Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C1C=CC=CC=1[S:12]([C:15]1[C@H:16]([CH3:46])[C@@H:17]2[C@@H:34]([C@H:35]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH3:36])[C:33](=[O:45])[N:18]2[C:19]=1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:21])(=O)=O)=O)C.[N+:49]([C:52]1[CH:65]=[CH:64][C:55]([CH2:56][O:57][C:58]([NH:60][CH2:61][CH2:62]S)=[O:59])=[CH:54][CH:53]=1)([O-:51])=[O:50]>>[Si:38]([O:37][C@@H:35]([C@H:34]1[C:33](=[O:45])[N:18]2[C:19]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)=[O:21])=[C:15]([S:12][CH2:62][CH2:61][NH:60][C:58]([O:57][CH2:56][C:55]3[CH:64]=[CH:65][C:52]([N+:49]([O-:51])=[O:50])=[CH:53][CH:54]=3)=[O:59])[C@H:16]([CH3:46])[C@H:17]12)[CH3:36])([C:41]([CH3:43])([CH3:44])[CH3:42])([CH3:39])[CH3:40]
Reactant: CCN(CC)C(=O)c1ccccc1S(=O)(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2[C@H]1C
Reactant: O=C(NCCS)OCc1ccc([N+](=O)[O-])cc1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H](C)[C@H]12
Yield: 87 %

Procedure:
Following a procedure similar to that described in Example 19(c), but using 4-nitrobenzyl (1R, 5S,6S)-2-(2-diethylcarbamoylphenylsulfonyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 42) and 2-(4-nitrobenzyloxycarbonyl)aminoethylmercaptan as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 87%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:18]([NH2:26])([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:19]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[N:26][C:18]([CH3:20])([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:19])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)CC(C)(C)N
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: Cc1ccccc1
Product: CC(C)(C)CC(C)(C)N=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.48 %

Procedure:
To a nitrogen-charged 250 mL, 4-necked round bottom flask equipped with a TEFLON-coated magnetic stirrer, a thermometer, nitrogen gas flow, addition funnel, and a Dean-Stark apparatus equipped with a condenser and a receiver was added 9.8590 g (0.042 moles) of 3,5,-di-t-butyl-4-hydroxybenzaldehyde followed by 100 mL of toluene with vigorous stirring. The solution was not clear and the aldehyde was not soluble in toluene at room temperature. 5.8 gm of t-octylamine was added into the reaction via addition funnel. The reaction flask was slowly heated to 60° C. by heating mantle, and the temperature was controlled by a THERM-O-WATCH® Controller/Monitor. The solution became clear dark reddish brown. The reaction was monitored for 2 hours at 60° C. by Thin Layer Chromatography (TLC). Then the temperature was raised to 110° C. to remove the water by azeotrope with toluene. The azeotrope of water and toluene was collected in a receiver attached to Dean-Stark. After the calculated amount of water was removed, the reaction was cooled to room temperature. The completion of the reaction was monitored by Infra Red Spectroscopy (IR) analysis and by the amount of water collected in the Dean-Stark receiver. The IR analysis confirmed the disappearance of wave number 1682 cm−1 (aldehyde C═O) and appearance of wave number 1621 cm−1 (imine C═N). The imine was collected by evaporating toluene using a rotary evaporator under water aspiration with 94.48% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][CH:11]([S:15]([OH:18])(=[O:17])=[O:16])[C:12]([OH:14])=[O:13].C(N=C=NCCCN(C)C)C.O[N:31]1[C:35](=[O:36])[CH2:34][CH2:33][C:32]1=[O:37]>CC(N(C)C)=O>[O:37]=[C:32]1[CH2:33][CH2:34][C:35](=[O:36])[N:31]1[O:13][C:12](=[O:14])[CH:11]([S:15]([OH:18])(=[O:16])=[O:17])[CH2:10][CH2:9][S:8][S:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O=C(O)C(CCSSc1ccccn1)S(=O)(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Solvent: CC(=O)N(C)C
Product: O=C(ON1C(=O)CCC1=O)C(CCSSc1ccccn1)S(=O)(=O)O
Yield: 80.2 %

Procedure:
A mixture of 4-(pyridin-2-yldisulfanyl)-2-sulfobutanoic acid (245 mg, 0.792 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (345 mg, 2.222 mmol) and 1-hydroxypyrrolidine-2,5-dione (120 mg, 1.043 mmol) were stirred in 8 ml of DMA overnight. The resulting solution was evaporated and the residue was purified on a silica column using MeOH/CH2Cl2 (1:10 to 1:5) containing 0.5% acetic acid as eluting solvent to afford 1-(2,5-dioxopyrrolidin-1-yloxy)-1-oxo-4-(pyridin-2-yldisulfanyl)butane-2-sulfonic acid (258 mg, 0.635 mmol, 80% yield).
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]([CH3:35])[C@@H:8]([NH:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=1)[C:9]1[O:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[N:12][N:13]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:11]2[O:10][C:9]([C@H:8]([NH:22][C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([C:31]([F:32])([F:34])[F:33])[CH:24]=3)[C@H:7]([OH:6])[CH3:35])=[N:13][N:12]=2)=[CH:19][CH:18]=1)#[N:21]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)c1nnc(-c2ccc(C#N)cc2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
To a pre-cooled (−55° C.) solution of 4-((1R,2R)-2-(tert-butyldimethyl-silyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-(trifluoromethyl)benzonitrile (790 mg, 1.50 mmol) in THF (100 mL) was added TBAF (1.80 mL, 1.80 mmol, 1 M solution in THF) over 10 min. Upon complete addition the reaction mixture was allowed to warm to 0° C. over 1 h, then stirred at 0° C. for a further 30 min and quenched with sat. aq. NH4Cl (100 mL). The resulting mixture was partitioned between H2O (50 mL) and EtOAc (200 mL). The aqueous layer was extracted with EtOAc (150 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography over silica gel (50-80% EtOAc in hexanes) to provided the title compound as a colourless amorphous solid (610 mg, 98%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.20 (dm, J=8.8 Hz, 2H), 8.00 (dm, J=8.8 Hz, 2H), 7.73 (d, J=8.6 Hz, 1H), 7.38 (d, J=2.4 Hz, 1H), 7.17 (dd, J=2.5, 8.8 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 5.17 (dd, J=5.7, 8.8 Hz, 1H), 4.45 (pentet, J=6.1 Hz, 1H), 1.42 (d, J=6.4 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[S:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=2)[O:21][CH:22]=1>>[C:28]([C:25]1[S:24][C:23]([C:20]2[O:21][CH:22]=[C:18]([CH2:17][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:19]=2)=[CH:27][CH:26]=1)#[N:29]
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: N#Cc1ccc(-c2nc(CCl)co2)s1
Product: N#Cc1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)s1
Yield: 70 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was reacted with 4-chlorometyl-2-(5-cyano-2-thienyl)oxazole to obtain 2-(5-cyano-2-thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 70%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 73-74° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=1)=[O:4].[CH3:17][O:18][C:19]1[CH:34]=[CH:33][C:22]([CH:23]([NH2:32])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:21][CH:20]=1>>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([CH:23]([NH:32][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[C:7]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=2)[OH:4])[C:22]2[CH:33]=[CH:34][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[CH:29][CH:28]=1
Reactant: CS(=O)(=O)Nc1cc(C(=O)CBr)ccc1F
Reactant: COc1ccc(C(N)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(NCC(O)c2ccc(F)c(NS(C)(=O)=O)c2)c2ccc(OC)cc2)cc1

Procedure:
The title compound was prepared by coupling of 2-bromo-1-[4-fluoro-3-[(methylsulfonyl)amino]phenyl]ethanone with 4,4'-dimethoxybenzhydrylamine (preparation described in Example 14) following the procedure described in step D of Example 1, except for the following modification: the crude product after coupling and reduction was chromatographed on silica gel using 75% EtOAc/hexane to elute pure title compound.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11](Cl)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.[CH2:15]([N:17](CC)CC)C.Cl.CN.C(Cl)(Cl)Cl>ClCCl>[CH3:15][NH:17][S:11]([C:6]1[C:5]2[CH:4]=[CH:3][N:2]=[CH:1][C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:13])=[O:12]
Reactant: CCN(CC)CC
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CNS(=O)(=O)c1cccc2cnccc12
Reaction time: 18 h
Yield: 77 %

Procedure:
In 50 ml of dichloromethane was dissolved 1.73 g of 5-isoquinolinesulfonyl chloride, and to the solution were added 1.54 g of triethylamine and 8.0 g of monomethylamine hydrochloride. The mixture was stirred at a temperature of 10° C. to 15° C. for 18 hours. The reaction solution obtained was washed with water, dried with magnesium sulfate, and then the dichloromethane was distilled therefrom under reduced pressure. The residue obtained was subjected to a silica gel column chromatography (silica: 50 g; solvent: chloroform) to give 1.30 g of N-methyl-5-isoquinolinesulfonamide, i.e., Compound (25) in a yield of 77%.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH:6]1[O:8][CH2:7]1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][SH:23]>O1CCCC1>[CH2:22]([S:23][CH2:7][CH:6]([OH:8])[CH2:5][O:4][CH:1]([CH3:2])[CH3:3])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: CC(C)OCC1CO1
Reactant: CCCCCCCCCCCCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCSCC(O)COC(C)C
Temperature: 60 °C

Procedure:
2,3-Epoxypropyl isopropyl ether (1.16 g.) in several ml. of dry tetrahydrofuran is added to a stirred suspension formed by the addition of 50 mg. of sodium hydride (56% dispersion in mineral oil) to 2.2 g. 8. of n-dodecylthiol in 50 ml. tetrahydrofuran. The mixture is then stirred at 60° C. After approximately 4 hours the solvent is removed from the reaction mixture and 20 ml. of water is added to the residue. The resultant aqueous mixture is extracted with ether and the ether extracts washed with water, dried over magnesium sulfate and evaporated to yield 1-(n-dodecylthio)-3-isopropoxy-2-propanol.
Reaction SMILES: [C:1]([C:4]1[CH2:9][CH2:8][CH2:7][NH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:10]([N:6]1[CH2:7][CH2:8][CH2:9][C:4]([C:1]([CH3:2])=[O:3])=[CH:5]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)C1=CNCCC1
Reactant: O=C(Cl)c1ccccc1
Product: CC(=O)C1=CN(C(=O)c2ccccc2)CCC1

Procedure:
Methyl 1-benzoyl-1,4,5,6-tetrahydro-3-pyridyl ketone was prepared from 3-acetyl-1,4,5,6-tetrahydropyridine and benzoyl chloride according to the procedure of Part b) of Example 1. The product was recrystallised from ethanol/water m.pt. 93°-95° C.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:9][CH:8]=1)=[O:6])[CH3:3].CC(C)([O-])C.[K+].[N:39]1([CH2:44][C:45](=O)[CH2:46][O:47][CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[CH:43]=[CH:42][N:41]=[CH:40]1>O1CCCC1>[N:39]1([CH2:44]/[C:45](/[CH2:46][O:47][CH2:48][C:49]2[CH:50]=[CH:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=2)=[CH:13]\[C:10]2[CH:9]=[CH:8][C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])=[CH:12][CH:11]=2)[CH:43]=[CH:42][N:41]=[CH:40]1
Reactant: COc1ccc(COCC(=O)Cn2ccnc2)cc1
Reactant: CCOC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(/C=C(/COCc2ccc(OC)cc2)Cn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A stirred suspension containing [[4-(ethoxycarbonyl)phenyl]methyl]triphenylphosphonium bromide (11.8 g, 0.0234 mol) in dry tetrahydrofuran (25 ml) at 0° C. under a nitrogen atmosphere was treated with potassium t-butoxide (2.58 g, 0.023 mol). The mixture was allowed to warm up to room temperature and stirred for an additional 90 minutes. The resulting orange mixture was treated with a solution of 1-(1H-imidazol-1-yl)-3-[(4-methoxyphenyl)methoxy]-2-propanone (7.1 g, 0.0273 mol) in dry tetrahydrofuran (25 ml) and stirred for 2 hours. The solvent was evaporated off under reduced pressure and the residue was dissolved in ethyl acetate (300 ml) washed with water (3×150 ml) and extracted into hydrochloric acid (3×200 ml of 5M). The acid solution was basified (K2CO3) and extracted with ethyl acetate (3×250 ml). The extracts were combined, dried over sodium sulfate and the solvent was evaporated off under reduced pressure to yield a crude product. The crude product was purified by column chromatography (silica gel 10% hexane in chloroform). The less polar isomer, ethyl 4-[3-(1H-imidazol-1-yl)-2-[[(4-methoxyphenyl)methoxy]methyl]-1E-propenyl]benzoate was obtained as a colourless oil having the following structural characteristics:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]#[N:9])=[CH:5][N:6]=1.N1C=CC=CC=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(Cl)Cl>[C:16]([NH:1][C:2]1[S:3][C:4]([S:7][C:8]#[N:9])=[CH:5][N:6]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: N#CSc1cnc(N)s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ncc(SC#N)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.3 %

Procedure:
To a mixture of 2-amino-5-thiocyanatothiazole (15.7 g, 0.1 mol) and pyridine (12 g, 0.15 mol) in methylene chloride (100 mL) was added acetic anhydride (1.2 g, 0.12 mol) at rt. The mixture was stirred at rt for 6 h. The mixture was concentrated to dryness and to the residue MeOH (50 mL) was added. The precipitates were collected and washed with water. The solid was dried and recrystallized from MeOH to afford 2-acetylamino-5-thiocyanatothiazole (15.2 g, 76%) as a solid, mp 212° C. 1H NMR (CD3OD) δ7.79 (s, 1 H), 2.23 (s, 3 H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[CH:11]1([C@H:14]([OH:16])[CH3:15])[CH2:13][CH2:12]1>C(Cl)Cl>[CH:11]1([C@H:14]([O:16][C:9](=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)[CH3:15])[CH2:13][CH2:12]1
Reactant: C[C@@H](O)C1CC1
Reactant: O=C=Nc1ccc(I)cc1
Solvent: ClCCl
Product: C[C@@H](OC(=O)Nc1ccc(I)cc1)C1CC1
Yield: 90.6 %

Procedure:
To a suspension of 4-iodophenylisocyanate (0.84 g, 3.5 mmol) in CH2Cl2 (6 mL) was added (R)-1-cyclopropylethanol (0.67 mL, 6.9 mmol). The solution was then directly subjected to silica gel chromatography (CH2Cl2) to provide (R)-(4-iodo-phenyl)carbamic acid 1-cyclopropyl-ethyl ester (1.05 g, 93%).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)([O-:17])=[O:16].[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[OH-].[Na+]>C(O)(=O)C.C(Cl)Cl>[CH:26]1([NH:32][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: NC1CCCCC1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CNC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
NaB(OAc)3H (11.0 mmol, 2.33 g) was added to a mixture of 4-nitro-benzaldehyde Compound 4a (10.0 mmol, 1.51 g), cyclohexylamine Compound 10a (10.5 mmol, 1.2 mL) and glacial acetic acid (5 drops) in CH2Cl2 (40 mL) and the resulting suspension was allowed to stir at room temperature for 12 hrs. An aliquot of the reaction mixture showed the formation of product (MS m/e 235, 100%). The reaction mixture was basified with 2N NaOH solution and was extracted with CH2Cl2. The organic layer was washed with brine, separated and dried over Na2SO4. The drying agent was filtered and the solvent was removed in vacuo to yield cyclohexyl-(4-nitro-benzyl)-amine Compound 10b as yellow oil (1.56 g, 67% yield), which was used in the next step without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH:14]([Sn](CCCC)(CCCC)CCCC)=[CH2:15]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:4]1[C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[N:6][CH:7]=[C:2]([CH:14]=[CH2:15])[CH:3]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: N#CC1(c2ncc(Br)cc2Cl)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cnc(C2(C#N)CC2)c(Cl)c1
Temperature: 25 °C
Yield: 50.9 %

Procedure:
4.7 g of 1-(5-Bromo-3-chloro-pyridin-2-yl)-cyclopropanecarbonitrile (step 2 of PREPARATION EXAMPLE 3) was dissolved in 40 ml anhydrous toluene, then 700 mg of tetrakis(triphenylphosphine)palladium(0) and 9.0 g vinyltributylstannane were added under a nitrogen atmosphere. The reaction mixture was heated on reflux for 3 hours. After cooling to ambient temperature, the reaction mixture was filtered, the filtrate was diluted with 100 ml of ethyl acetate, then washed with water and with saturated potassium fluoride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated. Crude material was obtained as a dark oil, which was purified by flash chromatography on silica gel with heptane/ethyl acetate as a solvent. Thus, 1.9 g of 1-(3-chloro-5-vinyl-2-pyridyl)cyclopropanecarbonitrile was obtained as a yellow oil. 1H-NMR (CDCl3): 8.40 ppm (s, 1H), 7.78 ppm (s, 1H), 6.67 ppm (dd, 1H), 5.87 ppm (d, 1H), 5.50 ppm (d, 1H), 1.77 ppm (m, 2H), 1.63 ppm (m, 2H).
Reaction SMILES: C[Al](C)C.[NH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[Br:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]2[C:20]3[C:27]4[CH2:28][CH2:29][CH:30]([C:32](OCC)=[O:33])[CH2:31][C:26]=4[S:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH:15]=[CH:16][CH:17]=1>C1(C)C=CC=CC=1>[Br:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]2[C:20]3[C:27]4[CH2:28][CH2:29][CH:30]([C:32]([N:5]5[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]5)=[O:33])[CH2:31][C:26]=4[S:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C1CCc2c(sc3ncnc(Nc4cccc(Br)c4)c23)C1
Reactant: C1CCNCC1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: O=C(C1CCc2c(sc3ncnc(Nc4cccc(Br)c4)c23)C1)N1CCCCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Anhydrous toluene (2 mL) was added to a 50 mL round bottom flask previously evacuated and refilled with argon or nitrogen gas (3×). This was cooled to 0° C. in an ice-water bath for 5 min. Trimethylaluminum, 0.2 mL (1.8 equiv, 2.0M solution in hexanes) was added and the reaction was stirred at 0° C. for 15 min before piperidine (1.1 equiv, 0.25 mmol) was added to the above solution. It was allowed to stir at 0° C. for 10 min before warming to rt for 20 min. A 3 mL toluene solution of 100 mg (0.23 mmol, 1 equiv) of ethyl 4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylate, 14, was added and the reaction mixture was heated at 100° C. until reaction was complete by TLC. The reaction mixture was cooled to 0° C. and quenched with 1N HCl. The reaction was adjusted to pH 9.0 with 1N NaOH and extracted with EtOAc (3×5 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to give a crude oil which was purified via flash column chromatography MeOH/CH2Cl2 1:9 to provide the required product, 27, as a white solid (100 mg, 92%). 1H-NMR (CD2Cl2-d4) δ 8.49 (s, 1H), 8.05 (d, 1H), 7.62–7.59 (m, 1H), 7.23–7.26 (m, 2H), 7.12 (s, 1H), 3.59 (q, 2H), 3.52 (t, 2H), 3.23–3.10 (m, 3H), 2.94 (dd, 1H), 2.20–2.19 (m, 1H), 2.10–2.08 (m, 1H), 1.71–1.58 (m, 7H); LCMS RT=3.28 min; [M+H]+=473.3.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH3:4].N=C=N.[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C@@H:24]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([N:41]([CH3:52])[C:42]([NH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:43])[CH:36]=2)=[CH:31][CH:30]=1)[C:25]([OH:27])=[O:26])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C@@H:24]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([N:41]([CH3:52])[C:42]([NH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:43])[CH:36]=2)=[CH:31][CH:30]=1)[C:25]([O:27][CH2:1][CH2:2][CH2:3][CH3:4])=[O:26])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCO
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](Nc3ccccc3C(=O)c3ccccc3)C(=O)O)cc2)c1
Agent: CN(C)c1ccncc1
Agent: N=C=N
Solvent: ClCCl
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](Nc3ccccc3C(=O)c3ccccc3)C(=O)OCCCC)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.1 %

Procedure:
4.7 mg (63.3 μmol) of n-butanol, 5.7 mg (8.5 μmol) of PS-DMAP resin and 68 mg (94.0 μmol) of PS-carbodiimide are added successively to a solution containing 25 mg (42.3 μmol) of (S)-2-(2-benzoylphenylamino)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propionic acid (Example 2) in 0.6 ml of DCM. After stirring for 16 h at ambient temperature and then 5 h at 40° C., the reaction medium is filtered and the solvents are evaporated off. The reaction crude is purified by chromatography on a column of silica and eluted with a heptane/ethyl acetate mixture. 5.5 mg of butyl (S)-2-(2-benzoylphenylamino)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propionate are obtained with a 20% yield.
Reaction SMILES: [Li]CCCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][N:8]=1.[CH2:14]1[O:16][CH2:15]1>CCOCC.C1COCC1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:14][CH2:15][OH:16])=[CH:9][N:8]=1
Reactant: C1CO1
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 40.2 %

Procedure:
BuLi (32.2 ml of a 1.6 M solution in hexanes, 52 mmol) added dropwise to a stirred solution of 2,5-dibromopyridine (11.09 g, 46.8 mmol) in Et2O (400 ml) at −78° C. under nitrogen. Upon complete addition the reaction mixture was stirred for 45 min and then a solution of ethylene oxide (6.74 g, 0.14 mol) in THF (70 ml) was added. The reaction mixture was warmed to room temperature, stirred for 1 h and then quenched by addition of NH4Cl solution (sat., 150 ml). The organics were extracted with EtOAc (3×100 ml), washed with brine (100 ml) and dried (MgSO4). The material was concentrated under reduced pressure, whilst simultaneously dry-loading onto silica. The material was purified by column chromatography on silica eluting with Et2O and then EtOAc to give the pure alcohol (3.8 g, 40%).