Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:29]=1B(O)O.O>CN(C)C(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[ClH:20].[ClH:20].[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:29]=1[C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=[CH:17][N:18]=1
Reactant: Cc1cccc(C)c1B(O)O
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cccc(C)c1-c1nccnc1N1CCNCC1
Product: Cl
Temperature: 115 °C
Reaction time: 3 h

Procedure:
Dissolve 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (1.00 g, 3.35 mmol) in N,N-dimethylacetamide (purged with nitrogen) (12 mL). Add potassium carbonate (1.11 g, 8.04 mmol) then 2,6-dimethylbenzeneboronic acid (602 mg, 4.02 mmol) and purge with nitrogen for 10 min. Add deoxygenated water (6 mL) and tetrakis(triphenylphosphine)palladium(0) (0.039 g, 0.034 mmol) and purge with nitrogen for 10 min. Heat at 115° C. for 20 hr. under nitrogen. Cool to room temperature, add water (20 mL), extract with DCM (3×20 mL) and pass through an IST Phase Separator Frit® and concentrate. Dissolve in methanol, filter off solid and purify filtrate by SCX-2® chromatography washing with methanol then eluting with 2 M ammonia in methanol. Concentrate, then stir in HCl in dioxane (4 M, 50 mL) for 3 hr. at room temperature. Reduce solvent, add potassium carbonate (2 g), filter and concentrate filtrate. Purify by SCX-2® chromatography, washing with methanol then eluting with 4 M ammonia in methanol, and concentrate. Add HCl in diethyl ether (1 M, 20 mL) and concentrate, then dry under vacuum at 40° C. to give the title preparation as yellow crystals (650 mg, 57%). MS (ES): m/z=269 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH:9]1([CH2:15][CH2:16]C2C=CC=CC=2O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:16][CH2:15][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: Oc1ccccc1CCC1CCCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Brc1cccc(OCCC2CCCCC2)c1
Yield: 93.7 %

Procedure:
To a solution of 3-bromophenol (15.0 g, 86.7 mmol), 2-cyclohexylethylphenol (12.0 ml, 86.7 mmol) and triphenylphosphine (23.0 g, 86.7 mmol) in tetrahydrofuran (200 ml) was added slowly a 40% solution of diethyl azodicarboxylate in toluene (38.0 ml, 86.7 mmol) in portions at 0° C. with stirring, and then the resulting mixture was stirred at room temperature for 7 hours. After stirring, the reaction mixture was evaporated in vacuo, and hexane was added to the residue. After filtration, the filtrate was evaporated in vacuo once again, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:100) as the eluent to afford 1-bromo-3-(2-cyclohexylethoxy)benzene (23.0 g, yield: 94%).
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:12]=[C:11]([SH:13])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:6])([CH3:5])[CH3:4].Br[CH:20]([CH2:24][CH2:25][CH2:26][CH3:27])[C:21]([OH:23])=[O:22].Cl>O.C(O)C>[C:3]([C:7]1[CH:12]=[C:11]([S:13][CH:20]([CH2:24][CH2:25][CH2:26][CH3:27])[C:21]([OH:23])=[O:22])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CCCCC(Br)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A base solution (22 grams of NaOH in 41 milliliters (ml) of water) was added to a solution of 2,6-di-t-butyl-4-mercaptophenol (64.3 grams; 0.27 mole) in 540 ml. of absolute ethanol with stirring while cooling the reaction mixture under nitrogen. Following the base addition, a solution of 2-bromohexanoic acid (52.8 grams; 0.27 mole) in 27 ml. of ethanol was added and the resulting reaction mixture was stirred at room temperature for about 6 hours and left standing overnight. The reaction mixture was then diluted with about 400 ml. of water and acidified with cold 6N HCl. The yellow brown precipitate resulting from the acidification was obtained by filtration, washed with water and recrystallized from a methylene chloride-hexane mixture. As a result of these operations, the desired 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)hexanoic acid compound was obtained as a white crystalline solid having a melting point of 140°-142° C. Analysis calculated for C20H32O3S: C, 68.15; H, 9.14; S, 9.10. Found: C, 68,14; H, 9.34; S, 8.86.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)([O-:3])=[O:2].[H-].[Na+].[H][H].Cl.[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22]Cl>CN(C=O)C>[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: [H][H]
Reactant: CN(C)CCCCl
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCN1CCc2cc([N+](=O)[O-])ccc21
Temperature: 60 °C
Yield: 48 %

Procedure:
4.92 g (30 mmol) of 5-nitroindoline is introduced by portions into a 250 ml double-necked flask, under argon atmosphere, containing a suspension of 2.4 g (60 mmol) of NaH (60%) in 60 ml DMF. The vigorous hydrogen evolution is accompanied by the formation of a red suspension. Agitation is maintained for 30 minutes at 23° C. before the addition, by portions, of 4.74 g (30 mmol) of 3-dimethylaminopropyl chloride hydrochloride. The reaction mixture is agitated and heated at 60° C. during 18 hours. The whole is finally poured into 200 ml of a water/ice mixture. The product is then extracted twice with 100 ml of AcOEt. The organic solution is washed successively with 100 ml of water and 100 ml of brine. After drying over MgSO4 and concentration under vacuum, the evaporation residue is purified by flash chromatography an a silica column (eluent: AcOEt/MeOH: 100/0 to 0/100). A dark yellow oil is obtained with a yield of 48%.
Reaction SMILES: [C:1]1(B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:18][C:19](=[O:33])[C:20]1[CH:30]=[C:29](Br)[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][C:21]=1Br)[CH3:17].C(=O)([O-])[O-].C([N+](CC)(CC)CC)C.C([N+](CC)(CC)CC)C.C(Cl)Cl.[C:59]1(C)[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>>[CH2:16]([O:18][C:19](=[O:33])[C:20]1[CH:30]=[C:29]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][C:21]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:17]
Reactant: CCOC(=O)c1cc(Br)c(C(=O)OCC)cc1Br
Reactant: CC1(C)OB(c2ccccc2)OC1(C)C
Reactant: Cc1ccccc1
Agent: CC[N+](CC)(CC)CC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2ccccc2)c(C(=O)OCC)cc1-c1ccccc1

Procedure:
To a 3 L 3-neck flask equipped with a mechanical stirrer, reflux condenser and rubber septum was added phenyl boronic acid pinacol ester 2a (128.9 g, 0.63 mol, 2 equiv.) and 2,5-dibromo-terephthalic acid diethylester 1a (120 g, 0.32 mol, 1 equiv.) as a suspension in toluene (500 mL). A further 500 mL of toluene was then added and the reaction mixture briefly stirred before degassing using a nitrogen purge for 1 hour at 40° C. After this period dichloro-bis(triphenyl phosphine) palladium (II) (0.55 g, 0.78 mmol, 1/8 mol % per bromide) was added as a dry powder. The reaction mixture was then stirred under nitrogen for 15 minutes at 40° C. before the addition of tetra-ethylammonium carbonate (790 mL, ca. 33 wt % aqueous solution, 2 equiv. per arylboronate). The reaction was then stirred at 90° C. under nitrogen overnight (ca. 16 hrs.). TLC analysis at this point (DCM, silica plates) revealed a bright fluorescent blue spot (Rf ca. 0.6) and the absence of any starting material. Once the reaction mixture had cooled the aqueous layer was extracted and the solvent removed under reduced pressure to yield a light brown solid residue which was recrystallised from methanol to give the title compound as white crystalline solid. Slow evaporation of the mother liquor provided a second crop of product (92 g total, 77%, >99% pure by GC).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH3:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([CH3:26])[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.CO>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:22]4[CH:23]=[C:24]([CH3:26])[CH:25]=[C:20]([CH3:19])[CH:21]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: Cc1cc(C)cc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc(C)cc(-c2ccc3c(c2)CC[C@H]2N(C)C(=O)CC[C@]32C)c1
Reaction time: 24 h
Yield: 85.8 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 3,5-dimethylphenylboronic acid (117 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution, 1.5 mL of toluene, and 1 mL of methanol, fitted with a reflux condenser, and the stirred mixture was healed at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 186 mg (86%) of the title compound as a white solid. mp 129°-130°. FDMS: m/e =333. α[D]589 =+73.31 (c=1.00, chloroform).
Reaction SMILES: [ClH:1].FC1C=C(C2C(OC3C=CC(OCCN4CCCCC4)=CC=3)=C3C(=CC=2)C=C(O)C=C3)C=CC=1.Cl.[F:37][C:38]1[CH:39]=[C:40]([C:44]2[CH:53]=[CH:52][C:51]3[C:46](=[CH:47][CH:48]=[C:49]([O:54]C)[CH:50]=3)[C:45]=2[O:56][C:57]2[CH:72]=[CH:71][C:60]([O:61][CH2:62][CH2:63][N:64]3[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]3)=[CH:59][CH:58]=2)[CH:41]=[CH:42][CH:43]=1>>[ClH:1].[N:64]1([CH2:63][CH2:62][O:61][C:60]2[CH:59]=[CH:58][C:57]([O:56][C:45]3[C:44]([C:40]4[CH:41]=[CH:42][CH:43]=[C:38]([F:37])[CH:39]=4)=[CH:53][CH:52]=[C:51]4[C:46]=3[CH:47]=[CH:48][C:49]([OH:54])=[CH:50]4)=[CH:72][CH:71]=2)[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]1
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCCC4)cc3)c(-c3cccc(F)c3)ccc2c1
Agent: Cl
Agent: Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cccc(F)c3)ccc2c1
Product: Oc1ccc2c(Oc3ccc(OCCN4CCCCCC4)cc3)c(-c3cccc(F)c3)ccc2c1
Yield: 52 %

Procedure:
Prepare this compound following the procedure to make 6-(3-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol hydrochloride above starting with 1-(2-{-4-[2-(3-fluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-azepane hydrochloride, to get a 52% yield of the free of the title compound after radial chromatography. Form the hydrochloride salt by adding 0.8 mL of a 1 M HCl in Et2O solution: mass spectrum (ion spray) m/z=472 (M−Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](/[N:11]=[CH:12]/[C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[Si](C)(C)[C:21]([CH:23]=[CH2:24])=[CH2:22].C1C[O:30]CC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:24][CH2:23][C:21](=[O:30])[CH2:22][CH:12]2[C:13]2[CH:18]=[N:17][CH:16]=[N:15][CH:14]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(/N=C/c1cncnc1)c1ccc(Cl)cc1
Reactant: C=CC(=C)[Si](C)(C)C
Reactant: C1CCOC1
Product: O=C1CCN(S(=O)(=O)c2ccc(Cl)cc2)C(c2cncnc2)C1
Temperature: 25 °C
Yield: 40 %

Procedure:
To a solution of 69 (2.12 g, 7.5 mmol) in THF (15 mL) was added 2-(trimethylsilyl)-1,3-butadiene (70, 2.18 g, 15 mmol). The reaction was heated at reflux for 36 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to yield 3.33 g crude material. The residue was purified by flash chromatography (3:1 hexanes/EtOAc) to yield 1.05 g (40%) 71 as a yellow solid. 1H NMR (CDCl3) δ 9.16 (s, 1H), 8.63 (s, 2H), 7.85 (d, 2H), 7.55 (d, 2H), 5.65 (d, 1H), 4.11-4.04 (m, 1H), 3.24-3.14 (m, 1H), 2.96-2.82 (m, 2H), 2.55-2.49 (m, 1H), 2.40-2.34 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:16]=[C:15]([C:17]([O:19]C)=[O:18])[CH:14]=[CH:13][C:12]=1[F:21].[Li+].[OH-]>C1COCC1.CO>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[CH:13][C:12]=1[F:21]
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(OC)cc2F)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of methyl 6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropicolinate (1.0 equiv.) in THF/MeOH (2:1, 0.09 M) was added LiOH (1.5 equiv.) and the reaction was stirred at room temperature for 1 hour. The solution was quenched with 1N HCl, extracted with ethyl acetate, washed with brine, dried with sodium sulfate, filtered and concentrated to give 6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropicolinic acid in 84% yield. LC/MS=284.1 (M+H), Rt=0.76 min.
Reaction SMILES: Cl.[NH:2]1[CH2:7]C[C:5]2(C3C(=CC=CC=3)CO2)[CH2:4][CH2:3]1.[F:16][C:17]1[N:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.FC1C=C(C(N2CCCC2=O)C(O)=O)C=CC=1F.[F:47][C:48]1[CH:53]=[CH:52][C:51]([CH:54]([C:58]2[CH:63]=[CH:62][C:61]([F:64])=[CH:60][CH:59]=2)[C:55]([OH:57])=O)=[CH:50][CH:49]=1>>[F:64][C:61]1[CH:62]=[CH:63][C:58]([CH:54]([C:51]2[CH:50]=[CH:49][C:48]([F:47])=[CH:53][CH:52]=2)[C:55]([N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][N:26]2[CH2:27][CH2:28][CH:23]([C:20]3[CH:21]=[N:22][C:17]([F:16])=[CH:18][CH:19]=3)[CH2:24][CH2:25]2)=[O:57])=[CH:59][CH:60]=1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: Fc1ccc(C2CCNCC2)cn1
Reactant: c1ccc2c(c1)COC21CCNCC1
Agent: Cl
Agent: O=C(O)C(c1ccc(F)c(F)c1)N1CCCC1=O
Product: CN(CCCN1CCC(c2ccc(F)nc2)CC1)C(=O)C(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
Example 9 was repeated except that spiro[isobenzofuran-1(3H), 4′-piperidine] hydrochloride which was used in Example 9-(2) was replaced with 4-(6-fluoro-3-pyridinyl)piperidine, and 2-(3,4-difluorophenyl)-2-(2-oxo-1-pyrrolidinyl)acetic acid which was used in Example 9-(4), with 2,2-bis(4-fluorophenyl)acetic acid, to provide the title compound.
Reaction SMILES: CC1O[C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2N=1.C(N([CH:18]([CH3:20])[CH3:19])C(C)C)C.[CH3:21][Si](Cl)(C)C.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[CH:10]12[CH2:4][CH:5]3[CH2:19][CH:18]([CH2:20][CH:8]([CH2:7]3)[C:9]1=[O:11])[CH2:21]2
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nc2ccc(O)cc2o1
Reactant: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6.6 g 2-methyl-benzoxazol-6-ol (formula IIb) in 100 ml of dry tetrahydrofuran, cooled to 0°, N-ethyldiisopropylamine and trimethylsilyl chloride are added. The mixture is stirred at room temperature for about 2 hours, cooled to −78°, and sodium bis(trimethylsilyl)amide solution is added in portions. To the mixture obtained solid 2-adamantanone (formula VI) is added and the mixture is kept at −78° for about one hour. The reaction mixture is allowed to warm up to room temperature and is pointed into 300 ml of 1 M NaHSO4 solution. The mixture is extracted with ethyl acetate and the organic layer is dried over sodium sulfate. The solvent is evaporated off and the residue is purified by chromatography. The above title compounds are obtained (m.p., respectively, 248-253° and 238-240°).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[N:10]([C:14]([F:17])([F:16])[F:15])[N:11]=[N:12][CH:13]=2)=[CH:4][C:3]=1SC.ClC1C=C(F)C(C2N(C(F)(F)F)N=NC=2)=CC=1S>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[N:10]([C:14]([F:16])([F:17])[F:15])[N:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CSc1cc(-c2cnnn2C(F)(F)F)c(F)cc1Cl
Agent: Fc1cc(Cl)c(S)cc1-c1cnnn1C(F)(F)F
Product: Fc1cc(Cl)ccc1-c1cnnn1C(F)(F)F
Yield: 85.7 %

Procedure:
2.2 g (7.1 mmol) of [2-chloro-4-fluoro-5(3-trifluoromethyltriazolyl)phenyl]methyl sulfide was converted to 2-chloro-4-fluoro-5(3-trifluoromethyltriazolyl)thiophenol in the same manner as in Reference Example 1 and then to 1.8 g of 1,1′-thiodi-[2-chloro-4-fluoro-5-(3-trifluoromethyltriazolyl)benzene (yield 85.7%) in the same manner as in Reference Example 5 (1), which was used in Example 2 (4) as the starting material.
Reaction SMILES: [C:1]([C:3]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]Br)#[N:2].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.CN(C)C=O>O>[C:1]([C:3]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)#[N:2]
Reactant: CCCCC(C#N)(CCCCCBr)c1ccc(Cl)cc1Cl
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(C#N)(CCCCCn1ccnc1)c1ccc(Cl)cc1Cl
Yield: 47.8 %

Procedure:
A mixture of 6-cyano-6-(2,4-dichlorophenyl)decyl bromide (14.2g., 0.036 mole) imidazole (10g., 0.15 mole) and 5 ml. N,N-dimethylformamide is heated at 120° C. for 24 hours. The reaction mixture is poured into water and extracted with ether. The combined ether extracts are dried over magnesium sulfate and filtered. Into the ethereal solution is bubbled dry hydrogen chloride gas until no more oily precipitate forms. The solvent is then decanted and the oily residue is taken up in acetone and neutralized with dilute ammonium hydroxide solution. The purified free base is extracted into ether and dried over magnesium sulfate. When the solvent is evaporated, a total of 6.5g. (47.8%) of product is obtained, which is identified by nmr.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16].O>C(Cl)Cl>[CH3:14][S:15]([O:6][C@@H:3]1[CH2:4][CH2:5][O:1][CH2:2]1)(=[O:17])=[O:16]
Reactant: O[C@@H]1CCOC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1CCOC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.7 %

Procedure:
A solution of (R)-tetrahydrofuran-3-ol (1.1 g, 12.5 mmol) and triethylamine (13.6 mL, 97.5 mmol) in CH2Cl2 was cooled in an ice-water bath. To this, methanesulfonyl chloride (3.0 mL, 39 mmol) diluted in CH2Cl2 (10 mL) was added dropwise. The reaction was left stirring for 12 hours at room temperature. Water was added, and organic phases extracted in CH2Cl2 (3×50 mL), which were subsequently dried onto silica and purified by silica gel chromatography (50% EtOAc:Hexanes to 100% EtOAc gradient) to afford (R)-tetrahydrofuran-3-yl methanesulfonate (0.97 g, brown oil, 47% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([CH3:7])(=[O:6])=[O:5].Cl[C:9]1[N:14]=[C:13]([C:15]2[S:19][C:18]([CH:20]([CH3:22])[CH3:21])=[N:17][C:16]=2[C:23]2[CH:24]=[C:25]([NH:29][S:30]([CH:33]3[CH2:35][CH2:34]3)(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:12]=[CH:11][N:10]=1>>[CH3:22][CH:20]([C:18]1[S:19][C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:1][CH2:2][CH2:3][S:4]([CH3:7])(=[O:6])=[O:5])[N:14]=2)=[C:16]([C:23]2[CH:24]=[C:25]([NH:29][S:30]([CH:33]3[CH2:34][CH2:35]3)(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[N:17]=1)[CH3:21]
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)C3CC3)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CS(=O)(=O)CCN
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)C3CC3)c2)c(-c2ccnc(NCCS(C)(=O)=O)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using 2-aminoethyl-methyl-sulfone (396 mg, 3.22 mmol) and N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}cyclopropanesulfonamide (140 mg, 0.322 mmol) the title compound was obtained as a white solid (41 mg, 23% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.84 (s, 1H), 8.17 (d, J=4.0 Hz, 1H), 7.48 (br. s., 1H), 7.37 (s, 2H), 7.33 (s, 1H), 7.27 (d, J=7.5 Hz, 1H), 6.34 (d, J=3.5 Hz, 1H), 3.67 (d, J=5.5 Hz, 2H), 3.35-3.44 (m, 2H), 3.25-3.30 (m, 1H), 3.02 (s, 3H), 2.54-2.64 (m, 1H), 1.37 (d, J=6.8 Hz, 6H), 0.92 (d, J=6.2 Hz, 4H). MS (ESI): 522.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[C:4]([CH3:10])[CH:3]=1.[OH-:11].[Na+].C[OH:14]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([OH:14])=[O:11])=[C:4]([CH3:10])[CH:3]=1
Reactant: CO
Reactant: Cc1cc(F)ccc1C#N
Reactant: [OH-]
Agent: [Na+]
Product: Cc1cc(F)ccc1C(=O)O

Procedure:
4-Fluoro-2-methylbenzonitrile (2.9 g), 5N NaOH (50 mL), and MeOH (50 mL) were set stirring at 100° C. for 18 hours. The solvent was removed under reduced pressure and the product was washed with CH2Cl2 and acidified to pH 1. The reaction was partitioned between ethyl acetate and water and the organic layer was washed with brine and dried over anhydrous Na2SO4 to yield a while solid (1.6 g). 1H NMR (300 MHz, CDCl3): δ 8.07-8.14 (m, 1H), 6.96-7.01 (m, 1H), 6.79-6.82 (m, 1H), 2.73 (br s, 3H).
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]3[C:22](=[N:23][CH:24]=2)[N:21]([C:25]([NH2:27])=[O:26])[CH2:20][CH2:19][CH2:18]3)[CH:12]=[N:13][CH:14]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH:1]1([C:4]([NH:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[CH:16]=[C:17]4[C:22](=[N:23][CH:24]=3)[N:21]([C:25]([NH2:27])=[O:26])[CH2:20][CH2:19][CH2:18]4)[CH:12]=[N:13][CH:14]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CC1
Reactant: NCc1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)N1CCCc2cc(-c3cncc(CNC(=O)C4CC4)c3)cnc21
Reaction time: 8 h

Procedure:
To the cyclopropanecarboxylic acid (16 mg, 0.18 mmol) is added a solution of 6-(5-aminomethyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (40 mg, 0.14 mmol) in DMF (1 mL) followed by HATU (100 mg, 0.26 mmol) in DMF (1 mL) followed by triethylamine (51 mg, 0.50 mmol). The mixture is stirred overnight. The mixture is concentrated in vacuo, dissolved in 2 mL of DMF, filtered and purified by reverse phase HPLC to afford the titled product.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3][CH2:2]1.[H-].[Na+].F[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[CH3:22])[C:18](=[O:23])[N:17]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[CH:16]=[CH:15]2.O>CC(N(C)C)=O>[NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:21]=2[CH3:22])[C:18](=[O:23])[N:17]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[CH:16]=[CH:15]3)[CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2ccc3cc(F)c(C)cc3c2=O)cc1
Reactant: OC1CCCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cn2ccc3cc(OC4CCCNCC4)c(C)cc3c2=O)cc1
Yield: 41 %

Procedure:
A solution of 58 mg (0.51 mmol) azepan-4-ol in 5 ml dimethylacetamide was stirred with 45 mg (1.52 mmol) 80 percent sodium hydride for 45 minutes at room temperature. Then 150 mg (0.51 mmol) 6-fluoro-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one in dimethylacetamide was added. The reaction mixture was heated to 80° C. for 3 days during which additional amounts of azepan-4-ol and sodium hydride were added until complete conversion of the 6-fluoro-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one was obtained. The reaction mixture was slowly added to 10 ml water and after 1 h of stirring the product was isolated by filtration and dried overnight in vacuum. 82 mg of 6-(azepan-4-yloxy)-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one were obtained.