Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.CN(C)[C:5](=[O:30])[CH2:6][O:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:12][CH2:11]1.CN(C)C(=O)C[O:36]CCN1CCN(C(C2C=CC=CC=2)C2C=CC([Cl:52])=CC=2)CC1>>[ClH:23].[ClH:52].[C:24]1([CH:16]([N:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][O:7][CH2:6][C:5]([OH:30])=[O:36])[CH2:11][CH2:12]2)[C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CN(C)C(=O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Agent: Cl
Product: O=C(O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Yield: 81.3 %

Procedure:
The procedure described in Example 13 is followed with the difference that, instead of the (RS)-N,N-dimethyl-{2-[4-(α-phenyl-p-chloro-benzyl)piperazin-1-yl]ethoxy}-acetamide dihydrochloride, 83.2 g (0.2 moles) of (RS)-N,N-dimethyl-{2-[4-(α-phenyl-p-chloro-benzyl)piperazin-1-yl]ethoxy}-acetamide base are used. Thus, 75.0 g (81.3%) of the title compound are obtained, m.p. 225-228° C. The purity of the product corresponds to the quality requirements given in Eur. Pharm., 3, 1997, 1084.
Reaction SMILES: [C:1]1([C:7]2([C:13](O)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1.C(OCC)(=O)C>[C:1]1([C:7]2([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1(c2ccccc2)CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCC1(c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-phenylcyclohexanecarboxylic acid (1.32 g) in tetrahydrofuran (30 mL) at 0° C. was slowly added 2 M LiAlH4 in tetrahydrofuran (6.46 mL). The resulting mixture was stirred at room temperature overnight and cooled to 0° C. Ice water was added to quench the reaction. The resulting mixture was diluted with ethyl acetate and washed with 1 N aqueous NaOH and water. The organic layer was dried over Na2SO4, filtered, and concentrated to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=2[O:22][CH3:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.C1(C)C=CC=CC=1>C1COCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[O:22][CH3:23])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc([N+](=O)[O-])ccc1OC1CN(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(N)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Yield: 101 %

Procedure:
Dissolve 3-(2-methoxy-4-nitro-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (210 g, 639 mmol) in THF (630 mL) and transfer with MeOH (1680 mL) to a stainless steel tank containing 10% palladium on carbon pre-wet with toluene. Hydrogenate the mixture on a Parr shaker for 2.5 h. Remove the catalyst by filtration through diatomaceous earth and rinse the solids with MeOH. Concentrate the filtrate in vacuo, and then co-evaporate the residue three times with heptane (500 mL each time) to obtain 190 g (99%) of the title compound as a tan solid which is used immediately in the next reaction. 1H NMR (300 MHz, CDCl3) δ: 6.48 (d, 1H, J=8.5), 6.30 (d, 1H, J=2.6), 6.17 (dd, 1H, J=2.4, 8.5), 4.77 (m, 1H), 4.19 (m, 2H), 4.04 (m, 2H), 3.81 (s, 3H), 3.59 (br s, 2H), 1.42 (s, 9H).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][CH2:8][NH:9][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[C:11]([O:13][CH3:14])=[O:12].[C:22](=O)([O-])O.[Na+].C=O.Cl>O.CC(C)=O.ClCCCl>[OH2:12].[ClH:21].[CH3:14][O:13][C:11](=[O:12])[CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[N:9]1[CH2:8][CH2:7][C:3]2[S:2][CH:6]=[CH:5][C:4]=2[CH2:22]1
Reactant: O=C([O-])O
Reactant: COC(=O)C(NCCc1cccs1)c1ccccc1Cl
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCCl
Solvent: O
Product: COC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Yield: 86.6 %

Procedure:
To 28.4 g (0.082 mol) of methyl [2-(2-thienyl)ethylamino](2-chlorophenyl)acetate hydrochloride, prepared according to example 9 or 10, are added 50 ml of 1,2-dichloroethane and the solution of 7.5 g (0.09 mol) of sodium hydrogen carbonate in 100 ml of water. The mixture is stirred well, the phases are separated, the aqueous phase is washed with 2×30 ml of 1,2-dichloroethane, the combined organic layer is dried over anhydrous sodium sulfate and the solvent is removed in vacuo. The residual 25 g material (acetate base) is dissolve din 90 ml of formic acid, to the solution 4 g (0.13 mol) of para formaldehyde is added and the mixture is stirred at 50° C. for 20 minutes. The majority of the formic acid is then distilled off in vacuo, the residue is dissolved in the mixture of 100 ml of water and 100 ml of 1,2-dichloroethane, the phases are separated, the aqueous phase is extracted again with 30 ml of 1,2-dichloroethane, the combined organic phase is shaken well with 100 ml of 5% sodium hdyrogen carbonate solution, the phases are separated and the organic phase is dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is dissolved in 45 ml of acetone and to the solution 6.5 ml (0.077 mol) of conc. hydrochloric acid is added at 5-10° C., under cooling. The product slowly crystallizes. The mixture is stirred for 1 hour at 0-10° C., then the crystals are filtered off, washed with 2×10 ml of acetone and dried. Weight: 26.7 g (theoretical: 30.8 g ) Yield: 86.6%, mp.: 138-140° C. (literature mp: 130-140° C.). The product was identified by elemental analysis, IR spectrum, 1H-NMR investigation and melting point determination.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:13])[C:6]1[CH:11]=[C:10](Cl)[CH:9]=[CH:8][N:7]=1)([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:22]2[CH:23]=[C:24]3[NH:30][CH:29]=[CH:28][C:25]3=[N:26][CH:27]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[NH:30]1[C:24]2[C:25](=[N:26][CH:27]=[C:22]([C:10]3[CH:9]=[CH:8][N:7]=[C:6]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:13])[CH:11]=3)[CH:23]=2)[CH:28]=[CH:29]1
Reactant: CC1(C)OB(c2cnc3cc[nH]c3c2)OC1(C)C
Reactant: CC(C)OC(=O)c1cc(Cl)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)c1cc(-c2cnc3cc[nH]c3c2)ccn1
Temperature: 65 °C
Yield: 56.9 %

Procedure:
A mixture of 4-chloropicolinic acid isopropyl ester (1.5 g, 7.5 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine (1.83 g, 7.5 mmol), dppf(Pd)Cl2 (270 mg, 5 mol %), and potassium carbonate (2.0 g, 15 mmol) in degassed toluene (8 mL), degassed water (4 mL) and degassed isopropanol (4 mL) was heated at 65° C. for 2 hours. The aqueous phase was discarded and the solvent removed under reduced pressure. The residue was purified by flash chromatography (rf: 0.41 in 20:1 ethyl acetate:methanol) to provide isopropyl 4-(1H-pyrrolo[3,2-b]pyridin-6-yl)picolinate (1.20 g, 57%) as a yellow powder. 282.1 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)C(C(NCCNC(=O)OC(C)(C)C)=O)=[N:3]1.[C:26]([O:29][CH2:30][CH3:31])(=[O:28])[CH3:27].CCCCCC>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:27]([C:26]([O:29][CH2:30][CH3:31])=[O:28])=[N:3]1
Reactant: CCOC(C)=O
Reactant: Cn1cc(-c2ccccc2)c(C(=O)NCCNC(=O)OC(C)(C)C)n1
Solvent: CCCCCC
Product: CCOC(=O)c1nn(C)cc1-c1ccccc1

Procedure:
In an analogous manner to that described in Examples I6 and 17. from 6.6 g (28.7 mmol) of ethyl 1-methyl-4-phenyl-3-pyrazolecarboxylate there were obtained 4.6 g 71.5%) of t-butyl [2-(1-methyl-4-phenyl-3-pyrazolecarboxamido)ethyl]carbamate as white crystals, melting point 145° (from ethyl acetate/hexane).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[C@@H:9]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH3:10])=[CH:4][CH:3]=1>CN(C)C=O.[Pd]>[OH:22][C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C@@H:9]([N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])[CH3:10]
Reactant: C[C@@H](C(=O)c1ccc(O)cc1)N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: CN(C)C=O
Product: C[C@@H]([C@H](O)c1ccc(O)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 94.3 %

Procedure:
To a solution of (S)-2-[2-(4-hydroxyphenyl)-1-methyl-2-oxo-ethyl]isoindol-1,3-dione (17.7 g) in N,N-dimethyl-formamide (60 mL), 10% palladium on carbon (7.1 g: containing 50% w/w water) was added. The mixture was stirred under hydrogen atmosphere (5.0 atm.) at room temperature for 10 hours. After removing insoluble matter by filtration, the filtrate was diluted with water (400 mL) and extracted with ethyl acetate. Organic layer was washed with brine, sodium bicarbonate solution, brine, 1 mol/L hydrochloric acid and brine, and dried over anhydrous sodium sulfate. After removing the solvent, the resulting residue was recrystallized from ethanol/hexane to obtain (1S,2R)-2-[2-hydroxy-2-(4-hydroxyphenyl)-1-methyl-ethyl]isoindol-1,3-dione (16.8 g : 57% yield, optical purity 100% e.e.).
Reaction SMILES: [O:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]=[CH2:12])=[CH:6][CH:5]=1)[C:2]#[N:3].[CH3:13][O:14][SiH:15]([O:18][CH3:19])[O:16][CH3:17]>C1(C)C(C)=CC=CC=1>[O:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][Si:15]([O:18][CH3:19])([O:16][CH3:17])[O:14][CH3:13])=[CH:6][CH:5]=1)[C:2]#[N:3]
Reactant: CO[SiH](OC)OC
Reactant: C=CCc1ccc(OC#N)cc1
Solvent: Cc1ccccc1C
Product: CO[Si](CCCc1ccc(OC#N)cc1)(OC)OC
Yield: 42 %

Procedure:
To 3.94 g (24.75 mmol) of purified 1-cyanato-4-(2-propenyl)benzene, prepared as described above, at 65° C. was added 10 μL of a 3% solution of Karstedt's™ catalyst (platinum-divinyltetramethyldisiloxane complex) in xylene (United Chemical Technologies, Bristol, Pa.). Trimethoxysilane (Aldrich) was added in 500 μL increments followed by 10 μL increments of the catalyst solution until NMR showed that the reaction was more than 80% complete. The product was distilled twice to yield 2.94 g (42%) of 3-(4-cyanatophenyl)propyltrimethoxysilane. The structure of the product was verified by IR and NMR.
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[C:16]2[CH:25]=[C:24]([C:26](O)=[O:27])[NH:23][C:17]=2[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=1.C(Cl)(=O)C(Cl)=O.C[N:41](C)C=O.[OH-].[NH4+]>ClCCl>[F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[C:16]2[CH:25]=[C:24]([C:26]([NH2:41])=[O:27])[NH:23][C:17]=2[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=1
Reactant: Cn1cc(-c2cc(S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)c2cc(C(=O)O)[nH]c2c1=O
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)c2cc(C(N)=O)[nH]c2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 965.6 %

Procedure:
To a solution of Example 252g (0.10 g, 0.21 mmol) in anhydrous dichloromethane (5 mL) was added oxalyl chloride (0.037 mL, 0.42 mmol) and dimethylformamide (0.816 μl, 10.5 μmol) The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated. The residue was redissolved in dichloromethane (5 mL) and treated with ammonium hydroxide (2 mL, 92 mmol) and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was partitioned between water (15 mL) and ethyl acetate (25 mL). The aqueous layer was extracted with additional ethyl acetate (2×15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was triturated with ethyl acetate and the resulting solid was filtered, washed with dichloromethane and dried under vacuo to provide the title compound (48 mg, 47% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.33 (s, 1H), 7.98 (s, 1H), 7.98-7.88 (m, 1H), 7.82 (s, 1H), 7.56-7.40 (m, 4H), 7.19 (m, 1H), 7.00 (d, J=8.8 Hz, 1H), 6.87 (s, 1H), 3.59 (s, 3H), 3.27 (s, 3H). MS (ESI+) m/z 474.1 (M+H)+
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=[C:10]([Br:12])[CH:11]=1)=O)C.[BH4-].[Li+].O.C(OCC)(=O)C>C1COCC1>[Br:12][C:10]1[N:9]=[C:8]2[N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[N:14]=[C:15]([CH3:16])[C:7]2=[C:6]([CH2:4][OH:3])[CH:11]=1
Reactant: CCOC(=O)c1cc(Br)nc2c1c(C)nn2C1CCCCO1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nn(C2CCCCO2)c2nc(Br)cc(CO)c12
Reaction time: 0.17 h
Yield: 105.6 %

Procedure:
A solution of 139 mg 6-bromo-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]-pyridine-4-carboxylic acid ethyl ester in 8 ml of dry THF was cooled to −20° C. and 18 mg of lithium borohydride was added. After 10 min at −20° C., the reaction was slowly brought to rt. After 1.5 h at rt water and ethyl acetate were added to the reaction. The phases were separated and the organic phase was dried over sodium sulphate, filtrated and concentrated in vacuo to obtain 130 mg (98%) of the title compound as a crude product, which was used without purification in the subsequent step.
Reaction SMILES: O[C:2]([CH3:13])([CH3:12])[C:3]#[C:4][C:5]([C:7]1[N:8]=[CH:9][S:10][CH:11]=1)=[O:6].C(NCC)C.C([OH:21])C>>[CH3:12][C:2]1([CH3:13])[C:3](=[O:21])[CH:4]=[C:5]([C:7]2[N:8]=[CH:9][S:10][CH:11]=2)[O:6]1
Reactant: CC(C)(O)C#CC(=O)c1cscn1
Reactant: CCO
Solvent: CCNCC
Product: CC1(C)OC(c2cscn2)=CC1=O
Reaction time: 0.75 h

Procedure:
To a stirred solution of 4-hydroxy-4-methyl-1-(thiazol-4-yl) pent-2-yn-1-one (0.1 g, 0.53 mmol) in ethanol (1 mL) was added diethyl amine (0.057 mL, 0.59 mmol) in EtOH (0.5 mL) dropwise at RT and the reaction mixture was stirred for additional 45 min. Then the EtOH was removed, diluted with EtOAc (10 mL), washed with water (5 mL), brine (5 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford 2, 2-dimethyl-5-(thiazol-4-yl) furan-3(2H)-one (0.1 g) as an oil.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.N1C=CC=CC=1.[ClH:33]>O>[ClH:33].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCNCC3)c(F)cc2c1=O

Procedure:
A mixture of 2.83 g (0.01 mol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (II), 4.4 g (0.051 mol) of anhydrous piperazine and 30 ml of dry pyridine is refluxed for 6 hours. The solvent is stripped off in vacuo, the residue is taken up in 25 ml of water, the pH is adjusted to 1 with concentrated hydrochloric acid, while cooling with ice and, when the mixture is cold, the precipitate is filtered off under suction and washed with cold 10% strength hydrochloric acid and ethanol. After drying in vacuo at 100° C., 3.05 g of 1-cyclopropyl-6,8-difluoro-7-(piperazin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride having a decomposition temperature of 354°-355° C. are obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:44]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C=O)C.CCCCCC.O>[CH2:44]([N:51]1[CH2:56][CH2:55][N:54]([C:14]([C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]([F:10])([F:22])[F:21])=[O:16])[CH2:53][CH2:52]1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(O)c1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
DIPEA (13.6 mL, 78.90 mmol) was added drop wise to 2-trifluoromethyl-benzoic acid (5 g, 26.30 mmol) in DMF (20 mL). EDCI (12.6 g, 65.75 mmol) and HOBT (4.26 g, 31.56 mmol) were added consecutively and after 10 mins, 1-benzyl-piperazine (5.56 g, 31.56 mmol) was added. The resulting mixture was stirred at room temperature overnight. Water was then added and the product was extracted with EtOAc and washed with brine. The organic phase was dried over Na2 SO4 and concentrated under reduced pressure to afford 12.6 g of crude product. Purification by column chromatography (using silica gel of mesh size of 60-120 and 30/70 EtOAc:hexane as the eluent) afforded 8.6 g (93% yield) of (4-benzyl-piperazin-1-yl)-(2-trifluoromethyl-phenyl)-methanone.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][CH:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])[C:10](OCC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[F:18][C:17]([F:19])([F:20])[CH:16]([CH3:21])[CH2:15][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH2:10][OH:11]
Reactant: CCOC(=O)C(CC(C)C(F)(F)F)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(CC(CO)NC(=O)OC(C)(C)C)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.4 %

Procedure:
To the solution of ethyl 2-((tert-butoxycarbonyl)amino)-5,5,5-trifluoro-4-methylpentanoate (500 mg, 1.596 mmol) in ethanol (2 mL) at 0° C. was added NaBH4 (604 mg, 15.96 mmol). The reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was quenched with aqueous ammonia. The solution was filter through a glass funnel and the resulting filtrate was concentrated to afford the tert-butyl (5,5,5-trifluoro-1-hydroxy-4-methylpentan-2-yl)carbamate (400 mg, 1.475 mmol, 92% crude yield) as a colorless gummy semisolid material. The material was carried on without further purification. LC/MS (ESI) m/e 172.1 [(M+H)+, calcd for C6H13F3NO 172.1] LC/MS retention time (Method A): tR=2.1 min.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[CH3:8][Si:9]([C:12]#[CH:13])([CH3:11])[CH3:10]>C1(C)C=CC=CC=1.C(NC(C)C)(C)C.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].[Cu]I>[CH3:8][Si:9]([C:12]#[C:13][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1)([CH3:11])[CH3:10]
Reactant: Brc1cncnc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1cncnc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
Tetrakis(triphenylphosphine)palladium(O) (727 mg, 0.6 mmol) was added to a stirred, degassed suspension of 5-bromopyrimidine (5.0 g, 31.4 mmol) and copper(I)iodide (120 mg, 0.6 mmol) in toluene and diisopropylamine (1:1, 200 ml) under nitrogen. The reaction mixture was heated to 60° C., trimethylsilylacetylene (4.89 ml, 34.6 mmol) was added and the reaction mixture was stirred for 3 hours at 60° C. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate (200 ml) and washed with saturated aqueous ammonium chloride solution (3×100 ml). The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (5% ethyl acetate/heptane) to give 5-trimethylsilanylethynyl-pyrimidine as a pale brown solid, 4.71 g (85% yield). LC at 215 nm; Rt 2.07: 88%, m/z (ES+): 177 (M+H).
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[CH:32]=[CH:31][C:13]([O:14][C:15]3[CH:24]=[C:23]4[C:18]([CH:19]([C:25]([O:27]C)=[O:26])[CH2:20][CH2:21][O:22]4)=[CH:17][C:16]=3[C:29]#[N:30])=[CH:12][CH:11]=2)=[O:9])[CH:2]=1.O[Li].O.O1CCOCC1.Cl>C1COCC1>[C:1]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[CH:32]=[CH:31][C:13]([O:14][C:15]3[CH:24]=[C:23]4[C:18]([CH:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][O:22]4)=[CH:17][C:16]=3[C:29]#[N:30])=[CH:12][CH:11]=2)=[O:9])[CH:2]=1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccccc5)c4)cc3)c(C#N)cc21
Agent: Cl
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc2c(cc1Oc1ccc(C(=O)Nc3cccc(-c4ccccc4)c3)cc1)OCCC2C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a solution of methyl 7-(4-(biphenyl-3-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (55.6 mg, 0.1102 mmol) in THF (2 ml) was added 1M solution of LiOH—H2O (220.4 μl, 0.2204 mmol). The mixture was stirred for 1 hour at ambient temperature. The mixture was quenched with 4M HCl dioxane (82.65 μl, 0.331 mmol). The crude mixture was purified on silica gel (MeOH in dichloromethane with 1% acetic acid gradient) to provide 40.4 mg of the title compound as a thin film (75%). MS (apci) m/z=491.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:13]([Cu])#[N:14].Cl.O>CN(C=O)C.[Fe](Cl)(Cl)Cl>[C:13]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1)#[N:14]
Reactant: O=C(c1ccc(Br)cc1)C1CC1
Reactant: N#C[Cu]
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C(=O)C2CC2)cc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
22.5 g of 4-bromophenylcyclopropylmethanone (100 mmol) and 10.3 g of CuCN (100 mmol) are dissolved in 15 ml of DMF and heated under reflux, with stirring, for 4 hours. The suspension is allowed to cool down to 70° C. and is then poured into a solution consisting of 40 g of iron(III) chloride, 10 ml of conc. HCl and 60 ml of water. The mixture is stirred at 70° C. for 20 minutes. It is then extracted three times with 90 ml of toluene on each occasion. The combined organic phases are washed with 250 ml of 2N hydrochloric acid and with 250 ml of 2N sodium hydroxide solution, and then concentrated. The solid residue is triturated with petroleum ether and filtered off with suction.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.O1CCCC1>[Pd].C(O)C>[CH3:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([NH2:10])=[C:5]([OH:9])[CH:6]=1
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1C
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(N)c(O)cc1C
Reaction time: 5 h
Yield: 77 %

Procedure:
To 4,5-dimethyl-2-nitrophenol(11.7 g, 0.07 mol), tetrahydrofuran(100 ml) and ethanol(40 ml) were added, and 10% palladium/activated carbon(0.57 g) was added slowly, and then the mixture was hydrogenated for 5 hours. The reaction mixture was concentrated and chromatographed by the same way above to obtain the titled compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:9]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]([C:31]3[N:35]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:34]4[CH:44]=[CH:45][CH:46]=[CH:47][C:33]=4[N:32]=3)[CH2:25][C:26](OCC)=[O:27])=[CH:20][CH:19]=2)=[N:10]1)[CH3:8].O>C1COCC1>[CH2:7]([N:9]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]([C:31]3[N:35]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:34]4[CH:44]=[CH:45][CH:46]=[CH:47][C:33]=4[N:32]=3)[CH2:25][CH2:26][OH:27])=[CH:20][CH:19]=2)=[N:10]1)[CH3:8]
Reactant: CCOC(=O)CC(c1ccc(-c2nn(CC)c3cccnc23)cc1)c1nc2ccccc2n1COCC[Si](C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCn1nc(-c2ccc(C(CCO)c3nc4ccccc4n3COCC[Si](C)(C)C)cc2)c2ncccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
LiAlH4 (11.99 mg) was added to a solution of ethyl 3-[4-(1-ethyl-1H-pyrazolo[4,3-b]pyridin-3-yl)phenyl)-3-(1-[{2-(trimethylsilyl)ethoxy}methyl]-1H-benzo[d]imidazol-2-yl)propanoate (90 mg) in THF (10 mL) at 0° C. The mixture was stirred at room temperature under a dry atmosphere for 1 h. The mixture was poured into water at room temperature and extracted with AcOEt. The organic layer was washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt) to give the title compound (80 mg).