Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:15]([OH:17])=O)=[CH:12][S:13][CH:14]=1.Cl.CN(C)CCCN=C=NCC.Cl.[OH:31][CH2:32][C:33]1([OH:37])[CH2:36][NH:35][CH2:34]1>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:15]([N:35]2[CH2:36][C:33]([CH2:32][OH:31])([OH:37])[CH2:34]2)=[O:17])=[CH:12][S:13][CH:14]=1
Reactant: OCC1(O)CNC1
Reactant: O=C(O)c1cscc1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(c1cscc1Nc1ccc(I)cc1F)N1CC(O)(CO)C1
Reaction time: 0.08 h
Yield: 106.8 %

Procedure:
4-[(2-fluoro-4-iodophenyl)amino]thiophene-3-carboxylic acid (200 mg, 0.551 mmol), 4-(dimethylamino)pyridine (202 mg, 1.65 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (127 mg, 0.662 mmol) were dissolved in DMF (3 mL). The mixture was stirred at ambient for 5 minutes and then 3-(hydroxymethyl)azetidin-3-ol hydrochloride (72 mg, 0.516 mmol) was added and the mixture was stirred for 15 h. The mixture was partitioned between ethyl acetate and 20% citric acid. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with 5% lithium chloride, saturated sodium bicarbonate and brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was crystallized from dichloromethane to afford 1-({4-[(2-fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)-3-(hydroxymethyl)azetidin-3-ol (247 mg, 0.551 mmol, quantitative yield) as off-white crystals: MS (EI) for C15H14FIN2O3S: 449 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.[OH-].[Li+]>CO.O>[C:15]([N:9]1[C:10]([C:11]([F:13])([F:14])[F:12])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)n1ncc(C(=O)O)c1C(F)(F)F
Temperature: 25 °C
Yield: 91.7 %

Procedure:
To a stirred mixture of 1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (3.000 g; 11.4 mmol) in methanol/water (1:1 ratio, 50 mL) was added lithium hydroxide (0.383 g; 16.0 mmol) at room temperature. The mixture was heated to reflux for 2 hr, then allowed to cool to room temperature and concentrated to approximately half of the original volume. The resulting mixture was acidified with 1N HCl to ˜pH 1 and extracted with methylene chloride. The extracts were dried over sodium sulfate, filtered and concentrated to provide 1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (2.47 g, 92%).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH2:9][CH2:10][O:11][C:12](=[O:14])[CH3:13])=[C:7]([Cl:15])[N:6]=[CH:5][N:4]=1.[F:16][C:17]1[C:18]([C:23]2[NH:24][CH:25]=[CH:26][N:27]=2)=[N:19][CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[Cl:15][C:7]1[C:8]([CH2:9][CH2:10][O:11][C:12](=[O:14])[CH3:13])=[C:3]([CH2:2][N:24]2[CH:25]=[CH:26][N:27]=[C:23]2[C:18]2[C:17]([F:16])=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[CH:5][N:6]=1
Reactant: CC(=O)OCCc1c(Cl)ncnc1CBr
Reactant: Fc1cccnc1-c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OCCc1c(Cl)ncnc1Cn1ccnc1-c1ncccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 162 (8.4 mmol), 3-fluoro-2-(1H-imidazol-2-yl)-pyridine (described above) (1.38 g, 8.4 mmol) and K2CO3 (1.17 g, 8.4 mmol) in DMF (6 ml) is stirred at room temperature overnight. To the mixture are added EtOAc (20 ml) and water (10 ml). The organic layer is separated and the aqueous layer is extracted with EtOAc (3×10 ml). The combined extracts are washed with brine (10 ml), dried (Na2SO4) and solvent evaporated. PTLC separation of the residue (5% MeOH in CH2Cl2) gives the product (163) as a white solid.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[CH2:22][CH2:21][CH2:20][C:19]4[N:23]([CH3:26])[N:24]=[CH:25][C:18]3=4)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[CH2:22][CH2:21][CH2:20][C:19]4[N:23]([CH3:26])[N:24]=[CH:25][C:18]3=4)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1ncc2c1CCCN2c1cnc2c(n1)c(C(=O)NC(C)(C)C)cn2COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1ncc2c1CCCN2c1cnc2[nH]cc(C(=O)NC(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.7 %

Procedure:
To a stirred solution of N-tert-butyl-2-(1-methyl-6,7-dihydro-1H-pyrazolo[4,3-b]pyridin-4(5H)-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (77 mg, 159 μmol) in CH2Cl2 (4 mL) was added TFA (740 mg, 500 μL, 6.49 mmol). After 24 h the solvents were evaporated and the residue was re-dissolved in 5 mL of a mixture of (CH2Cl2/methanol/ammonium hydroxide; 60:10:1). After stirring at room temperature for 24 h, the mixture was concentrated in vacuo to a yellow solid, which was purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco, 0 to 5% 9:1 methanol:ammonium hydroxide in CH2Cl2, 30 min) to give a product that was dissolved in CH2Cl2 and precipitated by addition of cyclohexane. The yellow solid formed was separated by decantation of the mother liquor and then dried under high vacuum to give N-tert-butyl-2-(1-methyl-6,7-dihydro-1H-pyrazolo[4,3-b]pyridin-4(5H)-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (33 mg, 59%) as a yellow solid. 1H NMR (CHLOROFORM-d) δ: 8.95 (br. s., 1H), 8.24 (s, 1H), 8.02-8.14 (m, 2H), 7.85 (s, 1H), 3.88-3.99 (m, 2H), 3.83 (s, 3H), 2.81 (t, J=6.6 Hz, 2H), 2.08-2.24 (m, 2H), 1.55 (s, 9H). MS (EI/CI) m/z: 354.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[C:15]([Cu])#[N:16]>CN1CCCC1=O>[C:15]([C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1)#[N:16]
Reactant: N#C[Cu]
Reactant: Brc1ccc2c(c1)[nH]c1cnccc12
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2c(c1)[nH]c1cnccc12
Yield: 6.7 %

Procedure:
A dark solution of example 1 (190 mg, 0.62 mmol) and CuCN (110 mg, 1.22 mmol) in N-methyl 2-pyrrolidone (1.5 ml) was heated in a sealed reaction tube at 200° C. for 48 h. The mixture was filtered and the filtrate was diluted with water (50 ml). A brown solid that precipitated was filtered, washed with water, saturated aqueous NaHCO3, and then methanol. This material was dissolved in DMSO and diluted with aqueous HCl. This homogeneous dark solution was decolorized with charcoal, filtered and concentrated to give a concentrated solution in DMSO. This DMSO solution was partitioned in (1:1) EtOAc-THF and saturated aqueous NaHCO3. The organic solution was dried (MgSO4) and concentrate to give 8 mg of 7-cyano-β-carboline.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)C=O.C(N(CC)C(C)C)(C)C.Cl[C:44]([O:46][CH:47]([CH3:49])[CH3:48])=[O:45]>C1(C)C=CC=CC=1>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:16]3[CH2:22][CH2:21][N:20]([C:44]([O:46][CH:47]([CH3:49])[CH3:48])=[O:45])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: CC(C)OC(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)OC(C)C)C3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.087 g, 0.23 mmol) in dry N,N-Dimethylformamide (1.00 mL, 12.9 mmol) at 0° C. was added N,N-Diisopropylethylamine (0.1190 mL, 0.6832 mmol) followed by 1.0 M of Isopropyl Chloroformate in Toluene (0.340 mL). The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was concentrated and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.66 (s, 1H), 8.18 (d, J=8.8, 2H), 7.48 (d, J=8.8, 2H), 6.18 (t, J=5.5, 1H), 4.84 (dt, J=12.5, 6.2, 1H), 4.49 (s, 2H), 3.79-3.68 (m, 4H), 3.55 (s, 2H), 3.47 (d, J=4.4, 4H), 3.18-3.05 (m, 2H), 2.68 (t, J=5.0, 2H), 1.24 (d, J=6.2, 6H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+469.3 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[C:4]([CH3:23])[CH:3]=1.[CH3:24][C@H]1CN(CC2C=CC(NC)=CC=2)CCN1C(OC(C)(C)C)=O.[BH4-].[Na+]>>[CH3:22][C@H:11]1[CH2:10][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH3:24])=[CH:3][C:4]=2[CH3:23])[CH2:14][CH2:13][N:12]1[C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16]
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Reactant: Cc1cc(N)ccc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Agent: [BH4-]
Agent: [Na+]
Product: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)c(C)c1
Temperature: 50 °C

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2S)-4-[(4-amino-2-methylphenyl)methyl]-2-methyl-1-piperazinecarboxylate (D80) using a method similar to that described for D3 in Description 3A although the reaction was heated at 50° C. for 16 h prior to addition of sodium borohydride and 5.5 h after addition. δH (CDCl3, 400 MHz) 7.00 (1H, d), 6.45 (1H, d), 6.39 (1H, dd), 4.17 (1H, br.s), 3.76 (1H, d), 3.57 (1H, br.s), 3.33 (1H, d), 3.27 (1H, d), 3.01 (1H, td), 2.82 (3H, s), 2.71 (1H, d), 2.58 (1H, d), 2.32 (3H, s), 2.11 (1H, dd), 1.90 (1H, m), 1.45 (9H, s), 1.17 (3H, d). MS (AP+): 356.2 (MNa+), 234.2, no molecular ion (MH+) observed.
Reaction SMILES: C([N:4]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:13])[CH3:12])=[CH:7][CH:6]=1)(=O)C>C(O)C>[CH:20]([C:17]1[CH:18]=[CH:19][C:14]([NH:4][C:5]2[CH:6]=[CH:7][C:8]([CH:11]([CH3:13])[CH3:12])=[CH:9][CH:10]=2)=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: CC(=O)N(c1ccc(C(C)C)cc1)c1ccc(C(C)C)cc1
Solvent: CCO
Product: CC(C)c1ccc(Nc2ccc(C(C)C)cc2)cc1
Reaction time: 30 h

Procedure:
N-Acetyl-N,N-di(4-isopropylphenyl)amine (5.4 g, 18.4 mmol) are heated to reflux in 100 ml of 20% aqueous ethanol. The reaction is monitored by thin-layer chromatography. After 30 h, no reactant is any longer detectable in the TLC. The ethanolic solution is poured into dist. water, and the brownish precipitate is filtered off with suction, dissolved in dichloromethane and dried with sodium sulphate. The solution is concentrated and chromatographed through a short silica gel column with 50% dichloromethane in hexane. The product fractions are concentrated to dryness and the product is dried under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=O)[C:5]([F:8])=[N:6][CH:7]=1.Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[N:12][OH:13])[C:5]([F:8])=[N:6][CH:7]=1
Reactant: NO
Reactant: O=Cc1cc(Br)cnc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: ON=Cc1cc(Br)cnc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a solution of 5-bromo-2-fluoro-pyridine-3-carbaldehyde (2) (20.0 g, 98.0 mmol) in 1:1 MeOH—H2O (250 mL) was added hydroxylamine hydrochloride (7.52 g, 108 mmol) and sodium carbonate (11.4 g, 108 mmol). The reaction mixture was stirred at rt for 1 hour. The solvent was evaporated in vacuo and the residue diluted with H2O (200 mL) and EtOAc (200 mL). The organic phase was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The product was obtained as a light pink solid (21.0 g, 93%); Rf: 0.4 (10% EtOAc-pet ether).
Reaction SMILES: [C:1]([O:4][C@H:5]1[N:8](C(C(OC)=O)=C(C)C)[C:7](=[O:17])[C@@H:6]1[C@H:18]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH3:19])(=[O:3])[CH3:2].I([O-])(=O)(=O)=O.[Na+].[Mn]([O-])(=O)(=O)=O.[K+].P([O-])([O-])([O-])=O>CC(C)=O.O>[C:1]([O:4][C@H:5]1[NH:8][C:7](=[O:17])[C@@H:6]1[C@H:18]([O:20][Si:21]([C:24]([CH3:25])([CH3:27])[CH3:26])([CH3:22])[CH3:23])[CH3:19])(=[O:3])[CH3:2]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1OC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 4 h
Yield: 43.3 %

Procedure:
In 300 ml of acetone were dissolved 3 g (7.5 mmole) of the product containing as a main component (3R, 4R)-4-acetoxy-3-[(R)-1-t-butyldimethylsilyloxyethyl]-1-(1-methoxycarbonyl-2-methylprop-1-enyl)azetidin-2-one, which had been obtained in Preparation 5. To the solution was added a solution of 6.43 g (30.1 mmole) of sodium metaperiodate and 120 mg of potassium permanganate in a mixture of 150 ml of water and 150 ml of a 0.1 M phosphate buffer solution (pH 7.02) at about 18° C. over 30 minutes, and then the mixture was stirred at that temperature for 4 hours. After completion of the reaction, the precipitate produced was filtered off and about 25 ml of the above buffer solution was added to the filtrate to adjust its pH to a value of 6.8. The acetone was distilled off at a lower temperature under reduced pressure and the residue was extracted with benzene. The benzene layers were collected and dried. The solvent was distilled off to give a crystalline solid, which was recrystallized from hexane to afford 0.934 g (43.3%) of the desired product as needles melting at 104°-106° C.
Reaction SMILES: C(NO)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[C:17]1([CH3:28])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([O:26][CH3:27])=[O:25].[Br:29]N1C(=O)CCC1=O>C(#N)C>[Br:29][CH2:28][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([O:26][CH3:27])=[O:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccccc1C
Agent: O=C(NO)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1ccccc1CBr
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of 102 g (0.74 mol) of benzohydroxamic acid 2, 111 g (0.80 mol) of pulverised potassium carbonate and 1400 ml of acetonitrile is heated to 60° C. After 0.5 h, 162 g of methyl o-bromomethylphenylacetate 1, which is obtained as 68% crude product from the bromination of methyl o-tolylacetate with N-bromosuccinimide, dissolved in 100 ml of acetonitrile, is added dropwise over 0.5 h at 60° C.-65° C. and the reaction mixture is stirred for 5.5 h at this temperature.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)(O)[O-].[Na+].[Br:19][CH2:20][C:21](Cl)=[O:22]>CN(C)C=O>[Br:19][CH2:20][C:21]([N:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:22]
Reactant: c1ccc(NCc2cccs2)cc1
Reactant: O=C(Cl)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CBr)N(Cc1cccs1)c1ccccc1
Temperature: 0 °C
Yield: 78.5 %

Procedure:
To a 0° C. stirring suspension of the N-(thiophen-2-ylmethyl)aniline (3.51 g, 18.53 mmol) and sodium bicarbonate (1.71 g, 20.38 mmol) in dimethylformamide (15.0 mL), it was added bromoacetyl chloride (1.54 mL, 18.53 mmol). The ice bath was removed and the flask was attached to a bubbler to allow gas evolution and expansion. The reaction was stirred overnight at room temp. Most of the volatiles were evaporated in vacuo, then the residue was taken up in dichloromethane and was washed with water first and then brine. The resulting organic layer was dried over MgSO4(s) and concentrated. The obtained crude was absorbed under vacuum on Florisil with the aid of DCM (dry load). The obtained dispersion was purified by column chromatography (Biotage system, hex:EtOAc 1-20% gradient over 30 CV, 40 g Silicycle silica column) The collected fractions were evaporated to afford 4.51 g of 2-bromo-N-phenyl-N-(thiophen-2-ylmethyl)acetamide (14.55 mmol; 78%), which was judged more than 97% pure by 1H-NMR analysis.
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[C:9]([CH3:15])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20](=[O:34])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][C:22]=1[O:29][CH2:30][CH2:31][CH2:32][CH3:33].COC(=O)C1C=CC(CN(C2C=CC(O[Si](C(C)(C)C)(C)C)=CC=2C)C)=CC=1C>>[CH3:18][O:19][C:20](=[O:34])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:17])[CH3:16])=[CH:8][C:9]=2[CH3:15])[CH3:14])=[CH:23][C:22]=1[O:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCOc1cc(C=O)ccc1C(=O)OC
Reactant: CNc1ccc(O[Si](C)(C)C(C)(C)C)cc1C
Agent: COC(=O)c1ccc(CN(C)c2ccc(O[Si](C)(C)C(C)(C)C)cc2C)cc1C
Product: CCCCOc1cc(CN(C)c2ccc(O[Si](C)(C)C(C)(C)C)cc2C)ccc1C(=O)OC

Procedure:
The title compound is prepared by reductive amination of [4-(tert-butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-methyl-amine with 2-butoxy-4-formyl-benzoic acid methyl ester, essentially as described in the synthesis of 4-({[4-(tert-butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-methyl-amino}-methyl)-2-methyl-benzoic acid methyl ester using the appropriate starting material. The title compound is obtained as syrup after workup. LC-ES/MS m/e 472.3 (M+1).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C:16]1[C:17]([Cl:38])=[C:18]([CH:33]=[C:34]([C:36]#[N:37])[CH:35]=1)[CH2:19][N:20]1[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]1)=O)(C)(C)C>C(Cl)Cl>[NH2:15][C:16]1[CH:35]=[C:34]([CH:33]=[C:18]([CH2:19][N:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)[C:17]=1[Cl:38])[C:36]#[N:37]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(N)c(Cl)c(CN2CCNCC2)c1
Reaction time: 1 h
Yield: 67.5 %

Procedure:
TFA (1.0 mL) was added to a solution of tert-butyl 4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanobenzyl)piperazine-1-carboxylate (59 mg, 0.13 mmol) in DCM (1.0 mL) at RT. After 1 hr, the solvent was removed and the residue was dissolved in MeOH and applied onto an SCX column. This was washed with MeOH and the product was eluted with 2N NH3 in MeOH to give 3-amino-4-chloro-5-(piperazin-1-ylmethyl)benzonitrile (22 mg) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[Br:19][C:20]1[CH:27]=[C:24]([CH:25]=[O:26])[C:23]([OH:28])=[CH:22][CH:21]=1.Cl>C1COCC1>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([OH:28])=[C:24]([CH:27]=1)[CH:25]([OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Brc1ccccn1
Reactant: O=Cc1cc(Br)ccc1O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Oc1ccc(Br)cc1C(O)c1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.8 %

Procedure:
To a solution of 2-bromopyridine (5.75 g) in THF (125 ml) was added, under argon atmosphere at -78° C., a 1.6M n-butyl lithium hexane solution (40.0 ml). The mixture was stirred for 15 minutes at the same temperature. To the reaction mixture was added a solution of 5-bromosalicylaldehyde (3.65 g) in THF (20 ml), which was stirred for 20 minutes at the same temperature, then for further 15 minutes while warming up to room temperature. The reaction mixture was poured into 3N HCl, which was washed with diethyl ether, followed by rendering the pH to alkaline side with the addition of 3N sodium hydroxide. The resultant was washed with diethyl ether, followed by being acidified to about pH 5 with 3N HCl. The weakly acodofoed reaction mixture was subjected to extraction with ethyl acetate, washed with water, dried (anhydrous sodium sulfate), and concentrated to dryness to give 5-bromo-2-hydroxy-α-(2-pyridyl)benzyl alcohol (3.50 g) (Compound D-1), whose phisical properties and spectrum data are shown in Table 13 and Table 14.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].[CH:24]([O:27][CH2:28][CH2:29][NH2:30])([CH3:26])[CH3:25]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:30][CH2:29][CH2:28][O:27][CH:24]([CH3:26])[CH3:25])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Reactant: CC(C)OCCN
Product: CC(C)OCCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 74 using 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 2-isopropoxyethanamine 1H NMR (400 MHz, DMSO-d6) δ 1.10 (d, J=6.06 Hz, 6 H) 3.42 (q, J=5.81 Hz, 2 H) 3.48-3.55 (m, 2 H) 3.55-3.64 (m, 1 H) 7.79 (d, J=8.34 Hz, 2 H) 8.15 (br. s., 2 H) 8.42 (d, J=7.58 Hz, 1H) 8.68 (br. s., 1 H) 8.77 (t, J=5.05 Hz, 1 H) 8.92 (s, 1 H) 13.54 (br. s., 1 H). MS m/z [M+H]+ 392.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:19])[O:10][CH:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9](=[O:19])[O:10][CH:11]3[CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[CH:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: O=C(Nc1cccc(Br)c1)OC1CN2CCC1CC2
Product: COc1cccc(-c2cccc(NC(=O)OC3CN4CCC3CC4)c2)c1
Yield: 71 %

Procedure:
Using general procedure E, quinuclidin-3-yl 3-bromophenylcarbamate, 3-methoxyphenylboronic acid and [PdCl2(pddf)]CH2Cl2 gave the title compound as a white solid (100 mg, 71%). 1H NMR (500 MHz, CDCl3) δ 7.63 (br s, 1H), 7.40-7.27 (m, 4H), 7.17 (d, J=8.0 Hz, 1H), 7.11 (m, 1H), 7.07 (br s, 1H), 6.89 (dd, J=8.0, 2.0 Hz, 1H), 4.85 (m, 1H), 3.85 (s, 3H), 3.30 (m, 1H), 2.99-2.70 (m, 5H), 2.12 (m, 1H), 1.92-1.84 (m, 1H), 1.75-1.68 (m, 1H), 1.62-1.55 (m, 1H), 1.48-1.40 (m, 1H) ppm. 13C NMR (125 MHz, CDCl3) δ 159.9, 153.4, 142.3, 142.1, 138.4, 129.8, 129.4, 122.3, 119.7, 117.7, 112.9, 112.8, 72.0, 55.4, 55.3, 47.4, 46.5, 25.4, 24.5, 19.5 ppm. Purity: >97% LCMS (214 nm & 254 nm); retention time 1.52 min; (M+1) 353
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[NH:9][N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:12]=2)[N:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([C:35]3[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=3)=[N:28][C:29]3[N:30]([CH:32]=[CH:33][N:34]=3)[CH:31]=2)=[CH:22][CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C.C(N(CC)CC)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[C:27]([C:35]3[CH:42]=[CH:41][C:38]([CH2:39][N:16]4[CH2:17][CH2:18][CH:13]([C:11]5[N:12]=[C:8]([C:4]6[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=6)[NH:9][N:10]=5)[CH2:14][CH2:15]4)=[CH:37][CH:36]=3)=[N:28][C:29]3[N:30]([CH:32]=[CH:33][N:34]=3)[CH:31]=2)=[CH:24][CH:25]=1
Reactant: O=Cc1ccc(-c2nc3nccn3cc2-c2ccc(F)cc2)cc1
Reactant: Cc1cccc(-c2nc(C3CCNCC3)n[nH]2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Cc1cccc(-c2nc(C3CCN(Cc4ccc(-c5nc6nccn6cc5-c5ccc(F)cc5)cc4)CC3)n[nH]2)n1
Reaction time: 1 h
Yield: 67.9 %

Procedure:
219 mg (0.69 mmol) 2-Methyl-6-(5-piperidine-4-yl-2H-[1,2,4]triazole-3-yl)-pyridine×2HCl are dissolved in 5.4 mL NMP. After addition of 0.2 mL triethylamine the reaction mixture is stirred for one hour. 200 mg (0.63 mmol) 4-[6-(4-Fluorophenyl)imidazo[1,2-a]pyrimidin-7-yl]-benzaldehyde and 0.06 mL acetic acid are added. The reaction mixture is stirred over night at room temperature. 147 mg (0.69 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is treated with saturated NaHCO3 and stirred for 20 minutes. The precipitate is filtered off, washed with water and dried. 233 mg (62.6%) of the desired product are obtained. 100 mg of this material are further purified by HPLC yielding 74.3 mg of the title compound as formiate.