Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:15]([O:17][C@H:18]4[C@H:22]5[O:23][CH2:24][C@@H:25]([OH:26])[C@H:21]5[O:20][CH2:19]4)=[N:16][C:11]3=[CH:10][C:9]=2[Cl:35])=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:43](=[O:50])[O:44][CH:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)[CH2:38][CH2:37]1>>[Cl:35][C:9]1[CH:10]=[C:11]2[N:16]=[C:15]([O:17][C@@H:18]3[CH2:19][O:20][C@@H:21]4[C@H:25]([OH:26])[CH2:24][O:23][C@H:22]34)[N:14]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:12]2=[N:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([N:36]2[CH2:37][CH2:38][CH:39]([NH:42][C:43](=[O:50])[O:44][CH:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)[CH2:40][CH2:41]2)=[CH:3][CH:4]=1
Reactant: O=C(NC1CCNCC1)OC1CCCC1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(Br)cc3)nc21
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(N4CCC(NC(=O)OC5CCCC5)CC4)cc3)nc21

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(5-(4-bromophenyl)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and cyclopentyl piperidin-4-ylcarbamate following a procedure analogous to that described for Intermediate 23. LC (method 1): tR=1.09 min; Mass spectrum (ESI+): m/z=714 [M+H]+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:40]([O:42][CH3:43])=[O:41]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH3:43])=[O:41])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OC)cc1)n2C)c1ccccn1
Yield: 48 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and methyl chloroformate. Yield: 48% of theory, C29H31N7O5 (557.6) Rf value: 0.62 (silica gel; dichloromethane/methanol=9:1) ##EQU72##
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[C:14]4[CH:26]=[CH:25][C:24](=[O:27])[N:23]([C:28]5[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=5[F:35])[C:15]=4[N:16]=[C:17](S(C)(=O)=O)[N:18]=3)[CH:7]=2)[CH2:3][CH2:2]1.[CH2:37]([NH:40][CH2:41][CH2:42][NH2:43])[CH2:38][CH3:39]>>[CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[C:14]4[CH:26]=[CH:25][C:24](=[O:27])[N:23]([C:28]5[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=5[F:35])[C:15]=4[N:16]=[C:17]([NH:43][CH2:42][CH2:41][NH:40][CH2:37][CH2:38][CH3:39])[N:18]=3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCCNCCN
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: CCCNCCNc1nc(-c2cc(C(=O)NC3CC3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1

Procedure:
The title compound is prepared from N-cyclopropyl-3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzamide and N-propyl-1,2-ethanediamine following the General Procedure for Sulfoxide/Sulfone Displacement, disclosed above. The concentrated reaction mixture is purified via reversed-phase HPLC. The desired product is obtained as a yellow solid (m.p. 120-134)>95% pure by HPLC (65 mg, 61%): LC-MS m/z 533 (M+H)+, 1.84 min (ret time).
Reaction SMILES: CS(O[CH2:6][C:7]#[C:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH2:16][NH:17][C:18]([C:20]1[N:21]=[C:22]2[N:27]([C:28](=[O:38])[C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:26][CH2:25][O:24][C:23]2([CH3:40])[CH3:39])=[O:19])(=O)=O.[CH3:41][S-:42].[Na+]>CN(C)C=O.C(OCC)(=O)C>[F:15][C:13]1[CH:12]=[CH:11][C:10]([CH2:16][NH:17][C:18]([C:20]2[N:21]=[C:22]3[N:27]([C:28](=[O:38])[C:29]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:26][CH2:25][O:24][C:23]3([CH3:39])[CH3:40])=[O:19])=[C:9]([C:8]#[C:7][CH2:6][S:42][CH3:41])[CH:14]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C#CCOS(C)(=O)=O)c(OCc1ccccc1)c2=O
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSCC#Cc1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
A solution of intermediate 183, 3-[2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenyl]prop-2-ynyl methanesulfonate (0.160 g, 0.28 mmol) in N,N-dimethylformamide (3 ml) was treated at 0° C. with sodium thiomethoxide (0.026 g, 0.37 mmol) and the resulting mixture stirred for 2 h. The reaction mixture was then diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Chromatography of the residue on silica gel (elution gradient of ethyl acetate in hexane) gave 0.114 g (78% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.64 (6H, s, 2×CH3), 2.28 (3H, s, SCH3), 3.45 (2H, s, SCH2), 4.05 (4H, m, 2×CH2), 4.69 (2H, d, J=6.1 Hz, NCH2), 5.31 (2H, s, OCH2), 6.98 (1H, m, aromatic), 7.15 (1H, dd, J=3 Hz and J=9.1 Hz, aromatic), 7.32-7.38 (4H, m, aromatics), 7.50-7.53 (2H, m, aromatics), 7.80 (1H, broad t, NH). HRMS (ESI+) calculated for C28H29FN3O4S [M+H+]: 522.1863; found: 522.1844.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][O:7][C:6]=1[CH3:10])=[O:4].[Br:11]N1C(=O)CCC1=O>C1(C)C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([Br:11])[O:7][C:6]=1[CH3:10])=[O:4]
Reactant: COC(=O)c1ccoc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Br)oc1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
2-Methyl-furan-3-carboxylic acid methyl ester (2.0 g, 14.3 mmol) was dissolved in toluene followed by addition of 2,2′-azobis(2-methylpropionitrile) (10 mg, 0.06 mmol). The mixture was cooled to 0° C. by an ice-water bath followed by addition of N-bromosuccinimide (2.8 g, 15.7 mmol). Upon completion of the addition, the ice-water bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 5-bromo-2-methyl-furan-3-carboxylic acid methyl ester 53a (1.9 g, yield 61%) as a colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([Cl:16])[C:13]([Cl:15])=[CH:14][C:9]=2[NH:8][C:7]1=[O:17])[CH3:2].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([Cl:16])[C:13]([Cl:15])=[CH:14][C:9]=2[N:8]([CH2:24][C:23]2[CH:26]=[CH:27][C:20]([Cl:19])=[CH:21][CH:22]=2)[C:7]1=[O:17])[CH3:2]
Reactant: CCOC(=O)Cn1c(=O)[nH]c2cc(Cl)c(Cl)cc21
Reactant: ClCc1ccc(Cl)cc1
Product: CCOC(=O)Cn1c(=O)n(Cc2ccc(Cl)cc2)c2cc(Cl)c(Cl)cc21

Procedure:
The procedure described in Example 1 was repeated (using the same molar proportions as before) except that 240 mg. (0.0008 mole) of 5,6-dichloro-2-oxo-1-benzimidazolineacetic acid ethyl ester and 134 mg. (0.00083 mole) of p-chlorobenzyl chloride were reacted to afford 3-(p-chlorobenzyl)-5,6-dichloro-2-oxo-1-benzimidazolineacetic acid ethyl ester as the desired final product.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[C:6]2[CH:13]=[C:12]([CH3:14])[C:11]([OH:15])=[CH:10][C:7]=2[S:8][CH:9]=1.[F:17][C:18]([F:36])([F:35])[C:19]1[CH:34]=[CH:33][C:22]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31]O)=[CH:21][CH:20]=1.COC(=O)CC1C2C=CC=C(O)C=2SC=1>>[CH3:14][C:12]1[C:11]([O:15][CH2:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH2:23][C:22]2[CH:33]=[CH:34][C:19]([C:18]([F:17])([F:35])[F:36])=[CH:20][CH:21]=2)=[CH:10][C:7]2[S:8][CH:9]=[C:5]([CH2:4][C:3]([OH:2])=[O:16])[C:6]=2[CH:13]=1
Reactant: OCc1ccccc1OCc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)Cc1csc2cc(O)c(C)cc12
Agent: COC(=O)Cc1csc2c(O)cccc12
Product: Cc1cc2c(CC(=O)O)csc2cc1OCc1ccccc1OCc1ccc(C(F)(F)F)cc1
Yield: 43 %

Procedure:
The title compound was prepared using compound 78C from the preceding step and compound 7A in a manner analogous to compound 77B. Thus, recrystallization from methanol afforded 0.42 g (43% yield) of the title compound as a cream-colored powder, mp 108-109° C. Calc for C27H23F3O4S: C, 64.79; H, 4.63; found: C, 64.64; H, 4.46. Step 5. Preparation of {5-Methyl-6-[2-(4-trifluoromethyl-benzyloxy)-benzyloxy]-benzo[b]thiophen-3-yl}-acetic acid (Compound 78)
Reaction SMILES: Br.[NH2:2][C:3]1[C:8]([CH2:9][OH:10])=[CH:7][C:6]([Br:11])=[CH:5][N:4]=1.C(N(CC)CC)C.Cl[C:20](OC(Cl)(Cl)Cl)=[O:21]>ClCCl>[Br:11][C:6]1[CH:5]=[N:4][C:3]2[NH:2][C:20](=[O:21])[O:10][CH2:9][C:8]=2[CH:7]=1
Reactant: Nc1ncc(Br)cc1CO
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1Nc2ncc(Br)cc2CO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 2-amino-5-bromo-3-hydroxymethylpyridine hydrobromide (Apollo, Cheshire, UK, 0.528 mmol) in dichloromethane (1.25 ml) and triethylamine (1.162 mmol) was cooled with an ice-bath. Was added to the RM trichloromethyl chloroformate (0.317 mmol) in dichloromethane and the RM was stirred for 30 min at 0° C. and 1 h at rt. The RM was diluted with dichloromethane, washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and separated by flash chromatography (heptane/EtOAc 0% to 80%). The fractions containing product were evaporated together to give the title compound as a yellow solid. (HPLC: tR 2.16 min (Method A); M+H=229, 231 MS-ES)
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:8]=[C:7]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[CH:17][N:18]4[CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[N:10]=2)[CH:6]=[CH:5][C:4]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[Na+:39].O>C(O)C>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:8]=[C:7]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[CH:17][N:18]4[CH2:23][CH2:24][C:25]([O-:27])=[O:26])[N:10]=2)[CH:6]=[CH:5][C:4]=1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1.[Na+:39]
Reactant: CCOC(=O)CCn1ccc2c(-c3noc(-c4ccc(-c5ccccc5)c(C(F)(F)F)c4)n3)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C([O-])CCn1ccc2c(-c3noc(-c4ccc(-c5ccccc5)c(C(F)(F)F)c4)n3)cccc21
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Ethyl 3-(4-{5-[2-(trifluoromethyl)-4-biphenylyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)propanoate (D64) (15 mg, 0.31 mmol) was dissolved in ethanol (50 ml) by warming to 40° C. for 10 minutes then 2N sodium hydroxide (4 ml, 8 mmol) was added followed by water (8 ml). The solution was left standing for 1 hour. Evaporated off the ethanol and filtered off the off-white solid. Mass of title compound as a beige obtained on drying was 42 mg. δH (400 MHz, methanol-d4) 2.69 (2H, t), 4.53 (2H, t), 7.17-7.18 (1H, m), 7.32-7.40 (3H, m), 7.46-4.49 (4H, m), 7.66 (1H, d), 7.75 (1H, d), 8.02 (1H, d), 8.53 (1H, dd), 8.63 (1H, d). MS (ES) C26H18F3N3O3 requires 477; found 478 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH:10]=4)[C@H:7]([CH3:22])[CH2:6][C:5]=2[CH:4]=1.I[CH2:24]I.C([Zn]CC)C.[Cl-].[NH4+]>ClCCl.CCCCCC>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@@:9]45[CH2:24][C@@H:10]4[CH2:11][C@H:12]([OH:21])[C@:13]5([CH2:15][CH2:16]3)[CH3:14])[C@H:7]([CH3:22])[CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C[C@@H](C)[C@H]1C3=CC[C@H](O)[C@@]3(C)CC[C@H]21
Reactant: ICI
Agent: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1ccc2c(c1)C[C@@H](C)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)C[C@H]3C[C@@]312
Temperature: 25 °C
Reaction time: 21 h

Procedure:
i)—A solution of (7α,17β)-3-methoxy-7-methylestra-1,3,5(10),14-tetraen-17-ol [Segaloff, A. et al, Steroids 22, 99 (1973); 25.4 g] and diiodomethane (27 ml) in dry dichloromethane (500 ml) was cooled to 0° C. A solution of diethylzinc in hexane (15% wt., 300 ml) was added in 1 h and the reaction mixture was stirred for 21 h at room temperature. Ice was added and the mixture was poured into a saturated aqueous solution of ammonium chloride. The product was extracted into diethyl ether; the combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Column chromatography afforded (7α,14β,15β,17β)-3-methoxy-7-methyl-14,15-methyleneestra-1,3,5(10)-trien-17-ol (6.50 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.Cl.[NH2:13][C@H:14]1[CH2:19][C@@H:18]([OH:20])[C@H:17]([CH3:21])[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:20][C@H:18]1[C@H:17]([CH3:21])[CH2:16][CH2:15][C@@H:14]([NH:13][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=2)[CH2:19]1
Reactant: CSc1ncc(C#N)c(Cl)n1
Reactant: C[C@@H]1CC[C@@H](N)C[C@H]1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C#N)c(N[C@@H]2CC[C@@H](C)[C@H](O)C2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a stirring solution of 4-chloro-2-(methylthio)-pyrimidine-5-carbonitrile (310 mg, 1.670 mmol) and (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride (304 mg, 1.837 mmol; synthesis described herein) in DMF (2.4 mL) was added DIEA (0.873 ml. 5.01 mmol). The resulting mixture was stirred at 60° C. for 2 h. LCMS showed the reaction to be complete. The solvent was evaporated under reduced pressure and the residue diluted with 150 mL ethyl acetate and 50 mL water. The layers were separated and the aqueous phase was extracted with 75 mL ethyl acetate. The combined ethyl acetate layers were washed with brine (2×50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to an oil that solidified upon standing to afford 4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-2-(methylthio)pyrimidine-5-carbonitrile (418 mg, 1.503 mmol, 90% yield). MS (ESI) m/z 279.3 [M+1]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:20]=[CH:19][C:11]([CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[O:6]=[C:5]1[CH2:4][CH2:3][CH2:2][N:7]1[C:8]1[CH:20]=[CH:19][C:11]([CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=1
Reactant: CCOC(=O)C=Cc1ccc(NC(=O)CCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(N2CCCC2=O)cc1
Temperature: 50 °C
Yield: 87.8 %

Procedure:
To a stirred solution of ethyl 4-(4-bromobutyramido)cinnamate (420 mg) in N,N-dimethylformamide (5 ml) was added potassium carbonate (552 mg) at ambient temperature and the resulting mixture was warmed at 50° C. for three hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography eluting with chloroform to afford ethyl 4-(2-oxo-1-pyrrolidinyl)cinnamate (281 mg) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)=[CH:4][CH:3]=1.[Mg].[CH2:17]([Si@H:22]1[CH2:27][CH2:26][C@H:25]([CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH:33](Br)[CH2:32][CH2:31]2)[CH2:24][CH2:23]1)[CH2:18][CH2:19][CH2:20][CH3:21]>[Cu]Cl.C1COCC1>[CH2:17]([Si@H:22]1[CH2:23][CH2:24][C@H:25]([CH2:28][CH2:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=4)=[CH:4][CH:3]=3)[CH2:32][CH2:31]2)[CH2:26][CH2:27]1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Fc1ccc(-c2ccc(Br)cc2)cc1F
Reactant: CCCCC[Si@H]1CC[C@H](CCC2CCC(Br)CC2)CC1
Agent: Cl[Cu]
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(F)c(F)c4)cc3)CC2)CC1

Procedure:
26.9 g (0.1 mol) of 4-bromo-3',4'-difluorobiphenyl was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of copper (I) chloride and 35.9 g (0.1 mol) of 4-(2-(trans-4-n-pentyl-4-silacyclohexyl)ethyl)cyclohexyl bromide. After a conventional after treatment, 4-(trans-4-(2-(trans-4-n-pentyl-4-silacyclohexyl)ethyl)cyclohexyl)-3',4'-difluorobiphenyl was obtained. The silacyclohexane rings of the product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 36.0 g (yield 76.9%) of the trans isomer.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][C:11]2([O:16][CH:15]([C:17](O)=[O:18])[CH2:14][N:13]([CH2:20][CH:21]([F:23])[F:22])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH2:29])[CH:27]=[CH2:28].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C(N(CC)CC)C>CC1CCCO1>[CH2:26]([NH:29][C:17]([CH:15]1[CH2:14][N:13]([CH2:20][CH:21]([F:23])[F:22])[CH2:12][C:11]2([CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:25][CH2:24]2)[O:16]1)=[O:18])[CH:27]=[CH2:28]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)F)CC(C(=O)O)O2
Reactant: C=CCN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CC1CCCO1
Product: C=CCNC(=O)C1CN(CC(F)F)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Reaction time: 2 h
Yield: 83.2 %

Procedure:
To 9-(tert-butoxycarbonyl)-4-(2,2-difluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2-carboxylic acid (520 mg, 1.43 mmol), prop-2-en-1-amine (118 μL, 1.57 mmol) and T3P (2.12 mL of 50% w/w, 3.59 mmol) in 2-methyltetrahydrofuran (4 mL) was added triethylamine (597 μL, 4.28 mmol) at room temperature and the reaction mixture was stirred for 2 hours. The reaction mixture was then quenched with saturated NaHCO3 solution (3 mL) and stirred for an additional 10 minutes, then diluted with EtOAc and the layers were separated. The aqueous layer was extracted once more with EtOAc, and the combined organics were dried over Na2SO4, filtered and concentrated in vacuo to an oil. The residue was purified by silica gel column chromatography using 0-50% EtOAc in hexanes to yield tert-butyl 2-(allylcarbamoyl)-4-(2,2-difluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (480 mg, 83%). ESI-MS m/z calc. 403.2. found 404.5 (M+1)+; Retention time: 1.78 minutes (3 min run).
Reaction SMILES: [N:1]1([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][CH2:2]1.[O:20]=[C:21]1[N:27]([CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C@@H:37]([C:48](O)=[O:49])[CH2:38][C:39]3[CH:44]=[C:43]([CH3:45])[C:42]([OH:46])=[C:41]([CH3:47])[CH:40]=3)=[O:35])[CH2:30][CH2:29]2)[CH2:26][CH2:25][C:24]2[CH:51]=[CH:52][CH:53]=[CH:54][C:23]=2[NH:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:20]=[C:21]1[N:27]([CH:28]2[CH2:29][CH2:30][N:31]([C:34]([O:36][C@H:37]([CH2:38][C:39]3[CH:40]=[C:41]([CH3:47])[C:42]([OH:46])=[C:43]([CH3:45])[CH:44]=3)[C:48]([N:17]3[CH2:16][CH2:15][CH:14]([N:1]4[CH2:2][CH2:3][CH:4]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:6]4)[CH2:19][CH2:18]3)=[O:49])=[O:35])[CH2:32][CH2:33]2)[CH2:26][CH2:25][C:24]2[CH:51]=[CH:52][CH:53]=[CH:54][C:23]=2[NH:22]1
Reactant: CCOC(=O)CCC1CCN(C2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCC1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Reaction time: 2 h

Procedure:
410 mg (1.20 mmol) ethyl 3-[1,4′]bipiperidinyl-4-yl-propionate (used as the bis-hydrochloride salt) were added at RT to a solution of 500 mg (1.04 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1h), 385 mg (1.20 mmol) TBTU and 0.48 mL (3.40 mmol) triethylamine in 10 mL DMF and the mixture was stirred for 2 h. The reaction mixture was purified by HPLC without any further working up. The fractions containing the product were combined, concentrated by evaporation i.vac. and the residue was stirred with saturated NaHCO3 solution. The precipitate formed was filtered off and dried.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH3:7][S:8][C:9]1[C:14]2[N:15]=[C:16]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1>ClC1N=C(N2CCS(=O)CC2)C2N=CN=C(Cl)C=2N=1>[C:4]([N:28]1[CH2:29][CH2:30][N:25]([C:16]2[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[C:13]3[N:12]=[CH:11][N:10]=[C:9]([S:8][CH3:7])[C:14]=3[N:15]=2)[CH2:26][CH2:27]1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: CSc1ncnc2c(N3CCSCC3)nc(N3CCNCC3)nc12
Reactant: C=C1CC(=O)O1
Agent: O=S1CCN(c2nc(Cl)nc3c(Cl)ncnc23)CC1
Product: CSc1ncnc2c(N3CCSCC3)nc(N3CCN(C(=O)CC(C)=O)CC3)nc12
Reaction time: 0.5 h

Procedure:
1.6 gm (0.02 mol) of diketene were slowly poured, while stirring, into a solution of 3.6 gm (0.01 mol) of 8-methylthio-2-piperazino-4-thiomorpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 177°-179° C.) in 50 ml of dioxane. After stirring for 30 minutes more, the solvent was evaporated in vacuo, and the residue was taken up in about 100 ml of water. The precipitated reaction product was suction-filtered off, washed with water and dried.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)(=[O:4])[CH:2]=[CH2:3].[C:20]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([C:44](O)=[O:45])=[CH:40][CH:39]=2)=[CH:34][C:33]=1[O:47][CH3:48])(=[O:23])[CH:21]=[CH2:22].C(Cl)CCl>CN(C1C=CN=CC=1)C>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:44]([C:41]2[CH:40]=[CH:39][C:38]([C:35]3[CH:36]=[CH:37][C:32]([O:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][O:24][C:20](=[O:23])[CH:21]=[CH2:22])=[C:33]([O:47][CH3:48])[CH:34]=3)=[CH:43][CH:42]=2)=[O:45])=[CH:14][CH:13]=1)=[O:19])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCCCOC(=O)c1ccc(O)cc1
Reactant: C=CC(=O)OCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1OC
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: C=CC(=O)OCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)OCCCCOC(=O)C=C)cc3)cc2)cc1OC

Procedure:
The preparation is analogous to Example 1 from 2.64 g (10 mmol) of 4-hydroxybenzoic acid 4-acryloyloxybutyl ester, 3.99 g (10 mmol) of 4′-(6-acryloyloxyhexyloxy)-3′-methoxybiphenyl-4-carboxylic acid, 0.12 g (1 mmol) of DMAP and 2.11 g (11 mmol) of EDC. Purification of the residue by chromatography on silica gel using cyclohexane/ethyl acetate (7:3) and recrystallisation once from ethanol yields 4′-(6-acryloyloxyhexyloxy)-3′-methoxybiphenyl-4-carboxylic acid 4-(4-acryloyloxybutoxycarbonyl)-phenyl ester.