Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH:7]([CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:6]2.[C-:25]#[N:26].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH:7]([CH2:13][C:25]#[N:26])[CH2:6]2
Reactant: [C-]#N
Reactant: COc1ccc2c(c1)CC(COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CC(CC#N)CO2

Procedure:
1.6 g (4.56 mmol) of the tosylate obtained in Step B are dissolved in 25 ml of anhydrous N,N-dimethylformamide; 0.724 g (11.5 mmol) of potassium cyanide is then added to the solution. After 4 hours of reflux under argon, the solvent is evaporated in vacuo; the residue is then taken up in a saturated solution of sodium hydrogen carbonate. The aqueous phase is then extracted with dichloromethane. The organic phases, dried over magnesium sulphate and then filtered, are concentrated under reduced pressure. The title nitrile is obtained pure in the form of an oil which crystallises slowly after chromatography on silica gel (eluant: AcOEt/PE: 25/75).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH2:24]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[CH2:25][CH2:26][CH3:27]>C(Cl)Cl>[CH2:24]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([N:13]2[CH2:12][CH2:11][CH:10]([N:6]3[C:5]4[CH:16]=[CH:17][C:2]([F:1])=[CH:3][C:4]=4[NH:8][C:7]3=[O:9])[CH2:15][CH2:14]2)=[O:33])=[CH:35][CH:36]=1)[CH2:25][CH2:26][CH3:27]
Reactant: O=c1[nH]c2cc(F)ccc2n1C1CCNCC1
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1ccc(C(=O)N2CCC(n3c(=O)[nH]c4cc(F)ccc43)CC2)cc1
Reaction time: 8 h
Yield: 12.3 %

Procedure:
To a solution of 5-fluoro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (29.4 mg, 0.125 mmol) in methylene chloride (1 mL) was added pyridine (0.12 μL, 0.15 mmol) and 4-n-butylbenzoyl chloride (26 μL, 0.138 mmol). The reaction mixture was stirred overnight then purified directly by column chromatography on silica gel by eluting with methylene chloride followed by ethyl acetate. The product fractions were combined and concentrated in vacuo to give 1-[1-(4-butyl-benzoyl)-piperidin-4-yl]-5-fluoro-1,3-dihydro-benzoimidazol-2-one (6.1 mg; 12%) was obtained as a glass.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCCCCCCCBr
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Yield: 65.2 %

Procedure:
A mixture of 4-bromo-4′-hydroxybiphenyl (50.00 g, 0.2008 mol), 1-bromooctane (50.38 g, 0.2610 mol), potassium carbonate (47.11 g, 0.3414 mol) and butanone (500 cm3) was heated under reflux overnight. The cooled mixture was filtered and the solvent removed on a rotary evaporator. The crude solid was recrystallised from ethanol to yield a white crystalline solid (47.30 g, 66%, m.pt. 120° C.).
Reaction SMILES: [CH:1]1([NH:7][S:8](=[O:11])(=O)[OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:13]>C1(C)C=CC=CC=1>[CH:1]1([NH:7][S:8]([Cl:13])(=[O:11])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(O)NC1CCCCC1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=S(=O)(Cl)NC1CCCCC1
Yield: 82.5 %

Procedure:
Under a nitrogen atmosphere, a solution of N-cyclohexylsulfamic acid (50 g, 279 mmol) and PCl5 (58.1 g, 279 mmol) in 150 mL of toluene is very gently warmed up to 100° C. and maintained at that temperature for 1 hour. Distillation of the solution yields N-cyclohexylsulfamoyl chloride as a colorless solid (45.5 g, 82%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[C:4]([F:10])[CH:3]=1.[CH2:11]([S:13](Cl)(=[O:15])=[O:14])[CH3:12]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][S:13]([CH2:11][CH3:12])(=[O:15])=[O:14])=[C:4]([F:10])[CH:3]=1
Reactant: CCS(=O)(=O)Cl
Reactant: NCc1ccc(Br)cc1F
Solvent: c1ccncc1
Product: CCS(=O)(=O)NCc1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(4-Bromo-2-fluorophenyl)methanamine (924 mg, 4.53 mmol) was dissolved in pyridine and ethane sulfonyl chloride (0.82 mL, 8.60 mmol) was added to the solution at 0° C. The mixture was stirred for 1 h at 0° C. Then, the mixture was quenched with 1N HCl and extracted with ethyl acetate. Drying over magnesium sulfate and evaporation of the ethyl acetate and purified by column chromatography gave N-(4-bromo-2-fluorobenzyl)-ethanesulfonamide in pure form (1.06 g, 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1
Reactant: COc1ccc2c(c1C#CC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1CCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A solution of tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)-ethynyl]piperidine-1-carboxylate (0.0721 g, 0.194 mmol) synthesized in Example B55, Step 1 in ethanol (3 mL) was added with 5% palladium/carbon (wetted with 50% water, 0.0700 g), and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the resulting filtrate was concentrated to obtain tert-butyl 4-[2-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)ethyl]piperidine-1-carboxylate (0.0593 g, 81%).
Reaction SMILES: [C:1]([S@:5](/[N:7]=[CH:8]/[C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][CH:10]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH2:22]1[CH2:26]OC[CH2:23]1.C([Li])(C)C.[NH4+].[Cl-]>O.CCOC(C)=O>[C:1]([S@:5]([NH:7][C@@H:8]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:20][CH:21]=1)[CH:22]([CH3:26])[CH3:23])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)c1ccc(/C=N/[S@](=O)C(C)(C)C)cc1
Agent: [Cl-]
Agent: [Li]C(C)C
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)[C@@H](N[S@](=O)C(C)(C)C)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To an oven-dried 50-mL round-bottom flask was added tert-butyl 4-[(E)-{[(R)-tert-butylsulfinyl]imino}methyl]benzoate (3.00 g, 9.70 mmol) and THF (48 mL). The solution was cooled to −78° C. then isopropyllithium (55.4 mL, 38.8 mmol, 0.70 M of in pentane) was slowly added via a syringe pump over 15 min. The resulting reaction mixture was stirred at −78° C. After 1 h, EtOAc (100 mL), sat. NH4Cl solution (20 mL), and water (10 mL) were added to the flask at this temperature. After separation, the aqueous layer was extracted with EtOAc (2×60 mL). Combined organic layers were washed with brine (20 mL), dried (MgSO4), and concentrated. Purification via flash chromatography (20% EtOAc-hexanes to 50% EtOAc-hexanes) afforded major diastereomer tert-butyl 4-[(1R)-1-{[(R)-tert-butylsulfinyl]amino}-2-methylpropyl]benzoate (1.59 g, 46%) as a white solid. [c]D20=−18.9 (c=1.0, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.96 (d, J=8.5 Hz, 2H), 7.31 (d, J=8.1 Hz, 2H), 4.18 (d, J=6.0 Hz, 1H), 3.45 (d, J=6.0 Hz, 1H), 2.22 (m, 1H), 1.58 (s, 9 μl), 1.24 (s, 9H), 0.94 (d, J=6.8 Hz, 3H), 0.80 (d, J=6.8 Hz, 3H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][S:9]([C:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([N:22]3[CH2:26][CH2:25][C@@H:24]([NH:27]C(=O)OC(C)(C)C)[CH2:23]3)=[O:21])=[CH:17][CH:18]=2)[N:13]([C:35]2[N:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:37][N:36]=2)[CH:12]=1)=[O:10]>ClCCl>[NH2:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:20]([C:16]2[CH:15]=[C:14]3[C:19]([C:11]([S:9]([CH3:8])=[O:10])=[CH:12][N:13]3[C:35]3[N:40]=[CH:39][C:38]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[CH:37][N:36]=3)=[CH:18][CH:17]=2)=[O:21])[CH2:23]1
Reactant: CS(=O)c1cn(-c2ncc(-c3ccccc3)cn2)c2cc(C(=O)N3CC[C@@H](NC(=O)OC(C)(C)C)C3)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)c1cn(-c2ncc(-c3ccccc3)cn2)c2cc(C(=O)N3CC[C@@H](N)C3)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 4M solution of TFA in dichloromethane (5.22 mL, 20.91 mmol) was added to 223d) (0.28 g, 0.52 mmol) in dichloromethane (16 mL) and the resulting mixture was stirred at room temperature for 3 h. The solution was concentrated, diluted with dichloromethane (40 mL), then washed with saturated potassium carbonate solution (2×20 mL) and dried over sodium sulfate. After evaporation of the solvent, the remnant was triturated with ether, pentane and acetone. Light yellow solid. Yield: 0.11 g (46% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=O)=[CH:7][C:6]=2[CH:12]=1.[CH:13]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:14].CCCCCCC.CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](/[CH:10]=[CH:15]/[CH:13]=[O:14])=[CH:7][C:6]=2[CH:12]=1
Reactant: O=Cc1cc2cc(Cl)ccc2o1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C/C=C/c1cc2cc(Cl)ccc2o1
Yield: 68.9 %

Procedure:
A solution of 5-chlorobenzofuran-2-carboxaldehyde (813 mg, 4.50 mmol) and formylmethylene triphenylphosphorane (1.37 g, 4.50 mmol) in CH2Cl2 (40 ml) was treated as sen in preparation 1. After a chromatography on silicagel (n-heptane/EtOAc 4/1) pure title compound (640 mg, 3.10 mmol, yield 68.8%) as yellow crystals was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:12](Br)[CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:12]([O:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])[CH:13]([CH3:15])[CH3:14]
Reactant: COC(=O)c1cncc(O)c1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cncc(OCC(C)C)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, to a solution of methyl 5-hydroxynicotinate (5.00 g) in DMF (50 mL) were added isobutyl bromide (5.33 mL) and potassium carbonate (9.04 g), and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give a crude product of the title compound (5.13 g) as a pale-brown oil. The obtained crude product was directly used for the next step.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:13].[N-:21]=[N+]=[N-].[Na+]>CS(C)=O>[CH3:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[C:3]([CH2:2][NH2:21])=[CH:12]2
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccccc1-c1nc2c(C)cccc2cc1CCl
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccccc1-c1nc2c(C)cccc2cc1CN

Procedure:
Prepared according to Procedure D using 3-(chloromethyl)-8-methyl-2-o-tolyl-quinoline (667 mg, 2.4 mmol) in DMSO (10 mL) was added NaN3 (500 mg, 3 eq). After purification, (8-methyl-2-o-tolylquinolin-3-yl)methanamine was obtained as pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(NC2C3C(=CC=CC=3)[O:43]CC2)=NC=1CC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:43][CH2:20][CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(NC2CCOc3ccccc32)c(CC)nc1Br
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1NC1CCOc2ccccc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-N-(3,4-dihydro-2H-chromen-4-yl)-3,6-diethylpyrazin-2-amine, ethylene glycol dimethyl ether and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ); 7.51, 7.36-7.23, 6.98-6.90, 5.37, 4.69, 4.32, 2.66, 2.51, 2.31, 1.29-1.17; HRMS (EI) calcd for C23H23Cl2N3O 427.1218, found 427.1224.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:2]1.Br[CH2:17][CH2:18][C:19]1[CH:28]=[CH:27][C:22]2[NH:23][C:24](=[O:26])[O:25][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C(C)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:17][CH2:18][C:19]3[CH:28]=[CH:27][C:22]4[NH:23][C:24](=[O:26])[O:25][C:21]=4[CH:20]=3)[CH2:14][CH2:15]2)=[N:2]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=c1[nH]c2ccc(CCBr)cc2o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccc(CCN3CCN(c4nsc5ccccc45)CC3)cc2o1

Procedure:
To a 125 ml round-bottomed flask equipped with condenser were added 4.82 grams (0.022 mol) of N-(3-benzoisothiazolyl)piperazine (prepared according to the procedure given in U.S. Pat. No. 4,411,901), 5.32 grams (0.022 mol) of 6-(2-bromo)ethylbenzoxazolone, 2.33 grams (0.022 mol) of sodium carbonate, and 50 ml of methyl isobutyl ketone. The mixture was refluxed for 18 hours. The reaction was cooled and partitioned between ethyl acetate and water. The ethyl acetate layer was isolated, washed with water and saturated aqueous sodium chloride solution dried over sodium sulfate, and evaporated to an oil. The oil was chromatographed on silica gel using ethyl acetate as eluent, and the product fractions collected and triturated with methylene chloride/isopropyl ether to give a white solid, 1 m.p. 185°-187° C. NMR (CDCl3): 1.7 (bs, 1 H), 2.8 (m, 8H), 3.6 (m, 4H), 6.9-8.0 (m, 7H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[C@@H:10]([CH3:12])[OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.Cl.[CH3:18][C:19]1[N:24]=[CH:23][C:22]([C:25]2[CH:26]=[N:27][C:28]([C@H:31]([NH2:33])[CH3:32])=[CH:29][CH:30]=2)=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C1COCC1>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([C:13](=[O:15])[NH:33][C@@H:31]([C:28]1[N:27]=[CH:26][C:25]([C:22]2[CH:23]=[N:24][C:19]([CH3:18])=[CH:20][CH:21]=2)=[CH:30][CH:29]=1)[CH3:32])[C@H:10]([OH:11])[CH3:12])([CH3:5])([CH3:6])[CH3:7]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(-c2ccc([C@@H](C)N)nc2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc([C@@H](C)NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O)nc2)cn1
Reaction time: 2 h
Yield: 107.7 %

Procedure:
To a mixture of N-Boc-(L)-threonine (0.13 g, 0.61 mmol), (R)-1-(6′-methyl-[3,3′]bipyridinyl-6-yl)-ethylamine dihydrochloride (0.16 g, 0.56 mmol) and HATU (0.23 g, 0.61 mmol) was added THF (1 mL) followed by diisopropylethylamine (0.48 mL, 2.8 mmol). After 2 h, the volatiles were removed under a stream of N2 and the resulting oil was purified by flash chromatography on silica gel (0→5% MeOH/CH2Cl2) yielding 250 mg of {(1S,2R)-2-hydroxy-1-[(R)-1-(6′-methyl-[3,3′]bipyridinyl-6-yl)-ethylcarbamoyl]-propyl}-carbamic acid tert-butyl ester as a tan solid, m/z 415.8 [M+H]+.
Reaction SMILES: [Si:1]([O:18][C@H:19]([CH3:34])[C@H:20]([NH:30]CCO)[C:21]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[C:23]([F:29])[CH:22]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([O:42][CH2:43][CH3:44])(=[O:41])[C:36]([O:38]CC)=O>>[Si:1]([O:18][C@H:19]([CH3:34])[C@H:20]([N:30]1[CH2:44][CH2:43][O:42][C:35](=[O:41])[C:36]1=[O:38])[C:21]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[C:23]([F:29])[CH:22]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](NCCO)c1cc(F)c(F)c(F)c1
Product: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H](c1cc(F)c(F)c(F)c1)N1CCOC(=O)C1=O

Procedure:
A solution of 2-[(1R,2R)-2-tert-butyldiphenylsilanyloxy-1-(3,4,5-trifluorophenyl)propylamino]ethanol (102 mg) in diethyl oxalate (2 ml) was stirred at 170° C. for one hour and 30 minutes. Diethyl oxalate was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (heptane:ethyl acetate 9:1 to 6:1) to obtain 48 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.C([Li])CCC.[C:16](OCC)(=[O:18])[CH3:17]>C1COCC1>[S:3]1[C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=[C:2]1[CH2:1][C:16]([CH3:17])=[O:18]
Reactant: CCOC(C)=O
Reactant: Cc1nc2c(s1)CCCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)Cc1nc2c(s1)CCCC2
Temperature: -78 °C
Reaction time: 2 h

Procedure:
1.50 g (9.78 mmol) of the compound from example 18A are dissolved in 10 ml of abs. THF and, at −78° C., 4.31 ml (10.77 mmol) of n-butyllithium (2.5 M solution in hexane) are added dropwise. After stirring at −78° C. for 2 hours, 1.46 g (16.6 mmol) of ethyl acetate are added as solution in 5 ml of abs. THF. The mixture is stirred at −78° C. for 1 h and then warmed to room temperature. It is then hydrolyzed with sodium bicarbonate solution, and the mixture is extracted three times with diethyl ether. The combined organic phases are dried over magnesium sulfate, and the solvent is removed in a rotary evaporator. 1.60 g (67% of theory) of the title compound are obtained in 80% purity (LC-MS) and are employed without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C1C(=O)N([Br:23])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>FC(C1C=CC=CC=1C)(F)F>[Br:23][CH2:15][C:13]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([O:3][CH2:1][CH3:2])[CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(C)cc1OCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cc1ccccc1C(F)(F)F
Product: CCOC(=O)c1ccc(CBr)cc1OCC
Reaction time: 24 h
Yield: 30.4 %

Procedure:
To a solution of ethyl 2-ethoxy-4-methylbenzoate (100 mg, 0.481 mmol) in 2 mL of trifluoromethyl toluene was added NBS (94 mg, 0.529 mmol) and AIBN (10 mg) in portions. The mixture was heated to reflux and stirred for 24 h. The reaction mixture was concentrated, diluted with 10 mL of EA, washed with 5 mL of 4 N NaOH, 5 mL of brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford ethyl 4-(bromomethyl)-2-ethoxybenzoate as brown oil (42 mg, 30%), which was used for the next step directly.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[CH:11](O)=[O:12]>>[CH:11]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6])=[O:12]
Reactant: O=CO
Reactant: NC(=O)c1cccc(N)c1
Product: NC(=O)c1cccc(NC=O)c1
Yield: 68 %

Procedure:
10 gm of 3-aminobenzamide and 80 ml of 98 to 100% formic acid were refluxed for 60 minutes. The formic acid was removed by evaporation under vacuum; the residual oily product was mixed with water and evaporated to yield a solid residue. This solid was crystallized from water to give 8.2 gm (yield=68%) of white, round crystals with a melting point of 176° C. to 177° C. Mass spectrum analysis indicated a molecular weight of 164.
Reaction SMILES: [OH:1][CH:2]([C@@H:14]([NH:28][C:29](=[O:43])[O:30][CH2:31][C:32]1([CH2:36][C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[CH2:35][CH2:34][CH2:33]1)[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])[C:3](=[O:13])[NH:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].OC([C@@H](NC(=O)OCC1(CC2C=CC=CC=2)CCCCC1)CCCCNC(N1CCOCC1)=O)C(=O)N[C@@H](C1C=CC=CC=1)C>>[N:22]1([C:20]([NH:19][CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]([NH:28][C:29](=[O:43])[O:30][CH2:31][C:32]2([CH2:36][C:37]3[CH:38]=[CH:39][N:40]=[CH:41][CH:42]=3)[CH2:35][CH2:34][CH2:33]2)[C:2](=[O:1])[C:3](=[O:13])[NH:4][C@@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:6])=[O:21])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: C[C@@H](NC(=O)C(O)[C@H](CCCCNC(=O)N1CCOCC1)NC(=O)OCC1(Cc2ccncc2)CCC1)c1ccccc1
Agent: C[C@@H](NC(=O)C(O)[C@H](CCCCNC(=O)N1CCOCC1)NC(=O)OCC1(Cc2ccccc2)CCCCC1)c1ccccc1
Product: C[C@@H](NC(=O)C(=O)[C@H](CCCCNC(=O)N1CCOCC1)NC(=O)OCC1(Cc2ccncc2)CCC1)c1ccccc1

Procedure:
[1-(4-Pyridinylmethyl)cyclobutyl]methyl(1S)-5-[(4-morpholinylcarbonyl)amino]-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate was prepared as in example 9j except that [1-(4-pyridinylmethyl)cyclobutyl]methyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)-5-[(4-morpholinylcarbonyl)amino]pentylcarbamate was substituted for (1-benzylcyclohexyl)methyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)-5-[(4-morpholinylcarbonyl)amino]pentylcarbamate. 1H NMR (300 MHz, 80° C., DMSO-d6) δ 8.92 (m, 1 H), 8.49 (m, 2H), 7.20-7.36 (m, 8H), 6.31 (m, 1H), 5.01 (qnt, J=7 Hz, 1H), 4.82 (m, 1H), 3.78 (s, 2H), 3.53 (t, J=5 Hz, 4H), 3.24 (t, J=5 Hz, 4H), 3.01 (m, 2H), 2.80 (s, 2H), 1.83-1.90 (m, 6H), 1.42-1.48 (m, 9H). ES-LCMS m/z 594 (M+H). HRMS C32H43N5O6 m/z 594.3291 (M+H)Cal; 594.3279 (M+Na)Obs.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4](OC)=[O:5].[CH3:13][NH2:14].O>O>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([NH:14][CH3:13])=[O:5]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: CN
Solvent: O
Product: CNC(=O)c1cc(Br)ccc1N
Temperature: 80 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A mixture of methyl 2-amino-5-bromobenzoate (Compound 106B, 65 g) and CH3NH2.H2O (1000 mL) was stirred at 80° C. overnight in a pressure tube. The mixture was diluted with H2O (1000 mL) and extracted with EtOAc (3×500 mL). The combined organic layers were dried over MgSO4, concentrated to afford the title compound (55 g, yield: 87%) as a gray solid. 1H NMR (CDCl3, 400 MHz): δ=2.93 (d, J=5.2 Hz, 3H), 5.48 (s, br, 2H), 6.04 (s, br, 1H), 6.54 (d, J=8.4 Hz, 1H), 7.24 (dd, J=2.0, 8.4 Hz, 1H), 7.38 (d, J=2.0 Hz, 1H).