Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=S1(=O)CCN(CC[NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([CH:46]([CH3:48])[CH3:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C@@H:20]([C:33]3[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=3)[CH2:19][CH2:18]4)[CH2:15][CH2:14]2)CC1.Cl[CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][N:56]([S:59]([CH3:62])(=[O:61])=[O:60])[CH2:55][CH2:54]1>>[CH:46]([C@H:43]1[C@@H:12]2[C@@H:13]3[C@@:26]([CH3:29])([CH2:27][CH2:28][C@@:11]2([NH:10][CH2:51][CH2:52][N:53]2[CH2:58][CH2:57][N:56]([S:59]([CH3:62])(=[O:61])=[O:60])[CH2:55][CH2:54]2)[CH2:45][CH2:44]1)[C@@:25]1([CH3:30])[C@@H:16]([C@:17]2([CH3:42])[C@@H:22]([CH2:23][CH2:24]1)[C:21]([CH3:32])([CH3:31])[C@@H:20]([C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=1)[CH2:19][CH2:18]2)[CH2:15][CH2:14]3)([CH3:48])[CH3:47]
Reactant: CC(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CS(=O)(=O)N1CCN(CCCl)CC1
Product: CC(C)[C@@H]1CC[C@]2(NCCN3CCN(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described in Example B2 for the synthesis of 4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 1-(2-chloroethyl)-4-(methylsulfonyl)piperazine (prepared as described below) as the alkylating reagent in Step 3. The product was isolated as a white solid (11 mg, 56%). LCMS: m/e 724.6 (M+H)+, 2.44 min (method 10). 1H NMR (500 MHz, Acetic) δ 8.02 (d, J=8.2 Hz, 2H), 7.36 (d, J=8.2 Hz, 2H), 3.63-3.29 (m, 7H), 3.25-3.14 (m, 1H), 3.13-2.99 (m, 4H), 2.93 (s, 3H), 2.50 (dd, J=13.0, 2.6 Hz, 1H), 2.32-0.98 (m, 26H), 1.25 (s, 3H), 1.12 (s, 3H), 1.08 (s, 3H), 0.93 (d, J=6.7 Hz, 3H), 0.86 (d, J=6.7 Hz, 3H), 0.83 (s, 3H), 0.79 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][C:31](Br)=[CH:32][CH:33]=4)[N:28]([CH3:36])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[O:24][CH3:25])(=[O:16])=[O:15])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:37][O:38][CH2:39][Sn](CCCC)(CCCC)CCCC>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([CH2:37][O:38][CH3:39])=[CH:32][CH:33]=4)[N:28]([CH3:36])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[O:24][CH3:25])(=[O:16])=[O:15])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(Br)ccc12
Reactant: CCCC[Sn](CCCC)(CCCC)COC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COCc1ccc2c(C(C(=O)NS(=O)(=O)c3ccc(C)cc3OC)c3ccc4c(c3)OCO4)cn(C)c2c1
Reaction time: 8 h
Yield: 11.6 %

Procedure:
To a solution of 3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-6-bromo-1-methyl-1H-indole (from Example 85, 300 mg, 0.53 mmol) in 1,4-dioxane (1.5 ml) under a nitrogen atmosphere was added methoxymethyltributylstannane (220 mg, 0.66 mmol), followed by tetrakis(triphenylphosphine)palladium(O) (35 mg). The mixture was heated to reflux for 16 hours, and then cooled. An additional portion of tetrakis(triphenylphosphine)palladium(O) (30 mg) was added, and reflux was continued for a further 8 hours. The solvent was removed in vacuo, and the residue was flash chromatographed using a gradient elution of a mixture of 1% methanol and 99% dichloromethane, through to 5% methanol and 95% dichloromethane, to give the title compound (33 mg).
Reaction SMILES: C1N=CN([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[S:7])C=1.[C:13]([O:17][C:18](=[O:31])[NH:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=CC(N)=[CH:26][CH:25]=1)([CH3:16])([CH3:15])[CH3:14]>CN(C)C=O>[C:13]([O:17][C:18](=[O:31])[NH:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:10][C:9]([N:8]=[C:6]=[S:7])=[CH:26][CH:25]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc(N)cc1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCOc1ccc(N=C=S)cc1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 90.4 %

Procedure:
To a cooled (−15° C.) solution of 1,1-thiocarbonyidiimidazole (756 mg, 4.115 mmol) (Aldrich) in N,N-dimethylformamide (11 mL) was added dropwise a solution of [3-(4-aminophenoxy)propyl]carbamic acid tert-butyl ester (1.02 g, 3.84 mmol) (from Step B above) in N,N-dimethylformamide (11 mL) over 25 minute. After the addition was complete, the mixture was stirred at −15° C. for 20 minute and then at room temperature for 1 h. Ice-water was added and the mixture was extracted with ether. The ether layer was dried (MgSO4), filtered, and evaporated. The residue was purified on silica gel with 85:15 hexane/ethyl acetate to give [3-(4-isothiocyanatophenoxy)propyl]-carbamic acid tert-butyl ester (1.07 g, 91% yield). HRMS, observed: 308.1197; Calcd for M+:308.1195.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:7](=[O:19])[C@H:6]1[CH2:20][CH2:21][CH2:22][NH:23][C:24]([NH:36]C(OCC1C=CC=CC=1)=O)=[N:25]C(OCC1C=CC=CC=1)=O)=[O:4].[ClH:47].[H][H]>[Pd].C(OCC)(=O)C.CO>[ClH:47].[CH3:1][O:2][C:3]([C@@H:5]1[N:8]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[C:7](=[O:19])[C@H:6]1[CH2:20][CH2:21][CH2:22][NH:23][C:24]([NH2:36])=[NH:25])=[O:4]
Reactant: COC(=O)[C@H]1[C@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1S(=O)(=O)c1ccc(C)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1[C@H](CCCNC(=N)N)C(=O)N1S(=O)(=O)c1ccc(C)cc1
Yield: 24 %

Procedure:
An ethyl acetate/methanol (2.5 mL/2.5 mL) solution of compound 8 (197 mg, 0.3 mmol) and 1N HCl (0.6 mL), containing 10% palladium on carbon catalyst, was stirred under one atmosphere of hydrogen until TLC indicated the disappearance of the starting 8. The suspension was filtered through a pad of Celite, and the filtrate was concentrated to afford 30 mg (24%) of the title product as a foam.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](ON=C(C1C=CC=CC=1)C#N)=[O:7])([CH3:4])[CH3:3].Cl.Cl.[CH2:21]([O:28][NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([O:28][NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCCCCNOCc1ccccc1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCCNOCc1ccccc1
Reaction time: 24 h

Procedure:
1 N NaOH (100 mL) was added to (6) (6.01 g, 21.4 mmol), followed by extraction with ether (5×50 mL). After a brine wash (50 mL), solvent was removed to give 4.39 g of (6) as the free amine. BOC-ON (5.10 g, 20.7 mmol ) in distilled THF (100 mL) was added to (6) (free amine, 21.1 mmol) in THF (165 mL) at 0° C. over 30 minutes. The reaction was stirred (0° C. to room temperature) for 24 hours and concentrated in vacuo. Cold 1N NaOH (100 mL) was added, followed by extraction with EtOAc (4×100 mL). The organic layer was washed with cold 1 N NaOH (3×80 mL), cold 0.5M citric acid (100 mL) and brine (2×100 mL). Removal of solvent gave 6.38 g (quantitative) of (7), which was used directly in the next step, as a liquid: NMR δ 1.2-1.7 (m+s, 15 H), 2.66-3.23 (m, 4 H), 4.5 (br s, 1 H), 4.67 (s, 2 H), 7.16-7.34 (m, 5 H) . An analytical sample was purified on a silica gel column, eluting with 15% EtOAc/CHCl3. Anal. calcd. for C17H28N2O3 : C, 66.20; H, 9.15; N, 9.08. Found: C, 66.13; H, 9.10; N, 9.05.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([CH2:14][N:15]2[CH:23]=[N:22][C:21]3[C:20](=[O:24])[NH:19][C:18]([NH2:25])=[N:17][C:16]2=3)[S:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C.O>[Br:1][C:23]1[N:15]([CH2:14][C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)[C:16]2[N:17]=[C:18]([NH2:25])[NH:19][C:20](=[O:24])[C:21]=2[N:22]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nc2c(ncn2Cc2cccs2)c(=O)[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc2c(nc(Br)n2Cc2cccs2)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-Bromosuccinimide (2.82 g; 15.7 mmol) was added to a cold (0° C.) suspension of 9-(2-thenyl) guanine (3.5 g; 14.1 mmol) in DMF (100 ml) and the mixture was stirred for 30 minutes at 0° C. and then at room temperature for 24 hours. The reaction mixture was then diluted with 75 mlof water and filtered. Recrystallization of the product from DMF gave the analytical sample, yield 3.1 g; mp 294°-295° C. (dec).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:19][C:20]1[C:21]([F:30])=[C:22](B(O)O)[C:23]([F:26])=[CH:24][CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:20]1[C:21]([F:30])=[C:22]([C:2]2[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=2)[C:23]([F:26])=[CH:24][CH:25]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OB(O)c1c(F)ccc(OCc2ccccc2)c1F
Reactant: COC(=O)c1cccc(Br)n1
Product: COC(=O)c1cccc(-c2c(F)ccc(OCc3ccccc3)c2F)n1
Yield: 95 %

Procedure:
Method 6 was followed using methyl 6-bromopicolinate (1.0 equiv.) and 3-(benzyloxy)-2,6-difluorophenylboronic acid (2.5 equiv.) to give methyl 6-(3-(benzyloxy)-2,6-difluorophenyl)picolinate as a light yellow solid in 95% yield. LC/MS=356.2 (M+H), Rt=1.03 min.
Reaction SMILES: Br.Br[CH:3]([N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C:4]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])=O.[NH2:19][C:20]([NH2:22])=[S:21]>C(O)C.Cl>[NH2:22][C:20]1[S:21][C:3]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)=[C:4]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[C:9]#[N:10])[N:19]=1
Reactant: NC(N)=S
Reactant: N#Cc1cccc(C(=O)C(Br)n2cncn2)c1
Agent: Br
Agent: Cl
Solvent: CCO
Product: N#Cc1cccc(-c2nc(N)sc2-n2cncn2)c1
Temperature: 95 °C

Procedure:
A mixture of 3-(2-bromo-2-[1,2,4]triazol-1-yl-acetyl)-benzonitrile hydrobromide (1.848 g, 5.00 mmol), thiourea (0.46 g, 1.2 mol) in ethanol is heated to 95° C. for 8 h. The solvent is removed under vacuum to give a foam which is dissolved in 3M hydrochloric acid. The product is precipitated as a white powder by the addition of concentrated aqueous ammonia to pH11. M.S. (MH+) 269.54.
Reaction SMILES: CN(C)[C:3]1[CH:4]=[C:5](CO)[CH:6]=[CH:7][CH:8]=1.[Br:12][C:13]1[C:14]([F:20])=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.CC1(C)C(C)(C)OB(C2C=NNC=2)O1>>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[C:14]=1[F:20]
Reactant: Oc1cccc(Br)c1F
Reactant: CN(C)c1cccc(CO)c1
Agent: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Fc1c(Br)cccc1OC1CCCCC1

Procedure:
The title compound was prepared by substituting cyclohexanol for (3-(dimethylamino)phenyl)methanol and 3-bromo-2-fluorophenol for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE 34A.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=5)[N:15]([CH3:24])[C:14]4=[O:25])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)O1.[C:54]([OH:60])([C:56]([F:59])([F:58])[F:57])=[O:55]>C(Cl)Cl>[F:57][C:56]([F:59])([F:58])[C:54]([OH:60])=[O:55].[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:24])[C:14](=[O:25])[C@:13]12[CH2:12][C@H:11]1[C:7]1[CH:6]=[C:5]2[C:10]([C:2]([C:34]3[CH:35]=[CH:36][C:37]([N:40]4[CH2:41][CH2:42][NH:43][CH2:44][CH2:45]4)=[CH:38][CH:39]=3)=[N:3][NH:4]2)=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(I)n[nH]c3c1)C(=O)N2C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(N5CCNCC5)cc4)n[nH]c3c1)C(=O)N2C
Yield: 42 %

Procedure:
The boc protected title compound was synthesized according to the method of Example A51B, except substituting (1R,2S)-2-(3-iodo-1H-indazol-6-yl)-5′-methoxy-1′-methylspiro[cyclopropane-1,3′-indolin]-2′-one (600 mg, 1.35 mmol) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (534 mg, 1.37 mmol). The Boc protected compound was purified by column chromatography (silica gel, hexanes/EtOAc, 100:0 to 5:95) which gave 400 mg. This material was dissolved in CH2Cl2 (12 mL) and TFA (3 mL) and the reaction stirred for 3 h at which time the solvent was removed and the residue purified by prep-HPLC which yielded the title product as a pale-yellow solid (339 mg, 42%); 1H NMR (400 MHz, CD3OD) δ 7.90 (d, J=8.2 Hz, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.48 (s, 1H), 7.17 (d, J=8.4 Hz, 2H), 7.00 (d J=8.6 Hz, 1H), 6.92 (d, J=8.5 Hz, 1H), 6.69 (d, J=8.6 Hz, 1H), 5.64 (s, 1H), 3.53-3.48 (m, 4H), 3.43-3.37 (m, 5H), 3.31 (s, 3H), 3.29 (s, 3H), 2.29-2.26 (m, 1H), 2.22-2.18 (m, 1H); MS ESI [M+H]+ 480.3, calcd for [C29H29N5O2+H]+ 480.24. Optical Rotation: [α]22D=−113° (c 0.62, MeOH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-:29].[K+].[K+].OO.[Na]>CS(C)=O.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:12]=[CH:13][C:14]([S:17]([C:20]2[CH:27]=[CH:26][C:23]([C:24]([NH2:25])=[O:29])=[CH:22][CH:21]=2)(=[O:18])=[O:19])=[CH:15][CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3F)cc2)cc1
Agent: OO
Agent: [K+]
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1ccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3F)cc2)cc1
Reaction time: 0.08 h
Yield: 182.4 %

Procedure:
To a solution of 4-({4-[(E)-2-(2,4-difluorophenyl)vinyl]phenyl}sulfonyl)benzonitrile (Example 53, 50 mg, 0.13 mmol) in dimethylsulfoxide (1.3 mL) was added potassium carbonate (9 mg, 0.07 mmol) in water (0.65 mL) and the reaction stirred for 5 minutes. Hydrogen peroxide (0.06 mL) was added and the reaction stirred for 2 hours. Saturated aqueous sodium sufite solution was added and the products extracted into ethyl acetate. The organic layer was dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with ethyl acetate, to give the title compound as a white solid (51 mg, 98%). (400 MHz, d6 DMSO): 8.15 (1H, s), 8.03 (4H, s), 7.96 (2H, d, J=8.5 Hz), 7.84 (3H, d, J=8.6 Hz), 7.61 (1H, s), 7.39 (2H, d, J=7.2 Hz), 7.33-7.27 (1H, m), 7.15 (1H, td, J=2.3, 8.6 Hz).
Reaction SMILES: [CH3:1][C:2]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:25])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH2:26]([OH:33])[C@@H:27]([C@@H:29](CO)[OH:30])[OH:28].C(=O)([O-])[O-].[K+].[K+].C(O)=O>CN(C)C=O>[CH3:1][C:2]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:25])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C@@H:26]([C@@H:27]([CH2:29][OH:30])[OH:28])[OH:33])=[O:7]
Reactant: OC[C@@H](O)[C@@H](O)CO
Reactant: COC(=O)CCC=C(C)CCCC(C)CCCC(C)CCCC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=CO
Product: CC(=CCCC(=O)OC[C@H](O)[C@H](O)CO)CCCC(C)CCCC(C)CCCC(C)C
Reaction time: 10 h

Procedure:
Under reduced pressure of 60-70 mmHg and nitrogen gas stream, 199 g (0.564 mol) of methyl 5,9,13,17-tetramethyloctadec-4-enoate was slowly added dropwise to a solution of 191 g (1.56 mol) of erythritol and 1.58 g (1.15 mmol) of potassium carbonate in dry N,N-dimethylformamide (700 mL) at 78-83° C. After the reaction mixture was stirred at the same temperature for 10 hours, formic acid was added at 75° C. to adjust the pH to 4. After the resulting solution was subjected to vacuum concentration, the residue was diluted with t-butylmethylether (1.5 L), and the insoluble matter generated was separated by filtration. The filtrate was washed with 10% sodium bicarbonate aqueous solution twice, and decolorized with activated carbon (8 g). After filtration, the filtrate was concentrated, and the residue was dissolved in ethanol, followed by filtration through cellulose powder. After the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate mixture) to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH2:19][CH2:18]1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]>>[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]
Reactant: CN1CCN(C2CCN(c3c(C(=O)C4CC4)cnc4ccc(Br)cc34)CC2)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CN1CCN(C2CCN(c3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)cc34)CC2)CC1
Yield: 66.6 %

Procedure:
Following general procedure D, {6-bromo-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]quinolin-3-yl}(cyclopropyl)methanone (30 mg, 0.066 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (41 mg, 0.150 mmol) to afford the desired product (23 mg, 67%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.77 (s, 1H), 8.28 (d, J=1.3 Hz, 1H), 8.05-7.99 (m, 2H), 7.58-7.53 (m, 1H), 7.46 (dd, J=11.6, 2.2 Hz, 1H), 3.55 (d, J=13.1 Hz, 2H), 3.25-3.15 (m, 2H), 2.93-2.47 (m, 10H), 2.39 (s, 3H), 2.12 (d, J=10.8 Hz, 2H), 1.96-1.82 (m, 2H), 1.34-1.28 (m, 2H), 1.27-1.20 (m, 2H); ESI MS m/z 523 [C29H32ClFN4O2+H]+; HPLC>99% (AUC), tR=10.14 min.
Reaction SMILES: [Cl:1][C:2](=[CH2:12])[CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.[Br:13][C:14]([Br:24])=[CH:15][C@H:16]1[C@@H:18]([C:19](Cl)=[O:20])[C:17]1([CH3:23])[CH3:22].N1C=CC=CC=1>C1C=CC=CC=1>[Br:13][C:14]([Br:24])=[CH:15][C@H:16]1[C@@H:18]([C:19]([O:9][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([CH2:3][C:2]([Cl:1])=[CH2:12])=[CH:5][CH:6]=2)=[O:20])[C:17]1([CH3:22])[CH3:23]
Reactant: CC1(C)[C@H](C(=O)Cl)[C@@H]1C=C(Br)Br
Reactant: C=C(Cl)Cc1ccc(CO)cc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: C=C(Cl)Cc1ccc(COC(=O)[C@@H]2[C@H](C=C(Br)Br)C2(C)C)cc1
Reaction time: 16 h

Procedure:
The alcohol of Example 2 (0.078 g) in benzene (2 ml) is added to (IR)cis 3-(2,2-dibromovinyl)2,2-dimethylcyclopropane carbonyl chloride (0.135 g) in benzene (3 ml). Pyridine (0.06 ml) is then added and the mixture stirred at 20° for 16 hours. This is chromatographed on florisil and the fraction eluted by 7% ether in petrol evaporated to a residue of 0.19 g (96%) ester, nD20 1.5692.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Br>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: BrCCOCCBr
Reactant: N#CCc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC1(c2ccc(Br)cc2)CCOCC1
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a solution of 2-(4-bromophenyl)acetonitrile (3.9 g) in tetrahydrofuran (50 mL) was added potassium t-butoxide (4.9 g) in an ice bath, and the mixture was stirred for 1 hr in an ice bath. 1-Bromo-2-(2-bromoethoxyl)ethane (5.8 g) was added thereto at the same temperature, and the mixture was stirred at room temperature for 10 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.7 g).
Reaction SMILES: [CH2:1]=[CH2:2].FF.[C:5]1([CH3:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[CH2:1]([C:8]1[CH:9]=[CH:10][C:5]([CH3:11])=[CH:6][CH:7]=1)[CH3:2]
Reactant: Cc1ccccc1
Reactant: C=C
Agent: FF
Product: CCc1ccc(C)cc1
Yield: 27.9 %

Procedure:
The same reactor used in Example 4 was charged with a feedstock containing a (3.6 wt.%, 10.4 mol %) concentration of ethylene in toluene. At a reaction temperature of 100° C., 5.95 g (9.0 mL) of a catalyst analyzed to contain 19.71 wt.% fluorine gave 49.4% ortho-, 22.7% meta-, and 27.9% para-ethyl-methyl-benzene with 44.4 mol % conversion, compared to 17.1 mol % conversion for a control catalyst in which the polymer had not been fluorinated.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].Br[C:27]1[CH:28]=[CH:29][C:30]([CH2:33][CH3:34])=[N:31][CH:32]=1>O1CCCC1>[CH2:33]([C:30]1[CH:29]=[CH:28][C:27]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:32][N:31]=1)[CH3:34]
Reactant: CCc1ccc(Br)cn1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(CC)nc1
Temperature: -78 °C

Procedure:
n-Butyllithium (2 ml, 1.6M in hexanes, 3.22 mmol) was added dropwise to an ice-cooled solution of diisopropylamine (0.45 ml, 3.22 mmol) in tetrahydrofuran (6 ml) under a nitrogen atmosphere, and the solution stirred for an hour. Tri-n-butyltin hydride (0.79 ml, 2.96 mmol) was added and the solution stirred for a further 2 hours, and then cooled to −78° C. A solution of 5-bromo-2-ethylpyridine (WO 97/01552) (500 mg, 2.69 mmol) in tetrahydrofuran (4 ml) was then added dropwise, and once addition was complete, the reaction was allowed to warm to room temperature, and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane and aqueous ammonium chloride solution. The layers were separated, the organic phase dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of pentane:ethyl acetate (100:0 to 90:10) to afford the tide compound, (210 mg, 19%) as a yellow oil.
Reaction SMILES: [C:1]([N:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[S:8][CH2:7][CH2:6]1)(=[O:4])[CH:2]=[CH2:3].S(Cl)([Cl:19])(=O)=O.O>C(Cl)Cl>[C:1]([N:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[S:8][CH:7]([Cl:19])[CH2:6]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)N1CCSc2ccccc2C1
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)N1Cc2ccccc2SC(Cl)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
4-Acryloyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (10 g) was dissolved in methylene chloride (150 ml) and sulfuryl chloride (9.3 g) was added thereto under ice cooling and agitated at 0° C. for 1 hour. To the reaction mixture water was added and extracted with chloroform. The chloroform phase was washed with a saturated saline solution and dried on sodium sulfate and thereafter the solvent was distilled out under reduced pressure. Residue was purified by silica gel column chromatography (Wako Gel C-200, 200 g) and eluted with a mixed solvent of n-hexane (70 parts)+ethyl acetate (30 parts) to give 4-acryloyl-2-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (10.5 g).