Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrBr.[CH2:3]([N:10]1[CH:17]=[C:16](Br)[C:14](=[O:15])[NH:13][C:11]1=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CS(C)=O.CN(C)C=O>[CH2:3]([N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=c1[nH]c(=O)n(Cc2ccccc2)cc1Br
Agent: BrBr
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: O=c1ccn(Cc2ccccc2)c(=O)[nH]1

Procedure:
This experiment was performed to verify the role of DMSO solvent in the generation of the bromine electrophile. Thus, this synthesis was done following the same procedure as for the synthesis of 1-benzyl-5-bromouracil, with the sole exception that DMSO was replaced by dimethylformamide (DMF), as solvent. Extraction was done by water-EtOAc and crystallization was done from EtOAc-Hexanes. After filtration, washing with hexanes and drying under high vacuum, 1.4 g of pure 1-benzyluracil, was isolated, as clean white crystals with properties shown below.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[CH:8][N:7]([C:10]2[CH:19]=[C:18]([O:20][CH:21]3[CH2:38][CH:37]4[CH:23]([C:24](=[O:44])[N:25]([CH3:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40](O)=[O:41])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:22]3)[C:17]3[C:12](=[C:13]([CH3:47])[C:14]([O:45][CH3:46])=[CH:15][CH:16]=3)[N:11]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:48]1([S:51]([NH2:54])(=[O:53])=[O:52])[CH2:50][CH2:49]1.ClC1C(OC)=CC=C2C=1N=C(C1SC=C(C(C)C)N=1)C=C2OC1CC2C(C(=O)N(C)CCCCC=CC3C(C(NS(C4CC4)(=O)=O)=O)(NC2=O)C3)C1>>[C:1]([C:5]1[CH:9]=[CH:8][N:7]([C:10]2[CH:19]=[C:18]([O:20][CH:21]3[CH2:38][CH:37]4[CH:23]([C:24](=[O:44])[N:25]([CH3:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40]([NH:54][S:51]([CH:48]6[CH2:50][CH2:49]6)(=[O:53])=[O:52])=[O:41])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:22]3)[C:17]3[C:12](=[C:13]([CH3:47])[C:14]([O:45][CH3:46])=[CH:15][CH:16]=3)[N:11]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-n3ccc(C(C)(C)C)n3)nc2c1C
Agent: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-n3ccc(C(C)(C)C)n3)nc2c1C

Procedure:
The title compound was prepared from 17-[2-(3-tert-butylpyrazol-1-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (127) and cyclopropylsulfonamide following the procedure reported for the preparation of N-[17-[8-chloro-2-(4-isopropylthiazole-2-yl)-7-methoxyquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]-octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (56): m/z=747 (M+H)+. 1H NMR (CDCl3): 0.95-1.12 (m, 2H), 1.13-1.30 (m, 2H), 1.31-1.55 (m, 11H), 1.63-2.05 (m, 4H), 2.20-2.55 (m, 9H), 2.80-2.98 (m, 1H), 3.03 (s, 3H), 3.36-3.47 (m, 2H), 3.61-3.70 (m, 1H), 3.97 (s, 3H), 4.60 (t, J=12.2 Hz, 1H), 5.04 (t, J=10.3 Hz, 1H), 5.26-5.46 (m, 1H), 5.61-5.69 (m, 1H), 6.35 (d, J=2.5 Hz, 1H), 6.42 (br s, 1H), 7.13 (d, J=9.1 Hz, 1H), 7.32 (s, 1H), 7.95 (d, J=9.1 Hz, 1H), 8.67 (d, J=2.5 Hz, 1H), 10.9 (br s, 1H).
Reaction SMILES: [Cl:1][CH:2]([C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[F:20])[S:3]([C:6]1[CH2:10][C:9]([CH3:12])([CH3:11])[O:8][N:7]=1)(=[O:5])=[O:4].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:31])(=O)=O)=CC=1>C1COCC1>[Cl:1][C:2]([C:13]1[C:14]([F:20])=[CH:15][CH:16]=[CH:17][C:18]=1[F:19])([F:31])[S:3]([C:6]1[CH2:10][C:9]([CH3:12])([CH3:11])[O:8][N:7]=1)(=[O:4])=[O:5]
Reactant: CC1(C)CC(S(=O)(=O)C(Cl)c2c(F)cccc2F)=NO1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Product: CC1(C)CC(S(=O)(=O)C(F)(Cl)c2c(F)cccc2F)=NO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.1 %

Procedure:
Phosphazene base 1-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2-lambda5-5,4-lambda5-5-catenadi(phosphazene) (P2-tBu) (2M in THF) (0.38 ml, 0.77 mmol) was added dropwise to a solution of 3-[chloro-(2,6-difluoro-phenyl)-methanesulfonyl]-5,5-dimethyl-4,5-dihydroisoxazole (0.2 g, 0.64 mmol) in THF (2 ml), and the solution was stirred for 10 minutes at room temperature. N-Fluorobenzenesulfonimide (NFSI) (0.15 g, 0.77 mmol) was added and the mixture was stirred for 1 hour. The reaction was quenched by addition of aqueous hydrochloric acid (2M). The mixture was diluted with ethyl acetate and the two phases were separated. The organic phase was washed several times with brine, dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel (eluent: ethyl acetate/hexane) to give the product (Compound No. 1.21 of Table 27) as a white solid (44 mg, 98% yield).
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:15]=2)[CH:11]=[CH:12][CH:13]=1)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:6][CH2:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: COc1cc(CNC(=O)OC(C)(C)C)cc(-c2cccc(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(CNC(=O)OC(C)(C)C)cc(-c2cccc(CO)c2)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of 1,1-dimethylethyl {[3′-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-5-(methyloxy)-3-biphenylyl]methyl}carbamate (1.5 g, 3.28 mmol) in THF (20 mL), the solution of nBu4NF (0.94 g, 3.61 mmol) in THF (10 mL) was added, and then the mixture was stirred at room temperature over night. After the solvent was removed under reduced pressure, the residue was diluted with EtOAc (30 mL). The organic layer was washed with water (10 mL×2), brine (10 mL×2), and dried over Na2SO4. The product 1,1-dimethylethyl {[3′-(hydroxymethyl)-5-(methyloxy)-3-biphenylyl]methyl}carbamate (0.9 g) was purified by flash column chromatography (PE:EA=3:1). (Yield: 80%). 1H NMR (400 MHz, CDCl3): δ 1.47 (s, 9 H), 3.86 (s, 3 H), 4.35 (d, J=7.6 Hz, 2 H), 4.76 (s, 2 H), 4.89 (s, 1 H), 6.83 (s, 1 H), 7.02 (s, 1 H), 7.09 (s, 1 H), 7.34-7.58 (m, 4H); 13C NMR (100 MHz, CDCl3): δ 28.4, 44.7, 55.4, 65.2, 79.6, 111.9, 118.7, 125.8, 126.1, 126.4, 129.0, 140.9, 141.2, 141.5, 142.8, 156.0, 160.3. HPLC: retention time: 11.558 min; purity: 98.7%; MS: m/z 343 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH:29]([CH2:37][CH3:38])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](=[O:12])[C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:29]([CH2:37][CH3:38])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: O=C(CCc1ccc(O)c(Br)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: CCC(Br)C(=O)OC(C)(C)C
Product: CCC(Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1Br)C(=O)OC(C)(C)C

Procedure:
Tert-butyl 2-(2-bromo-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-butanoate is prepared from 3-(3-bromo-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and tert-butyl 2-bromobutanoate according to general procedure D.
Reaction SMILES: [Br:1][C@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[CH3:10][C:11]([CH3:13])=[CH2:12].S(=O)(=O)(O)O>C(Cl)Cl>[C:11]([O:4][C:3](=[O:5])[C@H:2]([Br:1])[CH2:6][CH:7]([CH3:9])[CH3:8])([CH3:13])([CH3:12])[CH3:10]
Reactant: CC(C)C[C@@H](Br)C(=O)O
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)C[C@@H](Br)C(=O)OC(C)(C)C
Yield: 88 %

Procedure:
33 g of 2(R)-bromo-4-methylpentanoic acid (prepared from D-leucine) was dissolved in 100 ml of methylene chloride. To this solution, at -40° C. was introduced 47 g of 2-methylpropene while stirring, and after the addition of 0.8 ml of sulfuric acid the mixture was stirred overnight at room temperature. The reaction mixture was concentrated to 1/2 in vacuo and washed with 10% sodium carbonate aqueous solution and dried over anhydrous magnesium sulfate. The solution was then evaporated in vacuo, yielding 37.4 g of 2(R)-bromo-4-methylpentanoic acid t-butyl ester.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[S:5]([O-:9])([O-:8])(=[O:7])=[S:6].[Na+:10].[Na+].C(O)C>O>[CH2:1]([O:8][S:5]([O-:9])(=[O:7])=[S:6])[CH:2]=[CH2:3].[Na+:10]
Reactant: O=S([O-])([O-])=S
Reactant: C=CCBr
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCOS(=O)([O-])=S

Procedure:
A mixture of allyl bromide (100 g), sodium thiosulphate (212.5 g), ethanol (90 ml) and water (40 ml) was stirred and heated to reflux for 15 minutes, giving a homogeneous solution. The solution was allowed to cool somewhat, and ethanol and water were then evaporated under vacuum. The solid residue was added to absolute ethanol, and the solvent was then evaporated under vacuum to remove more water. The residue was stirred with hot ethanol (800 ml), and the suspension thus obtained was filtered. On cooling, the filtrate deposited a white solid (109.2 g). The NMR spectrum of the sold showed that it consisted of 80% by weight of sodium allylthiosulphate, 11% by weight of water and 9% by weight of inorganic salt.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:19][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])C>C(N)CC>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]2[NH:10][C:9]3[CH2:19][CH:6]([C:4]([NH:10][CH2:9][CH2:8][CH3:7])=[O:5])[CH2:7][C:8]=3[C:16]=2[CH:15]=1
Reactant: CCOC(=O)C1Cc2[nH]c3ccc(OC)cc3c2C1
Solvent: CCCN
Product: CCCNC(=O)C1Cc2[nH]c3ccc(OC)cc3c2C1
Temperature: 100 °C
Reaction time: 26 h
Yield: 246.1 %

Procedure:
1,2,3,4-Tetrahydro-7-methoxycyclopent[b]indol-2-carboxylic acid ethyl ester (9.5 g, 0.037 mole) was added to n-propyl amine (30 ml) in a sealed tube and heated to 100° C. with stirring for 26 hours. The mixture was then concentrated to yield a brown oil (12.4 g), which was eluted with 10% ethyl acetate in CH2Cl2 and then with 50% ethyl acetate in CH2Cl2 on a silica gel column via HPLC. The desired fractions were concentrated to yield the product as a tan solid 6.5 g, mp 141°-143° C. A portion of this material (1.2 g) was recrystallized from ether in ethyl acetate (5:1) to yield the product as a white solid, 0.8 g, mp 141°-143° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH:8]=2)[NH:3]1.[CH3:19]C(C)=O.C(=O)([O-])[O-].[K+].[K+].CI>CCOCC>[CH3:19][N:3]1[C:4]2[C:9](=[CH:8][C:7]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]1([CH3:18])[CH3:1]
Reactant: COC(=O)C(C)c1ccc2c(c1)C=CC(C)(C)N2
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CI
Product: COC(=O)C(C)c1ccc2c(c1)C=CC(C)(C)N2C

Procedure:
1.9 g of methyl 2-(1,2-dihydo-2,2-dimethylquinolin-6-yl)propionate (Compound 7) were added to 40 ml of acetone. 2.0 g of potassium carbonate and 2.0 ml of methyl iodide were added to the solution, and the mixture was heated and refluxed for 17 hours. After the mixture was cooled, the mixture was diluted with ether. Then the precipitate was filtered off, and the solvent was distilled off to give 1.9 g of methyl 2-(1,2-dihydro-1,2,2-trimethylquinolin-6-yl)propionate (Compound 16).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[Cl:13][C:14]1[CH:26]=[N:25][C:17]2[NH:18][C:19]3[CH2:24][CH2:23][NH:22][CH2:21][C:20]=3[C:16]=2[CH:15]=1.O>N1C=CC=CC=1>[Cl:13][C:14]1[CH:26]=[N:25][C:17]2[NH:18][C:19]3[CH2:24][CH2:23][N:22]([S:9]([C:5]4[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=4)[C:1]#[N:2])(=[O:11])=[O:10])[CH2:21][C:20]=3[C:16]=2[CH:15]=1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1cccc(S(=O)(=O)N2CCc3[nH]c4ncc(Cl)cc4c3C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
3-Cyanobenzenesulfonyl chloride (53 mg, 0.26 mmol) was added to a solution of 3-chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) in pyridine (2 mL), and the reaction was stirred overnight at room temperature. The reaction mixture was added to water (20 mL), and the resulting precipitate was filtered and dried under vacuum to provide 40 (68 mg, 76% yield) as a yellow solid. LC-MS (M+H=373, obsd.=373).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([N:19]3[CH:23]([OH:24])[C:22]4[S:25][CH2:26][CH:27]([O:30][CH3:31])[CH2:28][S:29][C:21]=4[C:20]3=[O:32])=[N:16]2)=[CH:11][CH:10]=1.Cl.Cl[C:35]([N:37]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]1)=[O:36].N1C=CC=CC=1>C(Cl)Cl>[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([N:19]3[CH:20]([O:32][C:35]([N:37]4[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]4)=[O:36])[C:21]4[S:29][CH2:28][CH:27]([O:30][CH3:31])[CH2:26][S:25][C:22]=4[C:23]3=[O:24])=[N:16]2)=[CH:11][CH:10]=1
Reactant: COC1CSC2=C(SC1)C(O)N(c1ccc3ccc(Cl)cc3n1)C2=O
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COC1CSC2=C(SC1)C(OC(=O)N1CCN(C)CC1)N(c1ccc3ccc(Cl)cc3n1)C2=O
Temperature: 45 °C
Yield: 41.7 %

Procedure:
Triethylamine (29.5 cc) is added, at about 15° C., to a suspension of 7-(7-chloroquinol-2-yl)-6-hydroxy-3-methoxy-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (6.0 g) and 1-chlorocarbonyl-4-methylpiperazine hydrochloride (30.2 g) in anhydrous methylene chloride (150 cc), and anhydrous pyridine (65 cc) is then added to the resulting mixture. The reaction mixture is heated for 10 hours at 45° C. After cooling, the mixture is diluted by adding methylene chloride (300 cc). The organic phase is washed twice with an N aqueous sodium hydroxide solution (total 600 cc) and five times with distilled water (total 1000 cc), dried over sodium sulphate and evaporated. The residue is treated with boiling ethanol (50 cc). After cooling the mixture for 1 hour at 2° C., the crystals are filtered off, washed twice with ice-cooled ethanol (total 20 cc) and dried under reduced pressure (20 mm Hg). The resulting product (4.6 g; m.p. 228° C.) is dissolved in a boiling mixture of acetonitrile (50 cc) and ethanol (150 cc). After cooling the solution for 16 hours at 2° C., the resulting crystals are filtered off, washed with ice-cooled ethanol (5 cc) and dried under reduced pressure (0.2 mm Hg) at 55° C. 7-(7-Chloroquinol-2-yl)-3-methoxy-6-(4-methylpiperazin-1-yl)carbonyloxy-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (3.3 g), melting at 228° C., is obtained.
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.FC(F)(F)COP([CH2:31][C:32]([O:34][CH3:35])=[O:33])(=O)OCC(F)(F)F.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH:48]1([O:53][C:54]2[CH:55]=[C:56]([CH:59]=[CH:60][C:61]=2[O:62][CH3:63])[CH:57]=O)[CH2:52][CH2:51][CH2:50][CH2:49]1>C1COCC1>[CH3:35][O:34][C:32](=[O:33])/[CH:31]=[CH:57]\[C:56]1[CH:59]=[CH:60][C:61]([O:62][CH3:63])=[C:54]([O:53][CH:48]2[CH2:52][CH2:51][CH2:50][CH2:49]2)[CH:55]=1
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)/C=C\c1ccc(OC)c(OC2CCCC2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To a solution of 18-crown-6 (17 g, 64 mmol) and bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate (4.5 g, 14 mmol) in 200 mL of THF was added potassium bis(trimethylsilyl)amide (31 mL of 0.5M THF solution, 15.5 mmol). After 15 min a solution of 3-cyclopentoxy-4-methoxybenzaldehyde (2.8 g, 13 mmol) in 5 mL of THF was then added dropwise. The resulting solution was stirred at -78° C. for 30 min and quenched with sat NH4Cl. The mixture was diluted with ether and washed with 1M H3PO4, H2O, and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (3:1, hexanes:ethyl acetate) provided (Z)-methyl-3-(3-cyclopentoxy-4-methoxyphenyl)-prop-2-enoate (3.1 g, 87%), containing a trace amount of the E-isomer. 1H-NMR (300 MHz): δ 3.74 (s, 3), 3.89 (s, 3), 5.82 (d, 1, J=13).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[C:7]([NH2:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[Cl:1][CH2:2][C:3]1[N:15]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:14][CH:5]=1
Reactant: NC(=O)c1ccccc1
Reactant: O=C(CCl)CCl
Product: ClCc1coc(-c2ccccc2)n1
Yield: 68 %

Procedure:
This compound was synthesized from 1,3-dichloroacetone and benzamide as described in example 71 step 1 (65 g, yield 68%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.06-8.04 (m, 2H), 7.72 (m, 1H), 7.49-7.46 (m, 3H), 4.59 (d, J=1.1 Hz, 2H). MS (ESI) m/z: Calculated for C10H8ClNO: 193.03. found: 194.2 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:18][CH3:19])[CH2:3][O:4]C1C=CC(C2C=CC(O)=CC=2)=CC=1.CC(CC)CO[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([Br:37])[CH:31]=2)=[CH:26][CH:25]=1.BrBr>O1CCOCC1>[CH3:1][CH:2]([CH2:18][CH3:19])[CH2:3][O:4][C:31]1[C:32]([Br:37])=[C:33]([OH:36])[CH:34]=[CH:35][C:30]=1[C:27]1[CH:26]=[CH:25][CH:24]=[CH:29][CH:28]=1
Reactant: CCC(C)COc1ccc(-c2ccc(O)c(Br)c2)cc1
Reactant: CCC(C)COc1ccc(-c2ccc(O)cc2)cc1
Agent: BrBr
Solvent: C1COCCO1
Product: CCC(C)COc1c(-c2ccccc2)ccc(O)c1Br
Temperature: 40 °C

Procedure:
4'-(2-Methylbutyloxy)-4-hydroxybiphenyl (15 g) obtained in Example 1, (i) was dissolved in 1,4-dioxane (50 ml), followed by dropwise adding a mixture of bromine (10.5 g) and 1,4-dioxane (140 ml), heating on a water bath at 40° C. for 4 hours with stirring, thereafter distilling off 1,4-dioxane under reduced pressure, adding toluene (300 ml) to the remaining solution, adding a 10% aqueous solution of sodium hydrogen sulfite till the color of bromine disappeared, three times washing with saturated aqueous solution of NaCl to make the liquid neutral, drying and distilling off toluene to obtain a raw product of 4'-(2-methylbutyloxy-3-bromo-4-hydroxybiphenyl (21 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([S:9]([OH:12])(=[O:11])=[O:10])[C:5]([O:7][CH3:8])=[O:6].[C:13]([OH:16])(=[S:15])[CH3:14].CCN(C(C)C)C(C)C>C1COCC1>[C:13]([S:15][CH2:2][CH2:3][CH:4]([S:9]([OH:12])(=[O:11])=[O:10])[C:5]([O:7][CH3:8])=[O:6])(=[O:16])[CH3:14]
Reactant: CC(O)=S
Reactant: COC(=O)C(CCBr)S(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(CCSC(C)=O)S(=O)(=O)O
Temperature: 70 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
5.0 g (19.2 mmol) of 4-bromo-1-methoxy-1-oxobutane-2-sulfonic acid in 100 ml of THF was added 3.0 ml of thioacetic acid and 9.0 ml of DIPEA in 100 ml of THF. The mixture was stirred overnight then refluxed at 70° C. for 1 hr, evaporated and co-evaporated with 3×100 ml of water after neutralized to pH 7 with NaHCO3. The mixture was redissolved in methanol, filtered through celite, concentrated and purified with SiO2 chromatography eluted with CH3OH/CH2Cl2/HCOOH 37.5:250:1 to 50:250:1) to afford 4.4 g (90% yield) of the title compound. 1H NMR (D2O) 3.95 (dd, 1H, J=4.1, 10.3 Hz), 3.83 (s, 3H), 3.74 (m, 2H), 3.22 (dd, 2H, J=7.4, 14.9 Hz), 2.39 (s, 3H); 13C NMR 203.88, 172.91, 67.32, 56.17, 29.04, 20.61; MS m/z−254.8 (M−H)
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:10]=1[CH2:11][N:12]1[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH:13]1[CH3:19].F[B-](F)(F)F.[CH2:31]([O+](CC)CC)[CH3:32]>C(Cl)Cl.O>[CH3:7][O:8][C:9]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:10]=1[CH2:11][N:12]1[CH:13]([CH3:19])[C:14]([O:18][CH2:31][CH3:32])=[N:15][CH2:16][CH2:17]1
Reactant: COc1ccc(CN2CCNC(=O)C2C)c(OC)c1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC1=NCCN(Cc2ccc(OC)cc2OC)C1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oven-dried (115° C.) sodium carbonate (18.6 g, 98 mmol, 2.25 eq.) was placed in a 500 mL round-bottom flask. The round-bottom flask was backfilled with Ar and then capped with a rubber septum. A solution of 4-(2,4-dimethoxybenzyl)-3-methylpiperazin-2-one 1.1a (20.6 g, 78 mmol, 1 eq.) in anhydrous DCM (250 mL) was added, followed by triethyloxonium tetrafluoroborate (18.6 g, 98 mmol, 1.25 eq.) in one portion. Thereafter, the reaction mixture was stirred further at RT for 1 h whereupon the reaction mixture was diluted with water (250 mL). The aqueous layer was extracted with DCM (3×150 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude compound was then purified on silica gel (EtOAc) to afford the desired product 1a as orange oil. Yield: 13.2 g, 58%. LCMS: P=93%, retention time=1.8 min, (M+H+H2O)+: 311; 1H-NMR (CDCl3): δ 7.23 (d, J=8.8 Hz, 1H), 6.48 (d, J=8.8 Hz, 1H), 6.44 (s, 1H), 4.02 (m, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 3.86 (d, JAB=14.0 Hz, 1H), 3.46 (d, JAB=14.0 Hz, 1H), 3.44 (m, 2H), 3.10 (m, 1H), 2.79 (m, 1H), 2.32 (m, 1H), 1.35 (d, J=6.8 Hz, 3H), 1.24 (t, J=6.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([O:33]CC4C=CC=CC=4)[C:10]=3[N:9]=2)=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([OH:33])[C:10]=3[N:9]=2)=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OCc4ccccc4)cccc32)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(O)cccc32)C1
Yield: 78 %

Procedure:
A solution of (RS) 2-(4-chlorophenoxymethyl)-4-benzyloxy-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl]-benzimidazole (245 mg, 0.42 mmol, 1.0 eq) in ethyl acetate (4.2 ml) was degassed and then treated with 5% palladium on carbon (250 mg). The resulting mixture was stirred under a hydrogen atmosphere. The reaction mixture was then filtered through a CELITE™ cake layer. The catalyst was washed thoroughly with ethyl acetate and ethanol. The filtrate was condensed on a rotoevaporator to yield the desired title product in 78% yield.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[CH:17][C:18]=1[F:19]>>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=1[F:19])[O:20][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Oc1ccc(F)c(Cl)c1
Product: N#Cc1cc(C=O)ccc1Oc1ccc(F)c(Cl)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 3-chloro-4-fluorophenol.
Reaction SMILES: [C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[NH:6]1)([O:3][CH3:4])=[O:2].N1C=CC=CC=1.Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].O>O1CCCC1.C(OCC)(=O)C>[C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:24])[CH3:25])[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[N:6]1[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])([O:3][CH3:4])=[O:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C1NC2C(=O)N(C(C(=O)OCc3ccccc3)=C(C)C)C2O1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)C1OC2C(C(=O)N2C(C(=O)OCc2ccccc2)=C(C)C)N1C(=O)OCc1ccccc1
Reaction time: 1.5 h
Yield: 61.9 %

Procedure:
To a solution of 360 mg of benzyl α-(3ξ-carbomethoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 5 ml of tetrahydrofuran are added 0.1 ml of pyridine and then 255 mg of benzyl chloroformate under ice-cooling, and the mixture stirred for 90 minutes, and then mixed with water and ethyl acetate. The organic layer is separated, washed with water, dried and concentrated to yield the residue, which is chromatographed on silica gel containing 10% water to yield 306 mg of benzyl α-(3ξ-carbomethoxy-2-carbobenzoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 61.7% yield.