Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[NH:14][CH:13]=[CH:12][C:11]2=O>>[Br:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[C:11]2[Cl:3]
Reactant: O=c1cc[nH]c2c(Br)cccc12
Reactant: O=S(Cl)Cl
Product: Clc1ccnc2c(Br)cccc12

Procedure:
A suspension of 2-bromoaniline (20.9 g) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (22.6 g) in 2-propanol (240 ml) was heated to reflux for 1 hour. The reaction solution was cooled to 0° C., and the deposit was then filtrated to obtain a pale yellow solid (35.0 g). A suspension of the obtained pale yellow solid (10.0 g) in Dowtherm (100 ml) was heated at 210° C. for 1 hour. After cooling, hexane (100 ml) was added to the reaction solution, and the deposit was filtrated to obtain 8-bromoquinolin-4(1H)-one (6.3 g). Thionyl chloride (5.9 ml) was added to 8-bromoquinolin-4(1H)-one (9.0 g), and the mixture was heated to reflux for 2 hours. The solvent was distilled off under reduced pressure, and chloroform was added to the residue. The reaction solution was neutralized with an aqueous sodium hydroxide solution with cooling in an ice bath and partitioned into organic and aqueous layers. The organic layer was washed with brine. The organic layer thus washed was dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 8-bromo-4-chloroquinoline (8.3 g) as a white solid. The obtained 8-bromo-4-chloroquinoline (0.050 g), 4-(1H-imidazol-4-yl)-1-methyl-1H-pyrazole hydrochloride (0.045 g), 8-quinolinol (0.0045 g), copper(I) oxide (0.0015 g), PEG (Mn=3400) (0.010 g), and cesium carbonate (0.17 g) were suspended in DMSO (2.1 ml). The suspension was purged with nitrogen, then sealed in the tube, and stirred at 110° C. for 2 hours. After cooling, the reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine and then dried over anhydrous sodium sulfate to obtain 8-bromo-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)quinoline as a pale yellow solid (0.073 g). Compound (119) was obtained as a pale yellow solid (yield based on 6 steps: 17%) according to Example 1(5) using the obtained 8-bromo-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)quinoline instead of compound (1d).
Reaction SMILES: [O:1]=[C:2]=[N:3]C1CC(C)(C)CC(C)(CN=C=O)C1.C([C:21]1C=C(C)C=[C:23]([C:28](C)(C)C)[C:22]=1[OH:32])(C)(C)C.C1OC1.C1OC1CC>>[C:22]([OH:32])(=[O:1])[CH:23]=[CH2:28].[NH2:3][C:2]([O:32][CH2:22][CH3:21])=[O:1]
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CCC1CO1
Solvent: C1CO1
Product: C=CC(=O)O
Product: CCOC(N)=O
Reaction time: 5 h

Procedure:
To a reaction vessel equipped with a stirrer, 100 gm of ARONIX M113 manufactured by Toagosei Chemicals, 124.7 gm of isophorone diisocyanate, 1 gm of dibutyltindilaurate, and 0.3 gm of 2,6-di-t-butyl-4-methylphenol were added. To this, 842.7 gm of a copolymerized diol of ethylene oxide and 1.2-butylene oxide [ethylene oxide:1,2-butylene oxide =2:8 (by weight)] of a number average molecular weight of 2,000 was added while maintaining the temperature in the 40° to 50° C. range, and the mixture was reacted for 2 hours. Then 32.6 gm of hydroryethylacrylate was added, after which the mixture was continuously stirred for 5 hours at 50° to 60° C. to complete the reaction. A urethane acrylate [A-3] of a number average molecular weight of about 7,120 was obtained.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:40])[NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:40])[NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccccc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(Nc1ccccc1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
210 mg (0.384 mmol) of (2R*,4S*)-2-benzyl-1-(phenylcarbamoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 58 mg (1.54 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR42## is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.33, FD-MS: M+ =450.
Reaction SMILES: FC1C=CC(N)=C(C2CCC3C(=CC=C(OC)C=3)C2)C=1.Cl.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:26](O)=O.[F:41][C:42]1[CH:47]=[CH:46][C:45]([NH:48][CH2:49][C:50]2C=CC(OCCN3CCCCC3)=C(F)C=2)=[C:44]([CH:66]2[CH2:75][CH2:74][C:73]3[C:68](=[CH:69][CH:70]=[C:71]([O:76][CH3:77])[CH:72]=3)[CH2:67]2)[CH:43]=1>>[CH2:49]([N:48]([C:45]1[CH:46]=[CH:47][C:42]([F:41])=[CH:43][C:44]=1[CH:66]1[CH2:75][CH2:74][C:73]2[C:68](=[CH:69][CH:70]=[C:71]([O:76][CH3:77])[CH:72]=2)[CH2:67]1)[CH2:26][C:25]1[CH:29]=[CH:30][C:31]([O:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:23]([F:22])[CH:24]=1)[CH3:50]
Reactant: COc1ccc2c(c1)CCC(c1cc(F)ccc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Agent: COc1ccc2c(c1)CCC(c1cc(F)ccc1N)C2
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1ccc(F)cc1C1CCc2cc(OC)ccc2C1

Procedure:
Synthesized from 4-fluoro-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-fluoro-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl][3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amine (448 mg) was used according to an analogous synthetic method to Example 36 to provide ethyl[4-fluoro-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl][3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amine (395 mg). This compound (393 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (300 mg).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:6]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=2[CH3:32])[C:26]([OH:28])=O)[C:7](=[O:22])[C:8]([Cl:21])=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[N:10]=1)[CH:2]=[CH2:3].ClC(OCC(C)C)=O.CN1CCOCC1.[CH2:48]([NH2:51])[CH:49]=[CH2:50]>CN(C)C(=O)C>[CH2:48]([NH:51][C:26](=[O:28])[C:25]1[CH:29]=[CH:30][C:31]([CH3:32])=[C:23]([N:6]2[C:7](=[O:22])[C:8]([Cl:21])=[C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:10]=[C:5]2[NH:4][CH2:1][CH:2]=[CH2:3])[CH:24]=1)[CH:49]=[CH2:50]
Reactant: C=CCNc1nc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(C(=O)O)ccc1C
Reactant: C=CCN
Agent: CC(C)COC(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Product: C=CCNC(=O)c1ccc(C)c(-n2c(NCC=C)nc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To a cooled (0° C.) solution of 3-[2-(allylamino)-5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (from Step 3) (0.37 g, 0.80 mmol) in N,N-dimethylacetamide (2 mL) was added isobutyl chloroformate (0.12 mL, 0.96 mmol) and 4-methylmorpholine (0.11 mL, 1.04 mmol). Stirred at 0° C. for 5 min, ambient temperature for 30 min. Added allyl amine (0.09 mL, 1.20 mmol). Stirred at ambient temperature for 2 h. Purified by preparatory HPLC using a 10-90% CH3CN/H2O (30 min) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z=494) were combined, freeze-dried, and lyophilized. Washed with 5% NaHCO3 (20 mL) and extracted with DCM (3×15 mL). The organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and dried in vacuo to give the desired product as a white solid (0.24 g, 60%). 1H NMR (CD3OD/400 MHz) δ7.93 (m, 1H), 7.67 (s, 1H), 7.55 (q, 2H, J=8.0 Hz), 7.00 (t, 2H, J=8.8 Hz), 5.90 (m, 1H), 5.80 (m, 1H), 5.51 (m, 2H), 5.21 (m, 1H), 5.09 (m, 3H), 3.95 (m, 4H), 2.14 (s, 3H). ESHRMS m/z 501.1520 (M+H calculated for C25H24ClF2N4O3 requires 501.1500).
Reaction SMILES: Cl[C:2]1([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH2:5][N:4]([CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:3]1.C(C1C=CC(C2CCN2C(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1)(C)(C)C>>[F:28][C:25]([F:26])([F:27])[C:22]1[CH:23]=[CH:24][C:19]([CH:2]2[CH2:3][N:4]([CH:6]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:5]2)=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1ccc(C2(Cl)CN(C(c3ccccc3)c3ccccc3)C2)cc1
Agent: CC(C)(C)c1ccc(C2CCN2C(c2ccccc2)c2ccccc2)cc1
Product: FC(F)(F)c1ccc(C2CN(C(c3ccccc3)c3ccccc3)C2)cc1

Procedure:
This compound was prepared from compound (31) using the procedure described for compound (11).
Reaction SMILES: [F:1][C:2]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[Mg]Br>>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[C:4]([C:3]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:2]=1[F:1])=[O:5]
Reactant: COc1ccc([Mg]Br)c(OC)c1
Reactant: CON(C)C(=O)c1cccc(C)c1F
Product: COc1ccc(C(=O)c2cccc(C)c2F)c(OC)c1

Procedure:
Prepared according to Method A step B from 2-fluoro-3-methyl-N-methoxy-N-methyl-benzamide (2.84 g, 14.4 mmol) and 2,4-dimethoxyphenylmagnesium bromide (26 mL, 0.5 M in THF) to give 1.13 g of the title compound as a white solid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([CH3:30])([CH3:29])[CH2:21][N:22]([CH2:27][CH3:28])[C:23]2=[O:26])=[CH:18][CH:17]=1.[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.C(O)(=O)C>ClCCl>[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([CH3:29])([CH3:30])[CH2:21][N:22]([CH2:27][CH3:28])[C:23]3=[O:26])=[CH:18][CH:17]=2)=[CH:34][CH:33]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCN1CC(C)(C)c2ccc(N)cc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN1CC(C)(C)c2ccc(NCc3ccc(Cl)cc3)cc2C1=O
Reaction time: 8 h
Yield: 32.4 %

Procedure:
Sodium triacetoxyborohydride (77 mg, 0.36 mmol) was added to a stirred solution of 7-amino-2-ethyl-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one (40 mg, 0.18 mmol), 4-chlorobenzaldehyde (31 mg, 0.22 mmol) and acetic acid (11 μl, 0.18 mmol) in anhydrous dichloromethane (6 ml) at room temperature. The reaction was stirred overnight and quenched with the addition of water. The organic phase was separated, washed with brine, then dried (MgSO4) and evaporated in vacuo. The resulting residue was purified by preparative tlc (20% ethyl acetate in petroleum ether) to afford the title compound as a colourless solid (20 mg, 32%). HPLC retention time 4.78 min. Mass spectrum (ES+) m/z 343 (M+H).
Reaction SMILES: [O:1]=[C:2]1[N:8]2[C@H:4]([CH2:5][C:6]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24](O[Si](C)(C)C)[CH:23]=3)=[C:7]2[C:9]([O:11]CC2C=CC([N+]([O-])=O)=CC=2)=[O:10])[C@H:3]1[C@H:33]([O:35][Si](C)(C)C)[CH3:34].C(=O)([O-])[OH:41].[Na+:44].P([O-])([O-])([O-])=O>C(#N)C.[Zn]>[OH:35][C@@H:33]([C@H:3]1[C:2](=[O:1])[N:8]2[C@@H:4]1[CH2:5][C:6]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=1[OH:41])=[C:7]2[C:9]([O-:11])=[O:10])[CH3:34].[Na+:44]
Reactant: C[C@@H](O[Si](C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cccc(O[Si](C)(C)C)c3)C[C@H]12
Reactant: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3ccccc3O)C[C@H]12
Reaction time: 0.25 h

Procedure:
To a solution of 4-nitrobenzyl (5R,6S)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-3-{3-[(trimethylsilyl)oxy]phenyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (207 mg) in acetonitrile (3 ml) was added under ice cooling 0.1N hydrochloric acid (0.3 ml), and the mixture was stirred for 15 minutes. After the solution was neutralized with a 0.1N aqueous sodium hydrogencarbonate solution (0.3 ml), further thereto 0.25M phosphate buffer (10 ml, pH6) and acetonitrile (7 ml) were added. Zinc dust (1.49 g) was added thereto and the mixture was vigorously stirred for an hour under ice cooling and for additional an hour at room temperature. The insoluble materials were removed with celite and washed with water and chloroform. Then, the filtrate and the washed solvent were combined to separate by a separating funnel. The aqueous layer was washed with chloroform, twice separated with a separating funnel and an organic solvent in the aqueous layer was removed under reduced pressure. The aqueous solution was purified by polymer chromatography (CHP-20P), and the fractions eluted with water were collected to be subjected to freeze-drying to give sodium (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(hydroxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (14 mg).
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]([OH:12])=[O:11].[CH3:13]O>>[CH3:13][O:11][C:10]([CH:6]1[CH2:7][CH2:8][CH2:9][NH:5]1)=[O:12]
Reactant: O=C(O)C1CCCN1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCCN1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
7 mL of thionyl chloride was dissolved in 50 mL of methanol in an ice-water bath, followed by addition of pyrrolidine-2-carboxylic acid 10a (5 g, 43.40 mmol). The mixture was warmed up to room temperature and stirred for 24 hours. The mixture was concentrated under reduced pressure to obtain methylpyrrolidine-2-carboxylate 10b (10 g) crude product as a white solid, which was directly used in the next step without purification.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[CH3:29][S:30][C:31](SC)=[CH:32][N+:33]([O-:35])=[O:34]>C(O)(C)C>[N+:33]([CH:32]=[C:31]([S:30][CH3:29])[NH:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=1)([O-:35])=[O:34]
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: CSC(=C[N+](=O)[O-])SC
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CC(C)O
Product: CSC(=C[N+](=O)[O-])NCCSCc1csc(NC(=N)N)n1
Reaction time: 54 h

Procedure:
A solution of 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine (from the dihydrochloride, 20.0 g; 66.0 mmoles) [prepared according to the procedure described in South Africa Pat. No. 78/2129] and 1,1-bis(methylthio)-2-nitroethylene [prepared according to the procedure described in Chem. Ber., 100, 591 (1967) or Acta Chem. Scand., 21 2797 (1967)] (10.9 g; 66.0 mmoles) in isopropanol (600 ml) was stirred at ambient temperature under a positive pressure of nitrogen for 2 hours, at reflux temperature for 1 hour and then at ambient temperature for 54 hours. The reaction mixture was cooled and filtered to give 15.8 g of 1-nitro-2-methylthio-2-{2-[(2-guanidinothiazol-4-yl)methylthio]ethylamino}ethylene as a yellow solid, mp 151°-156°, which was used without further purification in Step B below.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[CH3:19][O:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:23][CH:22]=1>>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:29]2[CH2:28][CH2:27][C:26]([CH2:25][C:24]3[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:34][CH:33]=3)([OH:32])[CH2:31][CH2:30]2)=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(CC2(O)CCNCC2)cc1
Reactant: BrCCOc1ccc(OCc2ccccc2)cc1
Product: COc1ccc(CC2(O)CCN(CCOc3ccc(OCc4ccccc4)cc3)CC2)cc1

Procedure:
The title compound, MS: m/e=448.5 (M+H+), was prepared from 1-(2-bromoethoxy)-4-(benzyloxy)-benzene and 4-(4-methoxy-benzyl)-piperidin-4-ol.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].[CH3:18][N:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[CH2:24][CH2:25]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(OCC)(=O)C.CCCCCCC.C1COCC1>[CH3:3][N:2]([CH3:1])[CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:25][CH2:24][CH:20]3[CH2:21][CH2:22][CH2:23][N:19]3[CH3:18])=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: CN1CCCC1CCO
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CN(C)CC1(c2ccc(OCCC3CCCN3C)cc2)CCOCC1
Yield: 27.2 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (405 mg, 1.72 mmol), 2-(1-methyl-pyrrolidin-2-yl)-ethanol (178 mg, 1.38 mmol), PPh3 (451 mg, 1.72 mmol), THF (8 ml) and DIAD (348 mg, 1.72 mmol) were reacted together according to general procedure C. The crude product was subjected to chromatography on alumina eluting with ethyl acetate:heptane (50:50) to provide the title compound (130 mg, 27%) as a colourless oil. 1H NMR (400 MHz, CDCl3) δ7.21 (d, 2H), 6.87 (d, 2H), 4.09-3.95 (m, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 3.09 (m, 1H), 2.40 (s, 2H), 2.35 (s, 3H), 2.30-1.99 (m, 6H), 1.96 (s, 6H), 1.93-1.63 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:8]([NH2:10])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:8]#[N:10])=[CH:18][CH:19]=1
Reactant: Cc1ccc(OC(C(N)=O)c2ccccc2Cl)cc1
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(OC(C#N)c2ccccc2Cl)cc1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
The product of Step A (0.650 g, 2.36 mmol) was added to phosphorous oxychloride (5.95 mL, 27 eq) at 0° C. followed by slow addition of 0.73 mL (2.2 eq) of triethylamine. The reaction mixture was warmed to room temperature for 10 minutes, refluxed for 50 minutes and then cooled to room temperature. The reaction mixture was concentrated in vacuo, and partitioned between ice water and toluene. The aqueous layer was extracted 3 times with toluene, and the combined toluene extracts were washed with 0.5N NaOH and H2O. The crude product was concentrated in vacuo and purified on a silica gel flash chromatography column (140×30 mm) eluted with 2% ethyl acetate/hexane to afford 0.555 g (91%) of the title compound.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].O=[CH:26][C@H:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:28]>C(Cl)Cl.[Zn]>[Br:21][C:20]([Br:24])=[CH:28][C@H:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH3:26]
Reactant: BrC(Br)(Br)Br
Reactant: C[C@H](C=O)NC(=O)OC(C)(C)C
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H](C=C(Br)Br)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of zinc (135 g, 2.08 mol), PPh3 (545 g, 2.08 mol) and CBr4 (682 g, 4.08 mol) in CH2Cl2 (2 L) was stirred at 0° C. for 1.5 hr. A solution of (R)-tert-butyl 1-oxopropan-2-ylcarbamate (114 g, 0.66 mol) in DCM was added in one portion, and the reaction mixture was stirred at 0° C. for another 3 hr. The mixture was quickly passed though a silica gel, and the solvent was evaporated to give the crude (R)-tert-butyl 4,4-dibromobut-3-en-2-ylcarbamate. To a cooled (−78° C.) solution of the crude compound (R)-tert-butyl 4,4-dibromobut-3-en-2-ylcarbamate in THF (2 L) was added dropwise 2.5 M BuLi (0.75 L, 1.88 mol) under nitrogen. The reaction was quenched with water and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, dried over MgSO4, filtered and concentrated to give the crude compound N.2, (R)-tert-butyl but-3-yn-2-ylcarbamate, which was used without further purification. 1H NMR (CDCl3) δ 4.47 (br s, 1H), 2.24 (s, 1H), 1.49 (s, 9H), 1.27 (s, 3H).
Reaction SMILES: [Br:1][C:2]([Br:13])=[CH:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10](Cl)=[O:11])[CH2:6][CH2:5]1.[CH2:14]([C:17]1([CH2:21][OH:22])[CH2:20][O:19][CH2:18]1)[CH2:15][CH3:16].N1C=CC=CC=1>ClCCl>[Br:1][C:2]([Br:13])=[CH:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:22][CH2:21][C:17]2([CH2:14][CH2:15][CH3:16])[CH2:20][O:19][CH2:18]2)=[O:11])[CH2:6][CH2:5]1
Reactant: O=C(Cl)C1CCC(C=C(Br)Br)CC1
Reactant: CCCC1(CO)COC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC1(COC(=O)C2CCC(C=C(Br)Br)CC2)COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
4-(2,2-Dibromovinyl)cyclohexanecarbonyl chloride (0.91 g) in dry dichloromethane (5 ml) was added to a cooled (0° C.) solution of 3-propyl-3-hydroxymethyloxetane (0.406 g) and pyridine (0.64 ml) in dry dichloromethane (10 ml) under a stream of nitrogen. The reaction mixture was allowed to warm to room temperature and to stir overnight. Further dichloromethane was added. The organic phase was then washed with dilute hydrochloric acid, saturated sodium bicarbonate solution and brine before drying over anhydrous magnesium sulphate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel, pre-eluted with hexane containing 1% triethylamine. Elution with hexane/ether (3:1) gave 3-propyloxetan-3-ylmethyl 4-(2,2-dibromovinyl)cyclohexanecarboxylate (0.6 g) as a mixture of cis- and trans-isomers.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:22][SiH:23]([Cl:25])[Cl:24]>>[CH2:14]([CH2:22][SiH:23]([Cl:25])[Cl:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[SiH](Cl)Cl
Reactant: ClCc1ccccc1
Agent: CCCCP(CCCC)CCCC
Product: Cl[SiH](Cl)CCc1ccccc1
Yield: 20.1 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.15 g (0.75 mmol) of tri-n-butylphosphine, 0.95 g (7.5 mmol) of benzyl chloride, and 4.31 g (37.5 mmol) of methyldichlorosilane were reacted at 200° C. for 2 hrs. The resulting mixture was distilled to give 0.31 g of benzylmethyldichlorosilane (bp; 214-215° C./740 mmHg, yield; 20%).
Reaction SMILES: C(O[C:9]([NH:11][C@H:12]([C:19]([N:21]1[CH2:33][CH2:32][CH2:31][C@H:22]1[C:23]([NH:25][CH2:26][CH2:27][C:28]([NH2:30])=[O:29])=[O:24])=[O:20])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)=[O:10])C1C=CC=CC=1.[CH3:34][OH:35]>[Pd]>[C:28]([OH:29])(=[O:35])[CH3:27].[NH:11]1[C:34](=[O:35])[CH2:14][CH2:13][C@H:12]1[C:9]([NH:11][C@H:12]([C:19]([N:21]1[CH2:33][CH2:32][CH2:31][C@H:22]1[C:23]([NH:25][CH2:26][CH2:27][C:28]([NH2:30])=[O:29])=[O:24])=[O:20])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)=[O:10]
Reactant: NC(=O)CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Reactant: CO
Agent: [Pd]
Product: CC(=O)O
Product: NC(=O)CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1
Reaction time: 24 h

Procedure:
1.0 g of benzyloxycarbonyl-L-histidyl-L-prolyl-β-alaninamide were dissolved in 50 ml of methanol and hydrogenated with the addition of palladium/carbon. The catalyst was filtered off and the filtrate concentrated in vacuo. The residue was dissolved in 10 ml of dimethylformamide and treated with 0.9 g of L-pyroglutamic acid pentachlorophenyl ester. The mixture was stored for 24 hours at room temperature and then concentrated in vacuo. The residue was dissolved in water and chromatographed on a Dowex 2 column (OH form). The fractions which were uniform in a thin-layer chromatogram were combined, acidified with acetic acid and lyophilised. Yield: 0.8 g. [α]D25 = -82.2° (c = 1 in 1 N acetic acid).