Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][C:7]([O:16][CH3:17])=[C:8]([O:14][CH3:15])[CH:9]=2)[N:4]=1.[Cl:18][C:19]1[C:20]([O:42][CH3:43])=[CH:21][C:22]([O:40][CH3:41])=[C:23]([CH2:25][CH2:26][C:27]2([CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[O:32][C:31](=[O:33])[CH2:30][C:29](=[O:34])[CH2:28]2)[CH:24]=1>>[Cl:18][C:19]1[C:20]([O:42][CH3:43])=[CH:21][C:22]([O:40][CH3:41])=[C:23]([CH2:25][CH2:26][C:27]2([CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[O:32][C:31](=[O:33])[C:30]([CH2:2][C:3]3[NH:12][C:11](=[O:13])[C:10]4[C:5](=[CH:6][C:7]([O:16][CH3:17])=[C:8]([O:14][CH3:15])[CH:9]=4)[N:4]=3)=[C:29]([OH:34])[CH2:28]2)[CH:24]=1
Reactant: COc1cc2nc(CCl)[nH]c(=O)c2cc1OC
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(O)=C(Cc3nc4cc(OC)c(OC)cc4c(=O)[nH]3)C(=O)O2)cc1Cl
Yield: 20 %

Procedure:
The title compound was prepared as described in Example B(53), using 2-(chloromethyl)-6,7-dimethoxyquinazolin-4(3H)-one (Example B(57), Step 1) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 20%. 1H NMR (300 MHz, DMSO-d6) δ 1.27-1.75 (m, 8H), 1.85 (m, 1H), 2.05 (m, 1H), 2.37 (m, 1H), 2.50 (m, 2H, overlap with DMSO-d5), 2.53 (d, J=18 Hz, 1H), 2.69 (d, J=18 Hz, 1H), 3.59 (m, 2H, overlap with H2O), 3.62 (s, 3H, overlap with H2O), 3.67 (s, 3H, overlap with H2O), 3.81 (s, 3H, overlap with H2O), 3.84 (s, 3H, overlap with H2O), 6.61 (s, 1H), 6.63 (s, 1H), 7.13 (s, 1H), 7.39 (s, 1H). LC-MS (APCI) calcd for C31H35ClN2O8: 598.21; found (M+H+) 599.1 m/z.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17]Br)=[N:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]([NH2:24])=[S:23].CC([O-])=O.[Na+]>CCO>[CH2:1]([O:8][C:9](=[O:20])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[C:22]([NH2:24])[S:23][CH:17]=2)=[N:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)c1ccc(C(=O)CBr)nc1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(-c2ccc(C(=O)OCc3ccccc3)cn2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-(2-bromo-acetyl)-nicotinic acid benzyl ester (0.16 g, 0.48 mmol), thiourea (0.0.038 g), and NaOAc (0.051 g) in EtOH (6 mL) was stirred at room temperature overnight. The mixture was concentrated in vacuo to give the crude product 6-(2-Amino-thiazol-4-yl)-nicotinic acid benzyl ester.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:16][C:17]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:18]=1[C:19](O)=[O:20]>>[F:16][C:17]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:18]=1[C:19]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([C:13](=[O:15])[CH3:14])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)=[O:20]
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3F)CC2)cc1

Procedure:
The title compound was prepared according to the procedure described for example K step 2 from 4′-piperazino-acetophenone and 2-fluoro-5-nitrobenzoic acid (16%, yellow solid, MS (m/e): 372.1 (M+H, 100%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([OH:15])([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.[O:17]([CH2:24][CH2:25][N:26]1[CH2:30]C[C@@H:28](O)[CH2:27]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[O:17]([CH2:24][CH2:25][N:26]1[CH2:27][CH2:28][C@@H:1]([O:2][C:3](=[O:16])[C:4]([OH:15])([C:5]2[S:6][CH:7]=[CH:8][CH:9]=2)[C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:30]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O[C@@H]1CCN(CCOc2ccccc2)C1
Reactant: COC(=O)C(O)(c1cccs1)c1cccs1
Solvent: Cc1ccccc1
Product: O=C(O[C@@H]1CCN(CCOc2ccccc2)C1)C(O)(c1cccs1)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
1.33 g of 2-Hydroxy-2,2-dithien-2-ylacetic acid methyl ester (0.0052 mol) were dissolved in 40 ml of toluene. To this solution were added 1.08 g (0.0052 mol) of (3R)-1-(2-phenoxyethyl)pyrrolidin-3-ol (Intermediate I-15), and 0.104 g (0.0026 mol) of HNa (60% dispersion in mineral oil). The mixture was stirred 30 min at room temperature, refluxed for 45 minutes, and then refluxed with continuous removal of distillate with replacement with fresh toluene when necessary for 1.5 hours. The cooled mixture was extracted with 2N HCl acid, the aqueous layer basified with K2CO3 and extracted with CHCl3. The organic layer was washed with water, dried over Na2SO4 and evaporated to yield 1.77 g of an oil which was purified by chromatography on silica gel eluting with chloroform/ethanol/NH4OH (200:8:1). Appropriate fractions were combined and evaporated to yield 1.22 g of the title product as an oil (54.7%). This product was solidified by formation of the oxalate salt.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: OCCc1ccccc1Br
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Brc1ccccc1CCOC1CCCCO1
Yield: 81.5 %

Procedure:
A solution of 2-(2-bromophenyl)ethanol (3.10 g, 15.4 mmol), 3,4-dihydro-2H-pyran (1.70 ml, 18.6 mmol) and p-toluenesulfonic acid monohydrate (10.0 mg, 5.35 mmol) in chloroform (30 ml) was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium carbonate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=30:1-10:1) to give 2-[2-(2-bromophenyl)ethoxy]tetrahydropyran (3.58 g, yield 81.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](SC)=[CH:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[CH3:17][NH2:18]>CCO>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8]([NH:18][CH3:17])=[CH:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CSC(=C[N+](=O)[O-])NCc1ccc(Cl)cc1
Reactant: CN
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCc1ccc(Cl)cc1
Temperature: 0 °C
Yield: 68.7 %

Procedure:
In 100 ml of EtOH on reflux was dissolved 2.59 g (0.01 mole) of 1-(4-chlorobenzyl)amino-1-methylthio-2-nitroethylene, and with refluxing continued, a solution of 1.94 g of 40% aqueous methylamine solution in 10 ml of EtOH was added dropwise over a period of 50 minutes. After completion of dropwise addition, the mixture was further refluxed for 15 minutes, at the end of which time it was cooled with ice-water, whereupon crystals separated out. The crystals were collected by filtration, washed with EtOH and ether in that orsder, and dried. The procedure gave 1.66 g of the title compound as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[NH:8][N:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].Br[CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[N:8]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[N:9]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[CH:11]=1)=[O:5])[CH3:2]
Reactant: CC(C)=CCBr
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Product: CCOC(=O)c1cc(-c2ccc(OC)cc2)nn(CC=C(C)C)c1=O
Yield: 87.6 %

Procedure:
Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and 1-bromo-3-methyl-2-butene as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 87.6%.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4]1.[F:17][C:18]([F:27])([F:26])[CH2:19][CH2:20][CH:21]([C:24]#[N:25])[C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:15]([O:14][C:12]([C:5]1[C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][N:3]([CH2:2][C:21]([CH2:20][CH2:19][C:18]([F:17])([F:26])[F:27])([C:22]#[N:23])[C:24]#[N:25])[CH:4]=1)=[O:13])[CH3:16]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: CCOC(=O)c1cn(CCl)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(CC(C#N)(C#N)CCC(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
0.23 g of 1-chloromethyl-4-trifluoromethyl-3-ethoxycarbonyl-1H-pyrole and 0.15 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 2 ml of N,N-dimethylformamide. 0.13 g of potassium carbonate was added to the solution under ice cooling, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.20 g of [(3-ethoxycarbonyl-4-trifluoromethyl-1H-pyrole-1-yl)methyl](3,3,3-trifluoropropyl)malononitrile (referred as the compound of the present invention (47), hereinafter) shown by below formula.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[O:47]1[C:51]([C:52](Cl)=[O:53])=[CH:50][CH:49]=[N:48]1.C(N(CC)CC)C>O1CCCC1>[O:47]1[C:51]([C:52]([NH:46][C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[C:12]([C:16]5[N:20]=[CH:19][N:18]([C:21]([C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)([C:22]6[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=6)[C:34]6[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=6)[N:17]=5)[CH:11]=4)[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[N:8]=3)[CH:41]=2)=[O:53])=[CH:50][CH:49]=[N:48]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: O=C(Cl)c1ccno1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1ccno1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) in 2.5 mL of tetrahydrofuran was added isoxazole-5-carbonyl chloride (0.066 g, 0.496 mmol), followed by triethyl amine (0.173 mL, 1.24 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and water. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 698 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]([CH:15]([CH3:17])[CH3:16])[C:11]=3[NH:12]2)=[CH:4][C:3]=1[N+:18]([O-])=O>CC(O)C.O.[Fe]>[NH2:18][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][C:2]=1[F:1])[NH:12][C:11]1[C:10]([CH:15]([CH3:17])[CH3:16])=[CH:9][CH:8]=[CH:7][C:6]2=1
Reactant: CC(C)c1cccc2c1[nH]c1cc(F)c([N+](=O)[O-])cc12
Agent: [Fe]
Solvent: O
Solvent: CC(C)O
Product: CC(C)c1cccc2c1[nH]c1cc(F)c(N)cc12
Yield: 65.2 %

Procedure:
3-Fluoro-benzohydrazine (3.3 g) and cyclohexanone (2.2 g) were added to ethanol (30 ml) and the mixture was stirred for 2 hours under reflux. The reaction mixture was concentrated and the resulting residue was recrystallized from hexane to obtain 7-fluoro-carbazole (1.81 g, 48%). Then, concentrated sulfuric acid (20 ml) was cooled to 0° C. and added with 7-fluoro-carbazole (2.1 g) and sodium nitrate (900 mg), and then the mixture was stirred for 10 minutes. The reaction mixture was poured on an ice layer and filtered to obtain 7-fluoro-6-nitro-carbazole (1.1 g, 42%). The resulting 7-fluoro-6-nitro-carbazole (500 mg) and KOH (200 mg) were stirred in acetonitrile as a solvent, and then the mixture was added dropwise with 2-iodopropane (500 mg) and stirred for 8 hours. The reaction mixture was added with water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (adsorbent: silica gel, developing solvent: ethyl acetate/hexane) to obtain 7-fluoro-1-isopropyl-6-nitro-carbazole (254 mg, 43%). The resulting 7-fluoro-1-isopropyl-6-nitro-carbazole (500 mg) and Fe (400 mg) were stirred in i-PrOH/water solvent (1:1) under reflux. The reaction mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (adsorbent: silica gel, developing solvent: ethyl acetate/hexane) to obtain 6-amino-7-fluoro-isopropyl-carbazole (290 mg, 65%). The resulting amino compound (500 mg) was dissolved in chloroform (10 ml), and the solution was added dropwise with phenyl chloroformate (190 mg) and stirred for 2 hours. The reaction mixture was added with water and extracted. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (adsorbent: silica gel, developing solvent: ethyl acetate/hexane) to obtain phenylurethane (263 mg, 61%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14](I)[CH:13]=2)=[O:10])=[CH:4][C:3]=1[O:19][CH3:20].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:13]=2)=[O:10])=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: COc1cc(CC(=O)Nc2cccc(I)c2)ccc1O
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CC(=O)Nc2cccc(-c3ccccc3)c2)ccc1O
Yield: 82.8 %

Procedure:
Intermediate 1 (500 mg), phenylboronic acid (300 mg), tetrakis(triphenylphosphine)palladium (0) (150 mg) are dissolved in tetrahydrofuran (20 ml), and thereto are added cesium carbonate (850 mg) and water (10 ml). The mixture is heated under reflux for 18 hours under argon atmosphere. The reaction solution is extracted with ethyl acetate, and the organic layer is dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the desired compound (360 mg).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[NH2:18][C:19]1[CH:28]=[CH:27][C:26]([CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH3:36][C:34]([CH3:37])([O:33][C:31]([NH:30][CH2:29][C:26]1[CH:27]=[CH:28][C:19]([NH:18][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]2)=[C:20]([C:21]([O:23][CH3:24])=[O:22])[CH:25]=1)=[O:32])[CH3:35]
Reactant: COC(=O)c1cc(CNC(=O)OC(C)(C)C)ccc1N
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cc(CNC(=O)OC(C)(C)C)ccc1NC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 15 h
Yield: 90.1 %

Procedure:
A solution of 1.66 g of benzyl 4-oxopiperidine-1-carboxylate and 1 g of methyl 2-amino-5-({[(1,1-dimethylethoxy)carbonyl]amino}methyl)benzoate obtained in stage 5.1 in 20 ml of DCM is added dropwise at AT to a suspension of 2.04 g of NaBH(OAc)3 in a mixture of 20 ml of DCM and 0.41 ml of AcOH. The mixture is stirred at AT for 15 h 00 and then a further 2.04 g of NaBH(OAc)3 are added. After stirring for 6 h 00, 1.66 g of benzyl 4-oxopiperidine-1-carboxylate are added and the mixture is stirred at AT for 48 h 00. A saturated NaHCO3 solution is added and extraction is carried out with DCM. The organic phase is washed with a saturated NaHCO3 solution and twice with a saturated NH4Cl solution. It is dried over Na2SO4 and filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, elution being carried out with an AcOEt/heptane mixture, (5/95, v/v) as far as (40/60, v/v), to give 1.6 g of the expected product.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([C:14](=[O:34])[N:15]([CH:31]2[CH2:33][CH2:32]2)[CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:20]=[C:19]([O:29][CH3:30])[CH:18]=2)[CH2:11][C@H:10]([NH2:35])[CH2:9]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.[Cl:45][C:46]1[CH:51]=[C:50](Cl)[N:49]=[CH:48][N:47]=1>CN(C=O)C>[CH:31]1([N:15]([CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:20]=[C:19]([O:29][CH3:30])[CH:18]=2)[C:14]([C@@H:12]2[CH2:11][C@H:10]([NH:35][C:50]3[CH:51]=[C:46]([Cl:45])[N:47]=[CH:48][N:49]=3)[CH2:9][NH:8][CH2:13]2)=[O:34])[CH2:32][CH2:33]1
Reactant: COCCCOc1cc(CN(C(=O)[C@@H]2C[C@H](N)CN(C(=O)OC(C)(C)C)C2)C2CC2)cc(OC)c1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCCOc1cc(CN(C(=O)[C@H]2CNC[C@@H](Nc3cc(Cl)ncn3)C2)C2CC2)cc(OC)c1
Reaction time: 16 h

Procedure:
To a solution of (3S*,5R*)-3-Amino-5-{cyclopropyl-[3-methoxy-5-(3-methoxy-propoxy)-benzyl]-carbamoyl}-piperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.10 mmol) in DMF (0.5 mL) are added i-Pr2NEt (26 uL, 0.15 mmol) and 4,6-dichloropyrimidine (23 mg, 0.15 mmol). After stirring for 16 h, the reaction mixture is quenched by H2O (30 mL) and extracted with EtOAc/Et2O (c.a. 1:1, 60 mL). The organic phase is successively washed with 5% KHSO4aq, 5% NaHCO3aq, H2O, and brine, then dried over Na2SO4. The solution is filtered and the solvent is evaporated in vacuo. The residue is purified by silica gel column chromatography to give Boc protected title compound. MS: 604 (Cl35) [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.88 min. The Boc protected compound is treated with 4N HCl-1,4-dioxane to give the title compound as a white amorphous solid. MS: 504 (Cl35) [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 2.66 min.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:17]=O)[CH:14]=[N:15][CH:16]=3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:19].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:20]([NH:27][CH2:17][C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[O:4][C:3](=[O:19])[N:2]([CH3:1])[C:6]=3[CH:7]=2)[CH:16]=[N:15][CH:14]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: Cn1c(=O)oc2ccc(-c3cncc(C=O)c3)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cn1c(=O)oc2ccc(-c3cncc(CNCc4ccccc4)c3)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-(3-Methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl)-pyridine-3-carbaldehyde (100 mg, 0.39 mmol), Benzylamine (46.4 mg, 0.43 mmol), acetic acid (50 uL) and sodium triacetoxyborohydride (25 0 mg, 1.18 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 2 h. The mixture was quenched with NaHCO3 (saturated solution) and extracted with CH2Cl2 (20 mL×3). The combined extracts were washed with brine and dried over anhydrous Na2SO4. After filtration and concentration, the residue was obtained as yellow solid. ESI-MS m/z: 346.1 [M+1]+, Retention time 1.11 min.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:7][S:8]([OH:11])(=O)=[O:9].[CH2:12]([C:14]1[C:15](=[O:26])[NH:16][C:17]([CH3:25])=[C:18]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)[CH3:13]>C(Cl)(Cl)Cl>[CH2:12]([C:14]1[C:15](=[O:26])[NH:16][C:17]([CH3:25])=[C:18]([C:20]2[S:21][C:22]([S:8]([Cl:7])(=[O:11])=[O:9])=[CH:23][CH:24]=2)[CH:19]=1)[CH3:13]
Reactant: CCc1cc(-c2cccs2)c(C)[nH]c1=O
Reactant: O=S(=O)(O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
Phosphorus pentachloride (4.67 g, 22.4 mmol) is placed in a three neck round bottom flask and cooled to 0° C. Chlorosulfonic acid (6.53 g, 56.0 mmol) is added slowly. The reaction is stirred until the fuming action stops and the reaction mixture becomes clear. Then a solution of 3-ethyl-6-methyl-5-(thiophen-2-yl)-1H-pyridin-2-one (4.92 g, 22.4 mmol) of the above reaction in chloroform (35 mL) is added dropwise, and stirring at 0° C. is maintained for 5 min, then at room temperature. After 30 min, the reaction is poured into ice water (200 mL) and extracted with dichloromethane. The organic layer is washed with water, dried (sodium sulfate), filtered and concentrated and the residue is triturated with hepatane-30% ethyl acetate to afford the title compound (6.88 g, 97% yield) as a yellow solid. MS: m/e=318 (M+H). 1H-NMR (D6-DMSO, δ ppm) 13.2 (br s, 1H); 7.25 (s, 1H); 7.05 (d, 1H, J=3.2 Hz); 6.82 (d, 1H, J=3.2 Hz); 2.39 (q, 2H, J=7.4 Hz); 2.27 (s, 3H); 1.10 (t, 3H, J=7.4 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:20]4[C:25]([C:26]=2[CH:27]=1)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:9][CH:8]=3.[CH2:36]([Sn](CCCC)(CCCC)CCCC)[CH:37]=[CH2:38].[Li+].[Cl-]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[CH2:38]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:20]4[C:25]([C:26]=2[CH:27]=1)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:9][CH:8]=3)[CH:37]=[CH2:36]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)Cn1c2ccccc2c2cc(-c3ccc4c(c3)c3cc(Br)ccc3n4CC(C)C)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCc1ccc2c(c1)c1cc(-c3ccc4c(c3)c3ccccc3n4CC(C)C)ccc1n2CC(C)C
Temperature: 90 °C
Reaction time: 24 h
Yield: 61.2 %

Procedure:
THF (20 ml) was added into a mixture of 5 (0.62 g, 1.18 mmol), allyltributyltin (0.78 g, 2.36 mmol), Pd(PPh3)4 (0.068 g, 0.06 mmol) and LiCl (0.092 g, 3.54 mmol). The reaction mixture was stirred at 90° C. for 24 hours. After evaporating off the solvent, the crude product was purified by gradient column chromatography on silica gel with hexane/methylene chloride 9:1 to 4:1 (v/v) as the eluent to yield 6 (0.35 g, 61%) as a white powder. 1H NMR (400 MHz, CDCl3, 298 K): δ(ppm) 8.40-8.38 (dd, 2H), 8.19-8.17 (d, 1H), 8.00 (s, 1H), 7.93-7.79 (m, 2H), 7.50-7.41 (m, 4H), 7.34-7.22 (m, 3H), 6.18-6.08 (m, 1H), 5.20-5.10 (m, 2H), 4.15-4.11 (m, 4H), 3.61-3.59 (d, 2H), 2.50-2.39 (m, 2H), 1.03-1.01 (m, 12H).