[N:12]([CH:9]1[CH2:10][CH2:11][N:6]([CH2:5][C:4]2[C:3]([O:2][CH3:1])=[CH:19][CH:18]=[CH:17][C:16]=2[O:20][CH3:21])[CH2:7][CH2:8]1)[CH:13]([CH3:15])[CH3:14])[CH3:32]
Reactant: CCOC(=O)CCCCCC(=O)Cl
Reactant: COc1cccc(OC)c1CN1CCC(NC(C)C)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCCC(=O)N(C(C)C)C1CCN(Cc2c(OC)cccc2OC)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 103.4 %

Procedure:
A solution of [1-(2,6-dimethoxybenzyl)piperidin-4-yl]isopropylamine (1.3 g, 4.6 mmol) and N,N-diisopropylethylamine (1.2 mL, 9.9 mmol) in dichloromethane (40 mL) was cooled to 0° C. under nitrogen. 6-Chlorocarbonylhexanoic acid ethyl ester (0.73 mL, 5.0 mmol) was added dropwise and the reaction mixture was stirred at 0° C. for 2 h and then at room temperature for an additional 2 h. The reaction mixture was then transferred to a separatory funnel and washed with NaHCO3 (2×) and brine (1×). The organic layer was then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the title intermediate as a yellow oil (2.2 g), which was used without further purification.
Reaction SMILES: C=C1CCCC(C)(C)[C@@H]1CC1C=C(OC)C(Br)=C(O[SiH](C)C)C=1C(C)(C)C.[CH2:28]=[C:29]1[C@@H:34]([OH:35])[CH2:33][C@H:32](Br)[C:31]([CH3:38])([CH3:37])[C@H:30]1[CH2:39][C:40]1[CH:45]=[C:44]([O:46][CH3:47])[C:43]([Br:48])=[CH:42][C:41]=1[O:49]C(=O)C.[SiH3]C1C=CC=CC=1O>>[OH:35][C@H:34]1[CH2:33][CH2:32][C:31]([CH3:37])([CH3:38])[C@H:30]([CH2:39][C:40]2[CH:45]=[C:44]([O:46][CH3:47])[C:43]([Br:48])=[CH:42][C:41]=2[OH:49])[C:29]1=[CH2:28]
Reactant: C=C1[C@@H](O)C[C@H](Br)C(C)(C)[C@H]1Cc1cc(OC)c(Br)cc1OC(C)=O
Agent: C=C1CCCC(C)(C)[C@@H]1Cc1cc(OC)c(Br)c(O[SiH](C)C)c1C(C)(C)C
Agent: Oc1ccccc1[SiH3]
Product: C=C1[C@@H](Cc2cc(OC)c(Br)cc2O)C(C)(C)CC[C@@H]1O

Procedure:
This set of diastereomeric alcohols was prepared from (2S)-1-methylidene-2-[2'-(tert-butyl)dimethylsilyloxy-4'-bromo-5'-methoxyphenyl]methyl-3,3-dimethylcyclohexane (51) (0.340 g, 0.75 mmol) in the manner previously described for the synthesis of alcohol 54, affording 302 mg (86%) of an inseparable 1:1 mixture of diastereomeric allylic alcohols (58). A portion (21.6 mg, 0.046 mmol) of this diastereomeric mixture was subjected to deprotection of the silylphenol in the usual manner, yielding mixture of free phenols, separable by flash column chromatography (silica gel, hexanes lethyl acetate, gradient elution), to give 7.2 mg (44%) of the less polar 1S,3S diastereomer (59), along with 6.5 mg (40%) of the more polar 1R,3S diastereomer (60) as white solids. The 400MHz 1H NMR spectrum and TLC. elution properties of each diastereomer 59 and 60 were identical to those previously reported for their respective enantiomeric hydroxy compounds 56 and 57. [Compound 59 is hereinafter also referred to as COMPOUND "B" or 120263]
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[CH3:32][CH:33]([C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH2:44])(=[O:43])=[O:42])=[CH:37][CH:36]=1)[CH3:34]>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:44][S:41]([C:38]3[CH:37]=[CH:36][C:35]([CH:33]([CH3:32])[CH3:34])=[CH:40][CH:39]=3)(=[O:43])=[O:42])=[O:24])=[CH:18][CH:19]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: CC(C)c1ccc(S(N)(=O)=O)cc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(C(C)C)cc3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 4-(1-methylethyl)benzenesulfonamide: 1H-NMR (CDCl3) δ 7.75 (2H, d, J=8.4 Hz), 7.47-7.24 (11H, m), 6.44 (1H, br.s), 3.54-3.47 (2H, m), 3.02-2.84 (3H, m), 2.33 (3H, s), 2.26 (3H, s), 1.25 (6H, d, J=6.9 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>CC(C)=O>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:10][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][CH:7]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(COc2cccc([N+](=O)[O-])c2)cc1

Procedure:
A mixture of 3-nitrophenol (18.49 g, 0.133 mol), anhydrous potassium carbonate (19.2 g, 0.139 mol), potassium iodide (21.0 g, 0.127 mol) and 4-methoxybenzyl chloride (19.82 g, 0.127 mol) in acetone (200 ml) was heated under reflux for 48 h.
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:5]1[CH:9]=[C:8]([C:10]2[CH:33]=[CH:32][C:13]3[N:14]([C:17]4[CH:18]=[C:19]([NH:28]C(=O)C)[CH:20]=[C:21]([N:23]5[CH:27]=[CH:26][CH:25]=[CH:24]5)[CH:22]=4)[CH:15]=[N:16][C:12]=3[CH:11]=2)[CH:7]=[N:6]1)[CH3:4]>C(O)C.C(OCC)(=O)C>[CH2:3]([N:5]1[CH:9]=[C:8]([C:10]2[CH:33]=[CH:32][C:13]3[N:14]([C:17]4[CH:18]=[C:19]([CH:20]=[C:21]([N:23]5[CH:27]=[CH:26][CH:25]=[CH:24]5)[CH:22]=4)[NH2:28])[CH:15]=[N:16][C:12]=3[CH:11]=2)[CH:7]=[N:6]1)[CH3:4]
Reactant: CCn1cc(-c2ccc3c(c2)ncn3-c2cc(NC(C)=O)cc(-n3cccc3)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCn1cc(-c2ccc3c(c2)ncn3-c2cc(N)cc(-n3cccc3)c2)cn1
Yield: 78 %

Procedure:
A mixture of 20% NaOH (5 ml) and the compound of Example 171 (0.9 g, 2.12 mmol) in 25 ml of ethanol was heated at 90° C. for 2 h. The mixture was diluted with ethyl acetate (100 ml) and the organic layer was washed with water (50 ml) and brine (25 ml). The solvent was distilled off and the residue was purified by column chromatography over silica gel to afford the compound in 78% yield (0.7 g).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].N1C=CN=C1.Cl[Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:18]([Si:17]([O:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([Br:1])=[C:3]([CH3:10])[CH:4]=1)([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(C)c1Br

Procedure:
At room temperature, 5.0 g (24.87 mmol) of 4-bromo-3,5-dimethylphenol, 2.03 g (29.84 mmol) of imidazole and 6.23 g (32.33 mmol) of chloro(triisopropyl)silane are stirred in 20 ml of dimethylformamide overnight. Saturated sodium bicarbonate solution is then added, and the mixture is extracted three times with diethyl ether. The combined organic phases are washed with water and dried with sodium sulphate, and the solvent is removed under reduced pressure. This gives 7.5 g (84% of theory) of 4-bromo-3,5-dimethylphenyl triisopropylsilyl ether.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Br:10])[C:5]#[N:6].[S:11](Cl)([CH3:14])(=[O:13])=[O:12].[H-].[Na+].[Cl-].[NH4+]>O.O1CCCC1.C(Cl)Cl>[Br:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[NH:1][S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: N#Cc1ccc(Br)c(N)c1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)Nc1cc(C#N)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
To a mixture of 3-amino-4-bromo-benzonitrile (1.98 g, 10 mmol), TEA (5.06 g, 50 mmol), and methylene chloride (50 ml), mesyl chloride (2.71 ml, 35 mmol) was added at 0° C. and the mixture was stirred at room temperature for 30 min. Water was added to the reaction solution, which was then extracted with dichloromethane. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were added with tetrahydrofuran (100 ml), water (400 μl) and sodium hydride (540 mg, 15.5 mmol), and stirred at room temperature for 16 hr. To the reaction solution, saturated aqueous solution of ammonium chloride (200 ml) was added followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.48 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[CH:20]2[CH2:24][CH2:23][CH2:22][NH:21]2)[CH:11]=1)(=[O:9])=[O:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:69](O)(=[O:76])[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1>CN(C=O)C.C(OCC)(=O)C>[C:69]([N:21]1[CH2:22][CH2:23][CH2:24][CH:20]1[C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH:18]=[CH:19][C:10]([S:7]([N:6]([CH2:5][C:4]1[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:3]=1[O:2][CH3:1])[C:25]1[S:26][CH:27]=[CH:28][N:29]=1)(=[O:9])=[O:8])=[CH:11]2)(=[O:76])[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(C4CCCN4)cccc3c2)c(OC)c1
Reactant: O=C(O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(C4CCCN4C(=O)c4ccccc4)cccc3c2)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-(2,4-dimethoxybenzyl)-5-(pyrrolidin-2-yl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide (Intermediate NN, 0.033 g, 0.065 mmol) and HBTU (0.037 g, 0.097 mmol) were dissolved in DMF (0.324 mL). Hunig's base (0.034 mL, 0.194 mmol) and benzoic acid (0.016 g, 0.130 mmol) were added and the reaction was stirred for four hours at room temperature. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (12 g silica gel column, gradient elution 0 to 100% EtOAc:Heptane) to afford 5-(1-benzoylpyrrolidin-2-yl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide as an off-white solid. m/z (ESI) 614.3 (M+H)+.
Reaction SMILES: [Li+].CCC[CH2-].[CH2:6]([C@@H:13]1[CH2:17][O:16][C:15](=[O:18])[NH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:19](Cl)(=[O:24])[CH2:20][CH:21]([CH3:23])[CH3:22].[Cl-].[NH4+]>O1CCCC1>[CH2:6]([C@@H:13]1[CH2:17][O:16][C:15](=[O:18])[N:14]1[C:19](=[O:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)CC(=O)Cl
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: [CH2-]CCC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
N-Butyllithium (2M in hexanes, 50 ml) was added to a solution of (R)-4-benzyloxazolidin-2-one (17 g) in tetrahydrofuran at −78° C. and the suspension was stirred for 30 minutes, then isovaleryl chloride (12 g) was added dropwise. The solution was stirred for 30 min, allowed to warm to room temperature, and saturated ammonium chloride (200 ml) was added. The mixture was evaporated in vacuo and extracted with diethyl ether (2×100 ml), the solvent washed with water and saturated brine, dried (Na2SO4) and evaporated to give the title compound as a colourless solid (25.0 g, 95%)
Reaction SMILES: [CH3:1][C:2]1[C:11]2[N:10]3[CH:12]=[CH:13][CH:14]=[C:9]3[C:8](=[O:15])[N:7]([CH2:16][C:17]([OH:19])=O)[C:6]=2[N:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][NH2:37])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C(N=C=NC(C)C)(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][CH2:36][NH:37][C:17](=[O:19])[CH2:16][N:7]3[C:6]4[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]=4[N:10]4[CH:12]=[CH:13][CH:14]=[C:9]4[C:8]3=[O:15])[CH2:32][CH2:33]2)=[CH:26][CH:27]=1
Reactant: COc1ccc(N2CCN(CCCN)CC2)cc1
Reactant: Cc1ccnc2c1n1cccc1c(=O)n2CC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(N2CCN(CCCNC(=O)Cn3c(=O)c4cccn4c4c(C)ccnc43)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.2 %

Procedure:
2-(1-Methyl-6-oxopyrido[2,3-e]pyrrolo[1,2-a]pyrazin-5(6H)-yl)acetic acid (30 mg, 0.12 mmol), 3-(4-(4-methoxyphenyl)piperazin-1-yl)propan-1-amine (43.6 mg, 0.17 mmol) and DMAP (1.4 mg, 0.012 mmol) were dissolved in 1 mL of DCM. Diisopropylcarbodiimide (0.09 mL, 0.58 mmol) was added. The mixture was stirred at room temperature for 16 hours and the product was purified by silica gel flash chromatography (DCM/MeOH=10:1, Rf=0.5) to give 30 mg (53%) white solid. 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J=4.9 Hz, 1H), 7.87 (dd, J=1.4, 2.9 Hz, 1H), 7.33 (dd, J=1.4, 4.0 Hz, 1H), 7.12 (s, 1H), 6.99 (d, J=5.0 Hz, 1H), 6.84 (s, 4H), 6.68 (dd, J=2.9, 4.0 Hz, 1H), 5.11 (s, 2H), 3.78 (s, 3H), 3.41 (dd, J=5.8, 12.0 Hz, 2H), 3.02-2.91 (m, 4H), 2.74 (s, 3H), 2.63-2.54 (m, 4H), 2.49 (t, J=6.4 Hz, 2H), 1.75-1.69 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 167.9, 155.8, 153.8, 145.4, 143.2, 142.3, 134.8, 124.1, 122.8, 122.6, 120.4, 118.0, 114.4, 113.5, 113.4, 57.3, 55.6, 53.4, 50.4, 44.2, 39.4, 25.2, 22.8. HRMS (m/z): calcd for C27H33N6O3 (M+H) 489.2609. found 489.2600.
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][CH:27]=3)[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.Cl.Cl.[N:51]1([CH:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[CH2:54][CH2:53][CH2:52]1.C(N(CC)CC)C.O>CN(C)C=O>[N:51]1([CH:55]2[CH2:60][CH2:59][N:58]([C:8]([NH:9][C:19]3[CH:24]=[C:23]([O:25][C:26]4[CH:27]=[CH:28][C:29]([NH:32][C:33]([C:35]5([C:38]([NH:39][C:40]6[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=6)=[O:47])[CH2:37][CH2:36]5)=[O:34])=[CH:30][CH:31]=4)[CH:22]=[CH:21][N:20]=3)=[O:7])[CH2:57][CH2:56]2)[CH2:54][CH2:53][CH2:52]1
Reactant: C1CN(C2CCNCC2)C1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1)N1CCC(N2CCC2)CC1
Reaction time: 62 h
Yield: 65 %

Procedure:
[4-(4-{[1-(4-Fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (50 mg) was dissolved in N,N-dimethylformamide (1.0 ml), and 4-(azetidin-1-yl)piperidine dihydrochloride (82.9 mg), triethylamine (0.0782 ml) and water (0.100 ml) were added thereto in this order, followed by stirring for 62 hr. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The separated organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure, and the resultant residue was suspended in diethyl ether (2 ml) and hexane (4 ml). The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (28.8 mg, 65.1%).
Reaction SMILES: C([NH:4][C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([NH:19]C(=O)C)[CH:13]=3)[S:8][C:7]=2[CH:6]=1)(=O)C.Cl>C(O)C>[NH2:19][C:12]1[CH:11]=[CH:10][C:9]2[S:8][C:7]3[C:16](=[CH:17][CH:18]=[C:5]([NH2:4])[CH:6]=3)[S:15][C:14]=2[CH:13]=1
Reactant: CC(=O)Nc1ccc2c(c1)Sc1ccc(NC(C)=O)cc1S2
Agent: Cl
Solvent: CCO
Product: Nc1ccc2c(c1)Sc1ccc(N)cc1S2
Temperature: 25 °C
Yield: 91 %

Procedure:
A mixture of 5.75 g (0.0174 mole) of 2,7-bis(acetylamino)thianthrene, 12 ml of concentrated hydrochloric acid, and 140 ml of ethanol was heated under reflux for 6 hours. The reaction mixture was cooled to room temperature and a precipitate was collected by filtration. The precipitate was added to a mixture of 13.5 ml of concentrated hydrochloric acid and 355 ml of water and the insoluble matters were separated by filtration. The filtered mother liquor was poured into an aqueous solution of sodium hydroxide and the precipitate or 2,7-diaminothianthrene was collected by filtration. The yield was 3.7 g (0.0158 mole, 91% yield) and the purity was 88.2 area % (HPLC, 254 nm).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]([S:26][CH3:27])[CH2:14][C:15](=[O:25])[NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O)(C)(C)C.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[OH:34][C:28]([C:30]([F:33])([F:32])[F:31])=[O:29].[CH3:27][S:26][CH:13]([CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[CH2:14][C:15]([NH:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:25]
Reactant: CSC(CC(=O)NCCc1ccccc1)C1CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSC(CC(=O)NCCc1ccccc1)C1CCCN1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-(1-methylsulfanyl-2-phenethylcarbamoyl-ethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.15 g, 2.93 mmol) in CH2Cl2 (3 ml) was added TFA at 0° C. After being stirred at 0° C. for 30 min, the mixture was evaporated in vacuo to give 3-methylsulfanyl-N-phenethyl-3-pyrrolidin-2-yl-propionamide TFA salt as a crude oil (1.87 g), which was used without further purification in the next step [The diastereomers were separable by preparative HPLC (column: ODS-80Ts, eluent: 79/21 H2O:CH3CN/0.05% TFA)].
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.[N:13](OCCC(C)C)=[O:14].[OH-].[Na+]>O.C1(C)C(C)=CC=CC=1.CO>[OH:14][N:13]=[C:10]([C:11]#[N:12])[C:7]1[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=1
Reactant: CC(C)CCON=O
Reactant: COc1ccc(CC#N)cc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: CO
Solvent: O
Product: COc1ccc(C(C#N)=NO)cc1
Reaction time: 2 h
Yield: 80.6 %

Procedure:
64.5 g of methanol, 365 g of xylene, 80 g of sodium hydroxyde (2 mol) and 147 g (1 mol) of 4-methoxyphenylacetonitrile are charged to a reactor. Then 125 g (1.07 mol) of isopentyl nitrite are added dropwise at 40° C. over 2 hours. The reaction mixture is stirred initially for 2 hours at this temperature and the n for 20 hours at room temperature. Afterwards the reaction mixture is diluted with water to form an emulsion and the pH is adjusted to 14 with aqueous sodium hydroxide and the organic phase is separated. The aqueous phase is acidified with hydrochloric acid and the product is extracted with ether. The ether phase is dried and the ether is stripped off. Recrystallisation from toluene gives 142 g of α-hydroxyimino-4-methoxy-benzylcyanide, corresponding to a yield of 80.6% of theory.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16](Cl)[N:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][NH2:24]>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:24][CH3:23])[N:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: Clc1nccc(Oc2ccc(OCc3ccccc3)cc2)n1
Solvent: CS(C)=O
Product: CNc1nccc(Oc2ccc(OCc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(4-Benzyloxy-phenoxy)-2-chloro-pyrimidine (Step A, 2.03 g, 6.49 mmol) was dissolved in 10 mL DMSO in a sealed tube at 0° C. 2 N CH3NH2 (in THF) was added (4.9 mL, 9.7 mmol), and the tube was sealed, warmed first to RT for 2 h, then to 70° C. for 2 h with stirring. The reaction was cooled to RT and concentrated in vacuo to a DMSO solution. The crude solution was diluted into Et2O and 1 N NaOH (aq) was added. The layers were separated, and the organic layer was washed several times with water then brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography using a hexanes/EtOAc gradient to yield the title compound as a white solid. MS (MH+)=308.3; Calc'd 307.36 for C18H17N3O2.