Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]3[C:12]([CH2:15][CH2:16][C:17]4[N:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=5)[O:19][N:18]=4)=[N:13][N:14]=[C:6]3[N:5]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:4]=2[N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]3[C:12]([CH2:15][CH2:16][C:17]4[N:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=5)[O:19][N:18]=4)=[N:13][N:14]=[C:6]3[N:5]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:4]=2[N:3]=1
Reactant: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(CCc3noc(-c4ccc(OC)cc4)n3)nnc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(CCc3noc(-c4ccc(O)cc4)n3)nnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-bromo-3-2-[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]ethyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (190 mg, 0.36 mmol) in CH2Cl2 (12 mL) was added a solution of BBr3 in CH2Cl2 (1 M, 7.0 ml, 7.0 mmole) at room temperature. After stirring at room temperature overnight, the reaction mixture was concentrated and purified by preparative LCMS to give the desired product. LCMS calculated for C21H22BrN8O3 (M+H): 513.1, 515.1. Found: 513.1, 515.1.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]#[N:20])=[CH:16][CH:17]=3)[CH2:12][O:11]2)=[CH:6][CH:5]=1.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]Cl.CS(C)=O>C1COCC1.COC(C)(C)C>[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][C:10]1([C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[C:18]2[C:13](=[CH:14][C:15]([C:19]#[N:20])=[CH:16][CH:17]=2)[CH2:12][O:11]1
Reactant: CN(C)CCCCl
Reactant: N#Cc1ccc2c(c1)COC2c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
To a suspension of 60% sodium hydride (4.2 g) dispersed in THF (135 ml) was added dropwise at 40-50° C. a solution of 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (21.6 g) in THF (40 ml). The mixture was stirred at the same temperature for 30 min and a solution of 3-dimethylaminopropyl chloride (14.4 g) in t-butyl methyl ether (60 ml) was added dropwise. The mixture was stirred for 10 min and dimethyl sulfoxide (135 ml) was added dropwise. The mixture was stirred at 60-70° C. for 5 hr. The reaction mixture was poured into ice water (800 ml) and extracted 3 times with toluene (250 ml). The organic layer was extracted twice with 20% aqueous acetic acid solution (250 ml). The aqueous layer was neutralized, extracted twice with toluene (250 ml) and washed with water. The solvent was evaporated to give 1-(3-(dimethylamino)propyl)-1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (citalopram base) as a viscous oil (17.9 g, 61.1%).
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([OH:15])=O)[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[CH:21][C:20]=1[CH3:30])[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.CO>[C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([C:26]#[N:27])([CH3:29])[CH3:28])=[CH:21][C:20]=3[CH3:30])[CH3:18])=[O:15])[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1cc(C(C)(C)C#N)ccc1C(C)N
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(C(C)(C)C#N)ccc1C(C)NC(=O)Cn1cnc2cccc(C#N)c21
Yield: 43.1 %

Procedure:
To a solution of (7-cyano-1H-benzimidazol-1-yl)acetic acid (250 mg, 1.24 mmol) prepared according to scheme 3, 2-[4-(1-aminoethyl)-3-methylphenyl]-2-methylpropanenitrile (251 mg 1.24 mmol) prepared according to scheme 15 and DMAP (150 mg, 1.24 mmol) stirred in anhydrous DMF (4.0 mL) is added HATU (473 mg, 1.24 mmol) after 18 hours of stirring, the mixture is diluted with Methanol (200 μL) the solution is purified directly on a preparative LCMS system equipped with a Synergi Polar (4u) 21.2×50 mm column, mobile phase: A=water (0.1% TFA), B=MeCN using a short 40 to 60% B 10 min. gradient method. The pure fractions are combined the TFA neutralized with a 4 N NaOH solution and then extracted with ethyl acetate which is separated dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the expected product 2-(7-cyano-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-2-methylphenyl]ethyl}acetamide (206 mg, 43%) as a white solid. 1H NMR (400 MHz, METHANOL-D4) δ ppm 1.45 (d, J=6.84 Hz, 3H) 1.66 (s, 6H) 2.37 (s, 3H) 5.20 (q, J=6.84 Hz, 1H) 5.30 (s, 2H) 7.25 (d, J=1.95 Hz, 1H) 7.32 (dd, J=8.20, 2.15 Hz, 1H) 7.38 (dd, J=8.11, 7.71 Hz, 1H) 7.44 (d, J=8.20 Hz, 1H) 7.67 (dd, J=7.42, 0.78 Hz, 1H) 7.96 (dd, J=8.20, 0.98 Hz, 1H) 8.24 (s, 1H), MS [M+H], calcd: 386.2. found: 386.2.
Reaction SMILES: [CH2:1]([C:3]1[C:4](O)=[N:5][CH:6]=[CH:7][N:8]=1)[CH3:2].P(Cl)(Cl)([Cl:12])=O>>[Cl:12][C:4]1[C:3]([CH2:1][CH3:2])=[N:8][CH:7]=[CH:6][N:5]=1
Reactant: CCc1nccnc1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1nccnc1Cl
Temperature: 25 °C
Yield: 98 %

Procedure:
3-Ethyl-2-hydroxypyrazine (5 g) was heated with phosphorus oxychloride (15 ml) at reflux for 3 hours. The reaction was allowed to cool to ambient temperature and then poured onto 200 g of crushed ice. The mixture was extracted with dichloromethane (3×150 ml) and the combined extracts were dried (MgSO4). Volatile material was removed by evaporation to give a brown oil. The oil was purified by chromatography on silica gel, eluting with dichoromethane, to give 2-chloro-3-ethylpyrazine as a colourless oil (5.64 g, 98%); 1H MNR (d6 -DMSO, 200 MHz): 1.25 (t,3H), 2.93 (q,2H), 8.36 (d,1H), 8.59 (d,1H); mass spectrum (+ve CI): 143 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>>[O:6]=[C:4]([N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:3][C:1]#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: C1CCNC1
Product: N#CCC(=O)N1CCCC1
Yield: 72.4 %

Procedure:
Ethyl cyanoacetate (5.33 mL, 50 mmol) and pyrrolidine (20.87 mL, 250 mmol) were gently refluxed at 90° C. in an oil bath for 8 hours. Excess pyrrolidine was removed by concentration and the residue was triturated with diethyl ether. This was purified by silica gel column chromatography eluting with 50% acetone in n-hexane to provide the desired product (5.0 g). MS (DCI) m/e 139 (M+H)+, 156 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 3.90 (s, 2H), 3.27-3.38 (m, 4H), 1.73-1.91 (m, 4H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=3)=[N:13][CH:14]=2)O1.Br[C:24]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:25]=1[CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[N:27]1([CH2:26][C:25]2[CH:33]=[C:34]([C:37]([F:39])([F:38])[F:40])[CH:35]=[CH:36][C:24]=2[C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[N:19][C:18]([NH2:21])=[N:17][CH:16]=3)=[N:13][CH:14]=2)[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)nc2)OC1(C)C
Reactant: FC(F)(F)c1ccc(Br)c(CN2CCOCC2)c1
Product: Nc1ncc(-c2ccc(-c3ccc(C(F)(F)F)cc3CN3CCOCC3)cn2)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 427 using 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine and 4-(2-bromo-5-(trifluoromethyl)benzyl)morpholine. MS (ESI): mass calcd. for C21H20F3N5O, 415.16; m/z found, 416.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.96 (s, 2H), 8.67 (dd, J=2.3, 0.9, 1H), 7.97 (dd, J=8.2, 2.3, 1H), 7.89 (dd, J=8.2, 0.9, 1H), 7.86-7.84 (m, 1H), 7.72-7.65 (m, 1H), 7.52 (d, J=7.9, 1H), 3.63-3.58 (m, 4H), 3.54-3.48 (m, 2H), 2.41-2.28 (m, 4H).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:24])[NH:15][C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1.O>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:24])[NH:15][C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1c(O)c2ccccc2[nH]c1=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(NC1CCCCC1)c1c(O)c2ccccc2[nH]c1=O
Yield: 87.2 %

Procedure:
Cyclohexylamine (13.88 mL, 121.33 mmol) was added to a solution of Compound 112 (9.4 g, 40.44 mmol) in toluene (200 mL) and refluxed for 4 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered. The crude product was recrystallized by ether to yield 10.1 g (87%) of white solids. M.P. 223° C. 1H NMR (DMSO-d6): δ 1.3 (m, 4H), 1.6 (m, 2H), 1.7 (m, 2H), 1.9 (m, 2H), 3.8 (m, 1H), 7.25 (t, J=7.7 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.65 (t, J=7.2 Hz, 1H), 7.95 (d, J=7.7 Hz, 1H), 10.44 (b, 1H); EIMS (neg. mode): 285 (M−H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][CH2:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH2:4]1.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[O:20][CH3:21]>C(Cl)Cl>[CH3:21][O:20][C:19]([NH:2][CH:3]1[CH2:11][CH2:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH2:4]1)=[O:22]
Reactant: COC(=O)Cl
Reactant: NC1CCc2sccc2C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NC1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To 3.79 g of 5-amino-4,5,6,7-tetrahydrobenzo[b]thiophene.hydrochloride and 4.04 g of triethylamine dissolved in 30 ml of methylene chloride was added dropwise 1.89 g of methyl chlorocarbonate under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, the organic layer was collected by separation and dried, and then the solvent was removed. The resulting crystals were recrystallized from isopropyl ether to obtain 3.80 g of 5-methoxycarbonylamino-4,5,6,7-tetrahydrobenzo[b]thiophene.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]3[CH2:24][CH2:23][NH:22][CH2:21]3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:32]([O:35][CH2:36][CH2:37][CH2:38]Br)(=[O:34])[CH3:33]>CN(C)C=O.[I-].[Na+]>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]3[CH2:24][CH2:23][N:22]([CH2:38][CH2:37][CH2:36][O:35][C:32](=[O:34])[CH3:33])[CH2:21]3)=[CH:16][CH:15]=2)(=[O:11])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2ccc([C@@H]3CCNC3)cc2)cc1
Reactant: CC(=O)OCCCBr
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)OCCCN1CC[C@@H](c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cc2)C1
Temperature: 0 °C
Reaction time: 15 h
Yield: 94.3 %

Procedure:
0.21 g of 4-isopropyl-N-[4-((S)-pyrrolidin-3-yl)-phenyl]-benzenesulfonamide (0.62 mmol) were dissolved in 5 ml dimethylformamide. 0.0019 mg of sodium iodide (0.01 mmol) and 0.13 ml of triethylamine (0.94 mmol) were added, followed by addition of 0.136 mg of 3-acetoxy-1-bromo-propane (0.75 mmol). Stirring continued for 15 h at room temperature before the reaction mixture was poured onto 50 ml of crushed ice. The aqueous layer was extracted three times with ethyl acetate and the combined organic phases washed with water and saturated sodium chloride solution. The ethyl acetate phase was dried over magnesium sulfate, filtered, and evaporated to dryness under reduced pressure to yield 0.26 g of the crude product.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:22]=[CH:21][C:18]([CH2:19]O)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl.C(Cl)(Cl)Cl.O>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:22]=[CH:21][C:18]([CH2:19][NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(CO)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(CNc2ccccc2)cc1
Reaction time: 1.5 h
Yield: 39.8 %

Procedure:
Compound 34 (0.300 g, 1.01 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (0.284 mL, 2.03 mmol) and methanesulfonyl chloride (0.118 mL, 1.52 mmol) was added to the solution at 0° C., followed by stirring for 1.5 hours. The reaction mixture was added with water to decompose excess reagent, and diluted with chloroform, then washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Then, the residue was dissolved in dichloromethane (10 mL), triethylamine (0.283 mL, 2.03 mmol) and aniline (0.277 mL, 3.04 mmol) was added to the solution, followed by stirring at room temperature overnight. The reaction mixture was diluted with chloroform, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3). The desired compound was crystallized from diisopropyl ether to obtain Compound 35 (0.149 g, yield 40%).
Reaction SMILES: [C:1](Cl)(=O)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)[CH:10]=O.[Cl-].[NH4+].C(OCC)C>CN(C)C=O.BrCBr.[Zn]>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)[CH:10]=[CH2:1]
Reactant: CC(=O)Cl
Reactant: COc1cc(C=O)cc(OC)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOCC
Solvent: BrCBr
Solvent: CN(C)C=O
Product: C=Cc1cc(OC)cc(OC)c1
Reaction time: 0.25 h
Yield: 373.9 %

Procedure:
Zinc powder (purity; 85%, 14.75 g) is suspended in N,N-dimethylformamide (50 ml) under argon atmosphere, and thereto is added dropwise with stirring acetyl chloride (1.06 g) at 50° C. over a period of 10 minutes, and then the mixture is stirred for 15 minutes. To the mixture is added dropwise a solution of 3,5-dimethoxybenzaldehyde (10 g) in dibromomethane (15.69 g) over a period of 20 minutes, and the mixture is stirred for 30 minutes. The reaction solution is cooled with ice, and thereto is added dropwise a saturated aqueous ammonium chloride solution (40 ml), and further thereto is added diethyl ether. The insoluble materials are removed by filtration, and the filtrate is extracted with diethyl ether. The extract is washed successively with 10% hydrochloric acid, water, 10% aqueous sodium hydroxide solution, and a saturated aqueous sodium chloride solution, dried, and concentrated under reduced pressure to give 3,5-dimethoxystyrene (8.29 g).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]([CH3:23])=NC(NC(=O)OCC3C=CC=CC=3)C(=O)[NH:10][C:4]=2[CH:3]=1.C(=O)([O-])[O-:27].[K+].[K+].IC>CN(C)C=O.O.C(OCC)(=O)C>[NH2:10][C:4]1[CH:3]=[C:2]([Br:1])[CH:25]=[CH:24][C:5]=1[C:6](=[O:27])[CH3:23]
Reactant: CC1=NC(NC(=O)OCc2ccccc2)C(=O)Nc2cc(Br)ccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Br)cc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 148.2 %

Procedure:
162b (2.0 g, 4.98 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 ml), to this was added potassium carbonate (1.72 g, 12.44 mmol) and iodomethane (0.847 g, 5.97 mmol) and the reaction was sealed in a pressure flask and stirred for 12 hours at room temperature. The reaction was diluted with water and ethyl acetate (20/70 ml). The aqueous solution was then extracted with ethyl acetate (3×20 ml). The organic layers combined, washed with water (1×100 ml), dried over magnesium sulfate, filtered and the filtrate concentrated to give the title compound 162a (1.58 g, 77.596). 1H NMR (CDCl3, 300 MHz): δ 7.43-7.28 (m, 7H), 6.68 (d, 1H, J=8.1 Hz), 5.15-5.05 (m, 3H), 3.38 (s, 3H), 2.45 (d, 3H, 1.5 Hz) ppm.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].Cl.Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[BH4-].[K+]>O.C(O)C>[OH:4][CH:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)[CH2:2][N:33]1[CH2:34][CH2:35][CH:30]([O:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)[CH2:31][CH2:32]1
Reactant: O=C1Cc2cc(C(=O)CCl)ccc2N1
Reactant: c1ccc(OC2CCNCC2)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CCO
Solvent: O
Product: O=C1Cc2cc(C(O)CN3CCC(Oc4ccccn4)CC3)ccc2N1

Procedure:
A mixture of 4.19 g (20 mmoles) 5-chloroacetyl-3H-indol-2-one, 150 ml ethanol, 6 g sodium carbonate and 5 g 4-(2-pyridinyloxy)piperidine dihydrochloride is heated under reflux for 2 h 30 min. The mixture is cooled in an ice bath, 10 ml water and then 8 g potassium borohydride are added and stirring is continued at ambient temperature of1 h. 300 ml water are added, the mixture is extracted with ethyl acetate and the extract is evaporated and purified by chromatography on a silica column, eluting with a 96/4 mixture of dichloromethane/ methanol. After recrystallization in 2-propanol 1.88 g of pure compound are isolated.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[CH:7][C:8]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)=[O:5])[CH3:2].[F:21][C:22]([F:26])([F:25])[CH2:23][NH2:24].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[F:21][C:22]([F:26])([F:25])[CH2:23][NH:24][C:10]([C:9]1[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:8]=1/[CH:7]=[CH:6]/[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:12]
Reactant: CCOC(=O)C=Cc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: NCC(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cc(C(F)(F)F)ccc1C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
1.3 g of 2-(2-ethoxycarbonylvinyl)-4-trifluoromethylbenzoic acid (4.5 mmol) and 453 mg of 2,2,2-trifluoroethylamine (4.5 mmol) were dissolved in 5 ml of DMF and 0.93 g of DCC was added. The mixture was stirred at RT for 4 h. The urea by-product was removed by filtration and then the solvent was removed under reduced pressure. The residue was recrystallized from DIP to obtain 1.6 g (96%) of white crystals.
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[O-:16][CH2:17][CH3:18].[Na+].O>C(O)C>[CH2:17]([O:16][C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[CH3:18]
Reactant: CC[O-]
Reactant: N#Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1cc(C(F)(F)F)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a solution of 2-nitro-4-trifluoromethyl-benzonitrile (4.052 g, 18 mmol) in ethanol (25 mL) were added sodium ethoxide solution (13.4 mL, 36 mmol, 21% wt in ethanol) dropwise over 30 min. The reaction mixture was stirred at room temperature for 1 h. Water (50 mL) was added and the resulting mixture was stirred for 15 min. The solid was filtered off, washed with water and dried under vacuum for 3 d to give 2-ethoxy-4-trifluoromethyl-benzonitrile as a beige solid (2.85 g, 74%). It was used without further purification.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([NH2:5])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:7]1([CH2:6][C@H:2]([NH2:1])[CH2:3][NH2:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC[C@@H](N)Cc1ccccc1
Temperature: 0 °C
Yield: 97 %

Procedure:
To a stirred solution of (S)-2-amino-3-phenylpropanamide (2.92 g, 17.78 mmol) in tetrahydrofuran (50 mL) at 0° C. under nitrogen atmosphere was dropwise added lithium aluminum hydride (18.0 mL of 2.0 M solution in tetrahydrofuran, 36.0 mmol). The resulting reaction mixture was stirred at reflux for 2 h, and then cooled to 0° C. and quenched with sodium sulfate decahydrate. The resulting precipitate was filtered, and the filter cake was washed with ethyl acetate (250 mL). The filtrate was concentrated in vacuo to afford (S)-3-phenylpropane-1,2-diamine as yellowish oil in 97% yield (2.60 g): 1H NMR (300 MHz, CDCl3) δ 7.35-7.17 (m, 5H), 3.02-2.92 (in, 1H), 2.85-2.74 (m, 2H), 2.60-2.45 (m, 2H), 1.47 (br s, 4H).
Reaction SMILES: N#N.[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[C:7]([C:9]([OH:11])=O)[N:8]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:42][O:43][C:44]([C:47]1[N:48]=[C:49]([CH2:52][N:53]2[N:57]=[C:56]([NH2:58])[CH:55]=[N:54]2)[O:50][CH:51]=1)([CH3:46])[CH3:45]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:42][O:43][C:44]([C:47]1[N:48]=[C:49]([CH2:52][N:53]2[N:57]=[C:56]([NH:58][C:9]([C:7]3[N:8]=[C:4]([CH3:3])[O:5][C:6]=3[C:12]3[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=3)=[O:11])[CH:55]=[N:54]2)[O:50][CH:51]=1)([CH3:46])[CH3:45]
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: COC(C)(C)c1coc(Cn2ncc(N)n2)n1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(C)(C)c1coc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(C)c3)n2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-methyl-5-(m-tolyl)oxazole-4-carboxylic acid (WO 2009/077990, p. 112) (40.0 mg, 0.18 mmol) in CH2Cl2 (1.0 mL) was treated at rt with DMAP (5.6 mg, 0.05 mmol), HOBt (29.9 mg, 0.22 mmol), EDC (88.3 mg, 0.46 mmol) and DIPEA (0.13 mL, 0.74 mmol) and the resulting mixture was stirred for 45 min at rt. A solution of 2-((4-(2-methoxypropan-2-yl)oxazol-2-yl)methyl)-2H-1,2,3-triazol-4-amine (43.7 mg, 0.18 mmol) in CH2Cl2 (0.8 mL) was then added and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH2Cl2 (2.0 mL), the layers were separated and the org. phase was washed with water (2.0 mL), dried over MgSO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (4:6 hept-EA) gave the title compound as a colorless oil: TLC: rf (4:6 hept-EA)=0.35. LC-MS-conditions 06: tR=0.94 min, [M+H]+=437.34.