Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[CH:5]=[CH:4][C:3]=1[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19].[Cu][C:28]#[N:29]>CN(C)C=O.O>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1/[CH:9]=[CH:8]/[C:6]1[CH:5]=[CH:4][C:3]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[C:2]([CH:7]=1)[C:28]#[N:29]
Reactant: O=S(=O)(c1ccccc1)c1ccc(/C=C/c2ccc(F)cc2F)cc1Br
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(/C=C/c2ccc(F)cc2F)ccc1S(=O)(=O)c1ccccc1
Temperature: 130 °C
Yield: 43.7 %

Procedure:
2-Bromo-4-[(E)-2-(2,4-difluorophenyl)vinyl]-1-(phenylsulfonyl)benzene (Example 55, 130 mg, 0.3 mmol) and copper(I) cyanide (40 mg, 0.45 mmol) were combined in N,N-dimethylformamide (20 mL) and heated to 130° C. for 3 hours. Further copper(I) cyanide (40 mg, 0.45 mmol) was added and heating continued overnight. The cooled reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water (×3) and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 20–30% ethyl acetate/isohexane, followed by trituration with diethyl ether to give the title compound (50 mg, 44%). δH (360 MHz, d6 DMSO): 8.41 (1H, d, J=1.6 Hz), 8.28 (1H, d, J=8.4 Hz), 8.14 (1H, dd, J=1.7, 8.4 Hz), 8.01–7.98 (2H, m), 7.86–7.64 (4H, m), 7.58 (1H, d, J=16.6 Hz), 7.37 (1H, d, J=16.8 Hz), 7.32–7.28 (1H, m), 7.17 (1H, td, J=2.4, 8.5 Hz).
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][CH2:26][OH:27])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC.O>[OH:27][CH2:26][CH2:25][CH2:24][N:22]([CH3:23])[C:3]1[C:2]([C:32]2[CH:33]=[N:34][C:29]([CH3:28])=[CH:30][CH:31]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: CN(CCCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N(C)CCCO)cn1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-6-((3-hydroxypropyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 165.1, 92 mg, 0.189 mmol), (6-methylpyridin-3-yl)boronic acid (25.9 mg, 0.189 mmol) and Na2CO3 (60 mg, 0.566 mmol) in a mixture of DME (4.0 mL), EtOH (0.54 mL) and water (0.80 mL) was flushed with argon for 5 min. Pd(PPh3)2Cl2 was added (6.6 mg, 0.0094 mmol) and the mixture subjected to MW irradiation at 125° C. for 20 min. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure to give a residue that was triturated with THF and filtered. The filtrate was evaporated to dryness under reduced pressure and the crude product was purified by preparative LC-MS. TFA was removed using a SPE PL-HCO3 (StratoSpheres™ VariPure IPE) cartridge. Additional purification (Isolute Flash Silica gel cartridge, 5 g, elution of impurities with EtOAc, subsequent elution of product with MeOH) afforded the title compound. LC-MS (Condition 5) tR=1.65 min, m/z=461.2 [M+H]+, m/z=459.2 [M−H]−.
Reaction SMILES: I[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[C:26]([O:30][C:31](=[O:51])[N:32]([C:42]1[CH:47]=[CH:46][C:45]([CH:48]=[O:49])=[C:44]([CH3:50])[N:43]=1)[CH2:33][C:34]1[CH:35]=[N:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1)([CH3:29])([CH3:28])[CH3:27].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[C:26]([O:30][C:31](=[O:51])[N:32]([C:42]1[CH:47]=[CH:46][C:45]([CH:48]([OH:49])[C:2]2[C:10]3[CH:9]=[N:8][CH:7]=[N:6][C:5]=3[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=2)=[C:44]([CH3:50])[N:43]=1)[CH2:33][C:34]1[CH:35]=[N:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C=O)c(C)n2)cn1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cncnc21
Agent: CC(C)[Mg]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncncc34)c(C)n2)cn1
Temperature: -25 °C
Yield: 59.7 %

Procedure:
To 5-iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine (38, 0.37 g, 0.92 mmol) in a round bottom flask, 1.1 mL of tetrahydrofuran was added and the mixture cooled to −25° C. Isopropylmagnesium chloride (0.49 mL, 2.0 M in tetrahydrofuran, 0.97 mmol) was added and the reaction stirred, coming to 0° C. The reaction was cooled to −25° C. and (5-formyl-6-methyl-pyridin-2-yl)-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (74, 0.300 g, 0.839 mmol) in 2.5 mL of tetrahydrofuran was added. The reaction was stirred, coming to 0° C., then poured into aqueous saturated sodium bicarbonate and ethyl acetate. The organic layer was washed with brine, then dried over sodium sulfate, filtered and the filtrate adsorbed onto silica. This was purified by silica gel column chromatography eluting with 10-80% ethyl acetate in hexanes. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (75, 317 mg). MS (ESI) [M+H+]+=634.09.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20](O)[CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=1.B(F)(F)F.CCOCC>O1CCOCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH:20]([C:17]1[CH:16]=[CH:15][C:14]([CH3:13])=[CH:19][CH:18]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCC(O)c1ccc(C)cc1
Reactant: O=c1cc(O)c2ccccc2o1
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCCC(c1ccc(C)cc1)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a flame-dried flask containing a mixture of 650 mg of 4-hydroxycoumarin and 980 mg of 1-(4-methylphenyl)-butan-1-ol of Preparation 20 in 20 mL of dioxane under an argon atmosphere is added 2.5 mL of boron trifluoride etherate. The resulting yellow solution is left to stir at room temperature overnight. The volatiles are removed and the residue is partioned between diethyl ether and 1N sodium hydroxide. The basic aqueous phase is washed with diethyl ether and acidified to pH=1 with 6N hydrochloric acid. The resulting precipitant is repeatedly extracted with dichloromethane (methanol-chloroform co-solvents). The combined dichloromethane extracts are washed once with dilute sodium bicarbonate to remove most of the unreacted 4-hydroxycoumarin, then brine, dried (magnesium sulfate), and finally concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed with 40% to 50% ethyl acetate in hexane to yield 660 mg of the title product as a white solid.
Reaction SMILES: Br[CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[C:17]([F:24])[CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[Mg].Br[CH2:27][C@H:28]1[CH2:33][CH2:32][Si@H:31]([CH2:34][CH2:35][CH2:36][CH:37]=[CH2:38])[CH2:30][CH2:29]1>[Cu]I.P(OCC)(OCC)(OCC)=O.C1COCC1>[CH2:34]([Si@H:31]1[CH2:30][CH2:29][C@H:28]([CH2:27][CH2:2][C@H:3]2[CH2:8][CH2:7][C@H:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[C:17]([F:24])[CH:16]=4)=[CH:11][CH:10]=3)[CH2:5][CH2:4]2)[CH2:33][CH2:32]1)[CH2:35][CH2:36][CH:37]=[CH2:38]
Reactant: CCOc1ccc(-c2ccc([C@H]3CC[C@H](CBr)CC3)cc2)cc1F
Reactant: C=CCCC[Si@H]1CC[C@H](CBr)CC1
Agent: [Cu]I
Agent: [Mg]
Solvent: CCOP(=O)(OCC)OCC
Solvent: C1CCOC1
Product: C=CCCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(OCC)c(F)c4)cc3)CC2)CC1

Procedure:
39.1 g (0.1 mol) of 4-(trans-4-bromomethylcyclohexyl)-3'-fluoro-4'-ethoxybiphenyl was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 26.1 g (0.1 mol) of trans-1-bromomethyl-4-(4-pentenyl)-4-silacyclohexane. After a conventional after treatment, purification was conducted by means of chromatography to obtain 35.1 g (yield 71.3%) of 4-(trans-4-(2-(trans-4-(4-pentenyl)-4-silacyclohexyl)ethyl)cyclohexyl)-3'-fluoro-4'-ethoxybiphenyl.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:9]([Cl:19])[C:3]=1[O:4][CH2:5][C:6](=O)[CH3:7].[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][NH2:33])=[N:26][CH:27]=1.[Cl-].[NH+]1C=CC=CC=1.Cl>N1C=CC=CC=1>[F:34][C:21]([F:20])([F:35])[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][N:33]=[C:6]([CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:12][C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])=[CH:10][C:9]=2[Cl:19])[CH3:7])=[N:26][CH:27]=1
Reactant: CC(=O)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: NOCCCOc1ccc(C(F)(F)F)cn1
Agent: Cl
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Product: CC(COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NOCCCOc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
A mixture of 0.34 g of (2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)acetone, 0.24 g of O-(3-(5-trifluoromethyl-2-pyridyloxy)propyl)hydroxylamine, 0.14 g of pyridinium chloride, and 10 ml of pyridine was stirred at room temperature for 2 hours. The reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.40 g (yield, 71%) of (2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)acetone O-(3-(5-trifluoromethyl-2-pyridyloxy)propyl)oxime, nD23.0 1.5310.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[C:10](=[O:23])[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([N+:19]([O-])=O)=[C:14]([Cl:22])[CH:13]=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Cl-].[NH4+]>CO.O.[Fe]>[CH2:1]([O:3][P:4]([C:9]1[C:10](=[O:23])[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([NH2:19])=[C:14]([Cl:22])[CH:13]=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)c1cc2cc([N+](=O)[O-])c(Cl)cc2[nH]c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CCOP(=O)(OCC)c1cc2cc(N)c(Cl)cc2[nH]c1=O

Procedure:
A suspension of the compound obtained in Step C (7.0 g, 19.4 mmol), powdered iron (10.8 g, 194 mmol) and ammonium chloride (10.4 g, 194 mmol) is stirred at reflux for 1 hour in a mixture of 270 ml of methanol and 90 ml of water. The suspension is filtered hot over Celite and the Celite is rinsed several times with methanol. The filtrate is evaporated to dryness and the residue is suspended in water. The solid is filtered off, rinsed with water and dried to yield the title product in the form of orange crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:8][CH:7]=1.[S:37](Cl)([CH3:40])(=[O:39])=[O:38]>>[CH3:40][S:37]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH:13]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:8][CH:7]=1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOS(C)(=O)=O)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
Reaction of tert-butyl (3RS,4RS)-4-[4-(3-hydroxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with mesyl chloride analogously to the procedure described in Example 54(h) gave tert-butyl (3RS,4RS)-4-[4-(3-methylsulphonyloxy-propoxy)-phenyl]-3-(naphthalen-2-yl-methoxy)-piperidine-1-carboxylate as a yellow oil; Rf : 0.50 (SiO2, hexane:ethyl acetate=1:1).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:21]=[CH:20][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=2)=[C:8]([F:22])[CH:7]=1>C(O)=O.O>[F:22][C:8]1[CH:7]=[C:6]([CH:2]=[O:1])[CH:21]=[CH:20][C:9]=1[O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C3OCCO3)cc2F)cn1
Solvent: O
Solvent: O=CO
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 99.4 %

Procedure:
Take up 5-(4-[1,3]dioxolan-2-yl-2-fluorophenoxy)pyridine-2-carboxamide (0.316 g, 1.04 mmol) in 88% formic acid (5.2 mL). Stir at room temperature for 1.25 hours before diluting with water. Extract with dichloroethane (2×50 mL). Wash the organic layer with brine (1×25 mL), dry over Na2SO4, filter and concentrate to give the title compound (0.269 g, 99.6%): TOF MS ES+ 261.1 (M+H)+, HRMS calcd for C13H10N2O3F 261.0675 (M+H)+, found 261.0682, time 0.37 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR 9.0 min, 100% purity.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([C:45]2[C:46]([C:51]#[N:52])=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:44])[N:23]([C@H:33]2[CH2:38][CH2:37][C@H:36]([O:39][CH2:40][CH:41]([OH:43])[CH3:42])[CH2:35][CH2:34]2)[C:24]2[N:25]([N:30]=[CH:31][CH:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:51]2[NH:3][C:4](=[O:7])[O:5][N:52]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:44])[N:23]([C@H:33]2[CH2:38][CH2:37][C@H:36]([O:39][CH2:40][CH:41]([OH:43])[CH3:42])[CH2:35][CH2:34]2)[C:24]2[N:25]([N:30]=[CH:31][CH:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OCC(C)O)CC2)c2ccnn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n([C@H]2CC[C@H](OCC(C)O)CC2)c2ccnn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.43 g), sodium hydrogen carbonate (0.66 g) and dimethyl sulfoxide (3 mL) was stirred at 50° C. for 30 min, 3′-fluoro-4′-({4-[trans-4-(2-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.27 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.10 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.090 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.21 g, 68%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:5]=1[OH:11])=[O:3].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[CH:17]=O.[OH-].[K+].Cl>C(O)C.O>[OH:11][C:5]1[CH:6]=[C:7]([I:10])[CH:8]=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:17][C:16]1[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:14]([O:13][CH3:12])[CH:15]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: CC(=O)c1ccc(I)cc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(C=CC(=O)c2ccc(I)cc2O)cc(OC)c1OC
Reaction time: 119 h
Yield: 126.6 %

Procedure:
To a stirring suspension of 29 (0.55 g, 2.1 mmol) and 3,4,5-trimethoxy-benzaldehyde (0.66 g, 3.4 mmol, 1.6 equ) in ethanol (10 ml) was added potassium hydroxide (0.25 g, 4.5 mmol, 2.1 equ). The reaction mixture was stirred for 119 hours then diluted with water, acidified (1N HCl) and extracted with ethyl acetate (3×70 ml). The combined organic layers were then washed with saturated aqueous sodium bicarbonate (50 ml), saturated brine (50 ml), 10% sodium bisulfite solution (3×50 ml) and then saturated brine (50 ml) again. The organic layer was then dried (MgSO4) and concentrated in vacuo to give a yellow solid (1.17 g). This solid was heated in methanol, and the undissolved solid collected. The filtrate was concentrated and then heated in methanol again. More undissolved solid was collected. Undissolved solid is 32 (0.50 g, 54%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:18]1[CH:23]=[C:22]([F:24])[C:21]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([C:33]3[C:38]([CH3:39])=[CH:37][C:36]([CH3:40])=[CH:35][N:34]=3)[CH2:29][CH2:28]2)=[O:26])=[C:20]([F:41])[CH:19]=1>>[CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[N:11]1[C:18]1[CH:19]=[C:20]([F:41])[C:21]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([C:33]3[C:38]([CH3:39])=[CH:37][C:36]([CH3:40])=[CH:35][N:34]=3)[CH2:29][CH2:28]2)=[O:26])=[C:22]([F:24])[CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4[C@H](COCc5ccccc5)CCS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 60 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (536 mg) described in Preparation Example 1 and (4-bromo-2,6-difluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (911 mg) described in Preparation Example 111 and by the reaction and treatment in the same manner as in Example 4, the title compound (760 mg) was obtained.
Reaction SMILES: [OH2:1].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:13][O:14][CH:15]=[CH:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH2:26][CH2:27][CH3:28])[CH:21]=[C:20]2[CH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][C:31]=1[O:40][CH3:41].[CH3:42]O>C(Cl)Cl>[CH3:13][O:14][CH:15]([O:1][CH3:42])[CH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH2:26][CH2:27][CH3:28])[CH:21]=[C:20]2[CH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][C:31]=1[O:40][CH3:41]
Reactant: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(C=COC)ccc21
Reactant: O
Reactant: CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(CC(OC)OC)ccc21
Reaction time: 4 h
Yield: 88 %

Procedure:
para-Toluenesulfonic acid hydrate (0.55 g) was added to a stirred solution of methyl 4-[5-(2-methoxyvinyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate (0.2 g) in 1:1 methanol:methylene chloride (5 ml), under a nitrogen atmosphere. After 4 h, the mixture was evaporated at ambient temperature, and the product was purified by flash chromatography, eluting with 4:1 hexane:ethyl acetate, to give methyl 4-[5-(2,2-dimethoxyethyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate (0.19 g, 88%) as an oil; partial NMR (300 MHz, DMSO-d6): 0.81(t, 3H, CH3), 1.71(m, 2H, CH2), 2.84(m, 2H, CH2), 3.20(s, 6H, 2xOCH3), 3.83(s, 3H, OCH3), 3.91(s, 3H, OCH3), 4.02(m, 4H, NCH2, ArCH2Ar'), 4.50(t, 1H, CH).
Reaction SMILES: [CH:1]1([CH2:17]C2C=C(C)C=CC=2S([O-])(=O)=O)[CH2:4][CH:3]([CH2:5][C:6]2C=C(C)C=CC=2S([O-])(=O)=O)[CH2:2]1.[C-]#[N:30].[Na+].C[N:33]([CH:35]=O)C>O>[CH:1]1([CH2:17][C:35]#[N:33])[CH2:4][CH:3]([CH2:5][C:6]#[N:30])[CH2:2]1
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)[O-])c(CC2CC(Cc3cc(C)ccc3S(=O)(=O)[O-])C2)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#CCC1CC(CC#N)C1

Procedure:
To a solution of cyclobutane-1,3-diylbis(methylene)bis(4-methylbenzenesulfonate) I-13 (1 equivalent) in DMF was added NaCN (6 equivalents) and was refluxed for 12 h. During workup, the reaction mixture was diluted with water and the desired compound was extracted with ethyl acetate. Evaporation of the organic solvent furnished I-14.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.ON1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2N=N1.Cl.[CH3:24][C:25]1[CH:26]=[CH:27][C:28]([C@@H:31]([NH2:33])[CH3:32])=[N:29][CH:30]=1.C(N(CC)C(C)C)(C)C.[CH2:43]1[CH2:47][O:46][CH2:45][CH2:44]1>O>[CH3:24][C:25]1[CH:26]=[CH:27][C:28]([C@@H:31]([NH:33][C:45]([C@H:44]2[CH2:43][C@@H:47]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:46])[CH3:32])=[N:29][CH:30]=1
Reactant: On1nnc2ccccc21
Reactant: C1CCOC1
Reactant: Cc1ccc([C@H](C)N)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc([C@H](C)NC(=O)[C@H]2C[C@@H]2c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.709 g, 3.70 mmol) and 1-hydroxybenzotriazole (0.667 g, 4.93 mmol) were added to a stirred mixture of IM46 (0.60 g, 3.70 mmol) and commercially available (S)-1-(5-methyl-pyridin-2-yl)-ethylamine hydrochloride (Supplier Netchem Inc., Catalog No 528193) (0.426 g, 2.47 mmol) and N,N-diisopropylethylamine (0.859 ml, 4.93 mmol) in THF (25 ml). The solution was stirred at rt overnight. Water was added and the mixture was extracted with EtOAc (3×80 ml). The combined organic phases were washed with brine, dried over MgSO4, filtered and the solvent was evaporated of in vac. The crude product was purified by silica gel chromatography (EtOAc in heptanes 1:1). Yield of Compound 2: 110 mg (16%). LC-MS (m/z) 281.1 (MH+), tR=0.91 min (method A).