Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([NH:10][C@H:11]([C:14]([OH:16])=[O:15])[CH2:12][OH:13])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H][H].F[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27]>CN(C)C=O.O>[N+:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[O:13][CH2:12][C@@H:11]([C:14]([OH:16])=[O:15])[NH:10][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])([O-:28])=[O:27]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](COc1ccccc1[N+](=O)[O-])C(=O)O
Reaction time: 4 h
Yield: 75.5 %

Procedure:
In 200 ml of N,N-dimethylformamide is suspended 10.1 g of 60% sodium hydride (oily), and a solution of 25 g of Boc-L-serine in 10 ml of N,N-dimethylformamide is added dropwise to the suspension in a stream of nitrogen at 0° C. with stirring. After stirring is continued at 0° C. until the evolution of hydrogen stops, 19 g of o-fluoronitrobenzene is added dropwise to the mixture. After the stirring at room temperature for 4 hours, the reaction mixture is poured in ice-cooled water containing dilute hydrochloric acid, followed by extraction with ethyl acetate. The organic layer is washed with water and dried, and then the solvent is evaporated off under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane-ethyl acetate=1:1) to give 30 g of O-(o-nitrophenyl)-Boc-L-serine as a colorless oil.
Reaction SMILES: C[N:2](/[CH:4]=[C:5](/[C:16](=O)[C:17]([F:20])([F:19])[F:18])\[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])C.Cl.[NH:23]([CH:25]1[CH2:30][CH2:29][C:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])([CH3:31])[CH2:27][CH2:26]1)N.CCN(C(C)C)C(C)C>CCO>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][C:28]1([CH3:31])[CH2:27][CH2:26][CH:25]([N:23]2[C:16]([C:17]([F:20])([F:19])[F:18])=[C:5]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])[CH:4]=[N:2]2)[CH2:30][CH2:29]1)[CH3:37]
Reactant: CN(C)/C=C(\C(=O)OCc1ccccc1)C(=O)C(F)(F)F
Reactant: CCOC(=O)CC1(C)CCC(NN)CC1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC1(C)CCC(n2ncc(C(=O)OCc3ccccc3)c2C(F)(F)F)CC1
Reaction time: 8 h
Yield: 73.5 %

Procedure:
A solution of (Z)-benzyl 2-((dimethylamino)methylene)-4,4,4-trifluoro-3-oxobutanoate (2.018 g, 6.70 mmol) in EtOH (20 mL) was added dropwise to a solution of ethyl 2-(4-hydrazinyl-1-methylcyclohexyl)acetate hydrochloride (1.6 g, 6.38 mmol) and DIPEA (2.452 ml, 14.04 mmol) in EtOH (31.9 ml) at ambient temperature. The reaction was allowed to stir overnight. The solvent was removed and the residual oil was purified using a 40 g REDISEP™ Gold SiO2 column eluting with 0-25% EtOAc/hexane using the Gold resolution method. Fractions containing the desired product were combined and concentrated in vacuo to provide benzyl 1-(4-(2-ethoxy-2-oxoethyl)-4-methylcyclohexyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (2.12 g, 4.69 mmol, 73.4% yield) as a mixture of isomers (colorless syrup). LCMS=453.4 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][CH2:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[C:11](OC(C)=C)(=[O:13])[CH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:10][O:9][C:7]([C:3]1[C:2]([O:1][C:11](=[O:13])[CH3:12])=[CH:6][S:5][CH:4]=1)=[O:8]
Reactant: COC(=O)C1CSCC1=O
Reactant: C=C(C)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)c1cscc1OC(C)=O
Temperature: -25 °C

Procedure:
A 320 g. portion of methyl tetrahydro-4-oxo-3-thiophenecarboxylate [Hromatka et al., Monat. Chemie, 104, 1520 (1973)] is dissolved in 650 ml. of isopropenyl acetate, 2.0 g. of p-toluenesulfonic acid is added and the mixture is refluxed overnight. The mixture is concentrated, dissolved in 750 ml. of methylene chloride, cooled to -25° C. and 160 ml. of sulfuryl chloride is added over a one hour period. The methylene chloride is distilled off giving 4-acetoxy-3-thiophenecarboxylic acid methyl ester.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Li]CCCC.[I:27]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.CCCCCC>[I:27][C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: II
Reactant: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Ic1c2ccccc2c(-c2ccccc2)c2ccccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
3.33 g (10 mmol) of 9-bromo-10-phenylanthracene was dissolved in 80 mL of tetrahydrofuran (abbreviation: THF), and cooled to −78° C. Then, in a reaction solution thereof, 7.5 mL (12.0 mmol) of n-buthyllithium (abbreviation: n-BuLi) (1.6 mol/L hexane solution) was dropped by a dropping funnel and then stirred for one hour. A solution in which 5 g (20.0 mmol) of iodine dissolved in 20 mL of THF was dropped therein, and the further stirred for 2 hours at −78° C. After reaction, a sodium thiosulfate aqueous solution was added therein and stirred. An organic layer was washed with a sodium thiosulfate aqueous solution and saturated saline, and then dried with magnesium sulfate. The mixture was filtrated naturally, then the filtrate was concentrated, and then recrystallized with ethanol, 3.1 g of 9-iodo-10-phenylanthracene that was a target substance was obtained as a light yellow solid at a yield of 83% (Synthesis scheme (b-3)).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2].[I-].[Cl:22][C:23]1[CH:31]=[C:30]([Cl:32])[C:29]2[N:25]([C:26]([CH3:37])=[CH:27][C:28]=2[CH2:33]N(C)C)[CH:24]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:33][C:28]2[CH:27]=[C:26]([CH3:37])[N:25]3[C:29]=2[C:30]([Cl:32])=[CH:31][C:23]([Cl:22])=[CH:24]3)[C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: Cc1cc(CN(C)C)c2c(Cl)cc(Cl)cn12
Reactant: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cc(C)n3cc(Cl)cc(Cl)c23)c2ccccc21
Yield: 38 %

Procedure:
To a solution of 3-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-hexanoic acid ethyl ester (30 mg, 0.11 mmol) in DMF (10 mL) were added (6,8-Dichloro-3-methyl-indolizin-1-ylmethyl)-dimethyl-amine iodide, CAS: (6,8-Dichloro-3-methyl-indolizin-1-ylmethyl)-dimethyl-amine iodide (65 mg, 0.16 mmol). and K2CO3 (45 mg, 0.33 mmol) at room temperature under nitrogen atmosphere. The solution was heated to 100 C for 2 hours. The solution was cooled down and water was added. The solution was extracted with EtOAc and the combined organic layer was dried with MgSO4. The solution was filtered and the filtrate was concentrated. The residue was purified by CombiFlash with 20% EtOAc in Hexane as the eluent to afford the desirable product 3-[3-(6,8-Dichloro-3-methyl-indolizin-1-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (20 mg, 38%) as a yellow foam.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12](C=O)[CH:11]=1.[C:18](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[CH2:18][NH:7][C:6]1[CH:8]=[CH:9][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=Cc1cccnc1
Reactant: CSc1ccc(N)cc1
Agent: [Na+]
Solvent: ClCCl
Product: CSc1ccc(NCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To 2.0 mL (16.07 mmol) of 4-(methylthio)aniline dissolved in 25 mL dichloromethane was added 1.52 mL (16.07 mmol) 3-pyridinecarboxaldehyde, followed by 5.11 g (24.11 mmol) sodium triacetoxyborohydride. The mixture was stirred at room temperature for 4 h, partitioned between EtOAc and brine, dried over MgSO4 and concentrated. Column chromatography, eluting with ethyl acetate/hexane, provided 3.70 g of 4-[(pyridin-2-ylmethyl)amino]thioanisole, pure by 1H NMR.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:3]1.[CH2:38](Br)[C:39]#[CH:40]>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:29])[CH2:3][CH:2]2[O:1][CH2:40][C:39]#[CH:38])=[CH:9][CH:10]=1
Reactant: C#CCBr
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Product: C#CCOC1CN(C(=O)OCc2ccccc2)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Method D, 0.255 g of benzyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 10f) and 0.022 g of propargyl bromide are reacted. The title compound is obtained as a colourless oil. Rf=0.40 (1:1 EtOAc-heptane); Rt=5.58.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[S:7])=[CH:4][C:3]=1[CH3:16].CI.[C:19]([O-])([O-])=O.[Cs+].[Cs+].O>C1COCC1>[CH3:19][S:7][C:6](=[N:8][CH2:9][Si:10]([CH3:11])([CH3:12])[CH3:13])[C:5]1[CH:14]=[CH:15][C:2]([Br:1])=[C:3]([CH3:16])[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C(=S)NC[Si](C)(C)C)ccc1Br
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CSC(=NC[Si](C)(C)C)c1ccc(Br)c(C)c1
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a solution of 4-bromo-3-methyl-N-trimethylsilanylmethyl-thiobenzamide (5.00 g, 15.8 mmol) in THF (30 mL) was added methyl iodide (1.97 mL, 4.49 g, 31.6 mmol) and Cs2CO3 (10.3 g, 31.6 mmol) at −5° C. After 1 h at this temperature, the mixture was allowed to reach room temperature and stirred over night. Water was added and the mixture was extracted three times with MTBE. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by filtration over a short plug of silica gel to give the title compound (4.4 g), which was used in the next step without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:9][C:10]([F:20])([F:19])[S:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.Cl[C:22]([CH3:26])([CH3:25])[C:23]#[CH:24]>CC(=O)CC>[F:20][C:10]([F:19])([F:9])[S:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:22]([CH3:26])([CH3:25])[C:23]#[CH:24])=[CH:16][CH:17]=1
Reactant: Oc1ccc(SC(F)(F)F)cc1
Reactant: C#CC(C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C#CC(C)(C)Oc1ccc(SC(F)(F)F)cc1
Reaction time: 20 h

Procedure:
13.8 g (0.1 mol) of dried potassium carbonate and 1.6 g (0.01 mol) of potassium iodide are suspended in a solution of 19.4 g (0.1 mol) of 4-(trifluoromethylthio)phenol in 250 ml of dry butanone and 15.4 g (0.15 mol) of 3-chloro-3-methyl-1-butyne are added dropwise. The mixture is then heated under reflux with stirring for 20 hours, 15.4 g of 3-chloro-3-methyl-1-butyne and 13.8 g of potassium carbonate are added once again and the mixture is further heated under reflux for 40 hours. Inorganic constituents are filtered off, the solution is concentrated, and the residue is taken up in 200 ml of methylene chloride and extracted using 1N NaOH solution. The organic phase is washed with water, dried and concentrated, and the residue is filtered through silica gel.
Reaction SMILES: [CH2:1]([C@:4]1([C:43]2[CH:48]=[C:47]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[C:46]([Cl:58])=[CH:45][C:44]=2[OH:59])[C@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:8]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:7]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:6]([CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:5]1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH-:69].[Na+].OO>C1COCC1.O>[Cl:58][C:46]1[C:47]([CH2:49][C:50]2[CH:51]=[CH:52][C:53]([CH2:56][CH3:57])=[CH:54][CH:55]=2)=[CH:48][C:43]([C@@:4]2([CH2:1][CH2:2][CH2:3][OH:69])[C@H:9]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@@H:8]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:7]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@@H:6]([CH2:34][O:35][CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[O:5]2)=[C:44]([OH:59])[CH:45]=1
Reactant: C=CC[C@@]1(c2cc(Cc3ccc(CC)cc3)c(Cl)cc2O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(Cc2cc([C@]3(CCCO)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a stirred solution of 34 (200 mg, 0.247 mmol) in dry THF (4 mL) was added 9-BBN in THF (2.0 mL, 0.5 M, 4.1 equiv). The resulting mixture was stirred at ambient temperature for 4 hours and then cooled 0° C. Water (2.5 mL), 1 M aqueous NaOH (0.8 mL) and 30% H2O2 (0.25 mL) were added at 0° C. The mixture was stirred for 1 hour at ambient temperature and 16 hours at 60° C. in a sealed vial. After cooling, the mixture was partitioned between water and EtOAc. The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified using preparatory TLC eluting with 18% EtOAc in petroleum ether to give 35 (200 mg, 99% yield). LCMS m/z 828 (M+H), 850 (M+Na).
Reaction SMILES: [N:1]([S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=[O:11])(=[O:6])=[O:5])=[N+:2]=[N-:3].S(Cl)([Cl:18])=O>>[N:1]([S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([Cl:18])=[O:11])(=[O:6])=[O:5])=[N+:2]=[N-:3]
Reactant: O=S(Cl)Cl
Reactant: [N-]=[N+]=NS(=O)(=O)c1cccc(C(=O)O)c1
Product: [N-]=[N+]=NS(=O)(=O)c1cccc(C(=O)Cl)c1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
11.3 grams (50 milimoles) of 3-(azidosulfonyl) benzoic acid and 31 grams (261 millimoles) of thionyl chloride were added to a 200 ml. round bottom flask equipped with a magnetic stirrer, nitrogen sparge, reflux condenser and heating mantle. The mixture was stirred for 3 hours at 65°C. and then the excess thionyl chloride was stripped under vacuum. A 75 per cent yield of 3-(azido-sulfonyl) benzoyl chloride was obtained and identified by spectroscopic analysis. Said benzoyl chloride was a straw-yellow liquid that slowly crystallized at room temperature and had a melting point of 41°C. and a refractive index of ND24.5 = 1.5751.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)([N:33]1C=CN=C1)=O.[O:43]1[CH2:47]CCC1>C(OCC)(=O)C>[CH3:47][O:43][NH:33][C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]2[N:9]=[C:8]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]=2[CH:12]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CCCCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reactant: C1CCOC1
Solvent: CCOC(C)=O
Product: CONC(=O)CCCCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
100 mg of 6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid was dissolved in 2 ml of tetrahydrofuran, mixed with 39 mg of carbonyldiimidazole, stirred for 30 minutes at 20° C. and then refluxed for 30 minutes. At 20° C., 21 mg of O-methylhydroxyaminohydrochloride was then added, and it was allowed to stir for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with 2N aqueous hydrochloric acid and saturated potassium bicarbonate solution. After drying on sodium sulfate, it was concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].P(Cl)(Cl)(Cl)(Cl)[Cl:12].P(Cl)(Cl)(Cl)=O>>[Cl:12][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnccc1Cl
Temperature: 135 °C
Yield: 45.1 %

Procedure:
4-Hydroxy-3-nitropyridine (10.0 g, 71.4 mmol) is added portionwise to a mechanically stirred mixture of phosphorous pentachloride (16.32 g, 78.6 mmol) and phosphorous oxychloride (16.2 mL) at 55-60° C. After the addition is complete, the temperature is raised to 130-140° C. for 4 hr. After cooling to room temperature, the phosphorous oxychloride is removed and the residue is cautiously treated with ice/water, made basic with sodium carbonate and extracted with ether. The combined extract is dried, filtered and concentrated to yield 4-chloro-3-nitropyridine (5.1 g, 45% yield) as a pale yellow solid.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:22]([C:21]2[CH:25]=[CH:26][C:18]([F:17])=[CH:19][CH:20]=2)[OH:23])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1ccc(F)cc1)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 4-fluorobenzoic acid
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][C:15]=12)=[O:10])[C:4]([O:6]C)=[O:5].N>CO.O>[CH3:1][C:2]([CH3:28])([CH3:27])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][C:15]=12)=[O:10])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C)CC2)C(C)(C)C
Agent: N
Solvent: O
Solvent: CO
Product: CN1CCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)O)C(C)(C)C)c2C1
Temperature: 50 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a solution (S)-methyl 3,3-dimethyl-2-(7-methyl-3-phenyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxamido)butanoate (Compound 86; 0.05 g, 0.13 mmol) in methanol/water was added 7N methanolic ammonia and the resulting mixture was stirred at 50° C. overnight. The mixture was concentrated, diluted with water and extracted with 10% i-PrOH/DCM. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give Compound 281 (0.021 g, 43%). 1H-NMR (400 MHz, DMSO-d6) δ: 0.99 (s, 9H), 2.41 (s, 3H), 2.74 (m, 2H), 3.85 (s, 2H), 4.03 (t, 2H), 4.30 (d, 1H), 7.48 (m, 3H), 7.73 (m, 2H), 12.95 (s, 1H); LCMS (+ESI) m/z 371.1 [M+H]+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[CH2:30](OC1C=CC(N)=CC=1)[C:31]1[CH:36]=[CH:35]C=C[CH:32]=1.[C:45](N1CCC(=O)CC1=C=O)([CH3:48])([CH3:47])[CH3:46].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CCOC(C)=O.C(Cl)Cl>[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([N:14]([CH2:35][CH:36]=[C:31]([CH3:30])[CH3:32])[CH:11]2[CH2:10][CH2:9][N:8]([CH2:6][CH2:46][CH:45]([CH3:48])[CH3:47])[CH2:13][CH2:12]2)=[CH:16][CH:17]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(OCc3ccccc3)cc2)CC1
Reactant: CC(C)(C)N1CCC(=O)CC1=C=O
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(CCC(C)C)CC1
Temperature: 0 °C
Yield: 94 %

Procedure:
The preparation of 4-(4-Benzyloxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (Ia): 4-Benzyloxyaniline hydrochloride salt (10 g, 42.4 mmol) was suspended in EtOAc (500 mL) and washed three times with saturated sodium bicarbonate solution, once with brine, dried over Na2SO4, and concentrated. The free base was dissolved in CH2Cl2 (250 mL), treated with 1-tert-butyl-carbonyl-4-piperidone (8.45 g, 42.4 mmol), stirred for thirty minutes and then cooled to 0° C. NaBH(OAc)3 (13.5 g, 63.6 mmol) was added and the reaction was allowed to warm to room temperature and stir for eighteen hours. The reaction was diluted with CH2Cl2 (250 mL), washed with saturated sodium bicarbonate solution and brine, dried over Na2SO4, and concentrated to give 15.3 g (94%) of the desired product. MS: 383 (M+1 for C23H30N2O3); TLC: SiO2, Rf0.39 (2:1 hexane/EtOAc).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[C:13]1([CH2:12][CH2:11][O:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1O
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccccc1OCCc1ccccc1
Temperature: 80 °C
Reaction time: 7.5 h
Yield: 34.9 %

Procedure:
A solution of 2-hydroxybenzaldehyde (0.20 mL, 1.9 mmol) in DMF (2.0 mL) was added with (2-bromoethyl)benzene (0.39 mL, 2.8 mmol) and potassium carbonate (0.78 g, 5.6 mmol), stirred at room temperature for 3.0 hours and at 80° C. for 7.5 hours. The reaction mixture was added with water and ethyl acetate to separate the mixture into organic layer and aqueous layer and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 80/20) to obtain 2-(2-phenylethyloxy)benzaldehyde (0.15 g, 36%).
Reaction SMILES: [CH2:1]([N:5]([CH2:25][CH2:26][CH2:27][CH3:28])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[CH:20][CH:21]=O)=[CH:16][CH:15]=2)=[C:8]([O:23][CH3:24])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:29]([C:31]1[C:32](=[C:47]([C:50]#[N:51])[C:48]#[N:49])[O:33][C:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:37]([F:40])([F:39])[F:38])[C:35]=1[CH3:36])#[N:30]>C(O)C>[CH2:25]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[CH:20][CH:21]=[CH:36][C:35]3[C:34]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:37]([F:40])([F:38])[F:39])[O:33][C:32](=[C:47]([C:50]#[N:51])[C:48]#[N:49])[C:31]=3[C:29]#[N:30])=[CH:16][CH:15]=2)=[C:8]([O:23][CH3:24])[CH:7]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC=O)s2)c(OC)c1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC=CC3=C(C#N)C(=C(C#N)C#N)OC3(c3ccccc3)C(F)(F)F)s2)c(OC)c1
Temperature: 50 °C
Yield: 55.8 %

Procedure:
In 4 ml of ethanol were dissolved 100 mg (0.25 mmol) of 3-[5-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]thiophene-2-yl]propenal and 87 mg (0.28 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene) propanedinitrile. After the mixture was stirred with heating at 50° C. for 4 hours, the product was separated by filtration and washed with ethanol. The product was purified by silica gel column chromatography to give 97 mg of a black crystal (yield: 55.5%).