Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([O:13][C:14]([N:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[Cl:25])[CH2:17]2)=[O:15])[CH2:10][C@H:9]1[C:26]([OH:28])=O)=O)(C)(C)C.Cl.[NH2:30][C@:31]1([C:37]([NH:39][S:40]([CH:43]2[CH2:45][CH2:44]2)(=[O:42])=[O:41])=[O:38])[CH2:33][C@H:32]1[CH:34]1[CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[ClH:25].[CH:43]1([S:40]([NH:39][C:37]([C@@:31]2([NH:30][C:26]([C@H:9]3[NH:8][CH2:12][C@H:11]([O:13][C:14]([N:16]4[CH2:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][C:22]=5[Cl:25])[CH2:17]4)=[O:15])[CH2:10]3)=[O:28])[CH2:33][C@H:32]2[CH:34]2[CH2:36][CH2:35]2)=[O:38])(=[O:42])=[O:41])[CH2:45][CH2:44]1
Reactant: N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C1CC1
Reactant: CC(C)(C)OC(=O)N1C[C@H](OC(=O)N2Cc3cccc(Cl)c3C2)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C1CC1)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(Cl)c3C2)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 163.7 %

Procedure:
(2S,4R)-1-(tert-butoxycarbonyl)-4-(4-chloroisoindoline-2-carbonyloxy)pyrrolidine-2-carboxylic acid 26 (0.35 g, 0.852 mmol), (1R,2S)-1-amino-2-cyclopropyl-N-(cyclopropylsulfonyl)cyclopropanecarboxamide hydrochloride 25 (0.287 g, 1.02 mmol) and HATU (0.389 g, 1.02 mmol) were dissolved in DriSolve DMF (8.5 mL), and cooled in an ice bath. DIEA (d 0.742) (0.445 ml, 2.56 mmol) was then added to reaction drop-wise. The reaction was allowed to warm up to rt slowly and stirred overnight. After reaching completion, the reaction was diluted with water (120 mL) and extracted with EtOAc (3×150 mL). The combined organic extract was washed with 0.5 N HCl (200 mL), brine (150 mL) and dried over Na2SO4. Removal of solvent yielded the crude product as a light yellowish foamy solid, which was purified by reverse phase chromatography (eluent: 5 to 95% MeCN/water), giving pure desired product as a white solid (0.40 g, 70% yield). LCMS (APCI+): 537.2 (MH+−Boc).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH2:2][C:3]#[CH:4].[C:11](Cl)(=[O:22])OC1C=CC([N+]([O-])=O)=CC=1.C[CH2:25][N:26](CC)CC.CN>C1COCC1.CO.O>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([NH:26][CH3:25])=[O:22])[CH2:7][CH2:6]1)[CH2:2][C:3]#[CH:4]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: C#CCCN1CCNCC1
Agent: CN
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C#CCCN1CCN(C(=O)NC)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 1-(but-3-ynyl)piperazine (445 mg) in THF (4 mL) was treated with 4-nitrophenyl carbonochloridate (649 mg) at rt for 5 min. A precipitate formed immediately, and the suspension was treated with Et3N (0.45 mL) to ensure complete reaction. The suspension was diluted wiht H2O (2 mL), MeOH (2 mL) and 40% aq. MeNH2 (4.0 mL) and stirred at rt for 3 days. Extraction with DCM (50 mL), washing (NaOH 2M), drying (Na2SO4) and concentration gave 4-(but-3-ynyl)-N-methylpiperazine-1-carboxamide (370 mg).
Reaction SMILES: Cl.[CH2:2]([N:9]([CH2:13][CH2:14]Cl)[CH2:10][CH2:11]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:16][CH:17]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:2]([N:9]1[CH2:13][CH2:14][N:16]([CH:17]2[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: ClCCN(CCCl)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(N2CCN(Cc3ccccc3)CC2)C1

Procedure:
6.33 g (29.0 mmol) of benzylbis(2-chloroethyl)amine hydrochloride were dissolved in ethanol (100 ml) and, while stirring, 5.00 g (29.0 mmol) of tert-butyl 3-aminoazetidine-1-carboxylate and 9.76 g (116 mmol) of sodium bicarbonate were added. The resulting reaction solution was heated under reflux for 4 h. The cooled reaction mixture was concentrated in vacuo, 100 ml of water were added and the aqueous phase was extracted with ethyl acetate (4×60 ml). The combined organic phases were washed with saturated aqueous NaHCO3 solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 2.5-5% methanol in dichloromethane). Yield: 6.27 g (65%) of yellow oil
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7](=[O:35])[C@@H:8]([NH:22][C@@H:23]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:24]([F:27])([F:26])[F:25])[CH2:9][S:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[C:18]([F:21])([F:20])[F:19])[CH2:5][CH2:4]1)#[N:2].[OH:36]OS([O-])=O.[K+].[OH2:42]>CO>[C:1]([C:3]1([NH:6][C:7](=[O:35])[C@@H:8]([NH:22][C@@H:23]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:24]([F:26])([F:27])[F:25])[CH2:9][S:10]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[C:18]([F:20])([F:21])[F:19])(=[O:36])=[O:42])[CH2:5][CH2:4]1)#[N:2]
Reactant: O
Reactant: N#CC1(NC(=O)[C@H](CSCc2cnccc2C(F)(F)F)N[C@@H](c2ccc(F)cc2)C(F)(F)F)CC1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: N#CC1(NC(=O)[C@H](CS(=O)(=O)Cc2cnccc2C(F)(F)F)N[C@@H](c2ccc(F)cc2)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-(1-cyanocyclopropyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-3-(4-trifluoromethyl-pyridin-3-ylmethylsulfanyl)-propionamide was dissolved in CH3OH (10 mL) and an aqueous solution of Oxone® (3 g in 10 mL H2O, 10 mmol) was added. The reaction mixture was stirred at room temperature 3 h. Solvent was removed under the reduced pressure. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine and dried with MgSO4. The solvent was removed under the reduced pressure and the crude product was purified by prep-HPLC to isolate the title compound from the diastereomeric mixture.
Reaction SMILES: [P:1]([CH2:14][CH2:15][P:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(CCP(CC)CC)(CC)CC.P(CCP(C)C)(C)C.P(CP(C1C=CC=CC=1)C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[P:1]([CH:14]=[CH:15][P:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Agent: CCP(CC)CCP(CC)CC
Agent: CP(C)CCP(C)C
Agent: c1ccc(P(CP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Product: C(=CP(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1

Procedure:
(C6H5)2PCH2CH2P(C6H5)2 ; (CH3CH2)2PCH2CH2P(CH2CH3)2 ; (CH3)2PCH2CH2P(CH3)2; (C6H5)2PCH2P(C6H5)2 ; and [(C6H5)2PCH2CH2 ]2P(C6H5).
Reaction SMILES: C1([C:7]2O[N:10]=[C:9]([NH2:12])[N:8]=2)C=CC=CC=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([N:13]2[CH:7]=[N:8][C:9]([NH2:12])=[N:10]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1
Reactant: Nc1noc(-c2ccccc2)n1
Product: Nc1ncn(-c2ccccc2)n1
Yield: 87 %

Procedure:
This compound was prepared from 5-phenyl-[1,2,4]oxadiazol-3-ylamine (Journal of Organic Chemistry 28, 1812 (1963) and aniline, via the rearrangement described by Ruccia et al., Journal of Heterocyclic Chemistry 8, 137 (1971). The title compound was isolated as a slightly brownish solid in a yield of 87%. MS ISP (m/e): 161.2 (100) [(M+H)+].
Reaction SMILES: [CH3:1][N:2]([CH2:4][C-:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1)[CH3:3].[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15].C[C:17]([O:20]C)(C)C>>[CH3:1][N:2]([CH2:4][C-:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH:17]=[O:20])[CH3:3].[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15]
Reactant: COC(C)(C)C
Reactant: CN(C)C[c-]1cccc1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Product: CN(C)C[c-]1cccc1C=O
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Charge an inertized reactor with 39.6 g of 1-[(dimethylamino)methyl]-ferrocene and 360 ml of MTBE. Distill about 160 ml of MTBE (4V) at atmospheric pressure. Cool the solution to −10° C. and slowly add 98.2 ml of a solution of t-BuLi in heptane (titer 16%). Stir the reaction mixture at −10° C. for 2 hours and then at 0° C., slowly add 25.2 ml of DMF. Continue stirring the reaction mixture at 20° C. for 2 hours then at 5° C., slowly add 135 ml of 1.5N aqueous HCl. Continue stirring the reaction mixture at 5° C. for 30 min, then at 20° C. for 30 min. Leave the reaction mixture to settle and withdraw the aqueous phase then the MTBE phase. Counter-extract the aqueous phase with 125 ml of MTBE. Filter the combined MTBE phases on activated charcoal then concentrate to 120 ml under vacuum. Add 80 ml of isopropanol then distill 420 ml of solvent to constant volume, under vacuum, by regular addition of isopropanol. At the end of distillation, dilute the reaction mixture to 280 ml with isopropanol. 39.9 g of the expected compound is obtained in solution in isopropanol.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[S:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH2:34][NH:33][CH2:32][CH2:31]2.C(N(C(C)C)CC)(C)C.[I-].[Na+]>C(#N)C>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([CH:7]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:33]2[CH2:32][CH2:31][C:30]3[C:35](=[CH:36][CH:37]=[C:28]([O:27][CH3:26])[CH:29]=3)[CH2:34]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(C(CCCCCBr)Sc2ccc(C)cc2)cc1OC
Reactant: COc1ccc2c(c1)CCNC2
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(CCCCCC(Sc1ccc(C)cc1)c1ccc(OC)c(OC)c1)C2
Temperature: 25 °C

Procedure:
To a solution of 4.23 g of 4-[6-bromo-1-[(4-methylphenyl)thio]hexyl]-1,2-dimethoxybenzene in 40 mL of acetonitrile is added 3.88 g of 6-methoxy-1,2,3,4-tetrahydroisoquinoline, 1.74 mL of diisopropylethylamine and 0.01 g of sodium iodide. The solution is heated to reflux for 43 hours and cooled to room temperature. The reaction mixture is partitioned between chloroform and aqueous potassium carbonate and the organic layer is dried over magnesium sulfate. The volatiles are removed at reduced pressure and the residue chromatographed on silica gel using a gradient elution of hexane to chloroform to methyl alcohol. The residue from the chromatography is dissolved in diethyl ether and passed through diatomaceous earth. This affords 4.4 g of the desired product as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:72])[C@@H:4]([NH:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[C:64](=[O:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[CH:15]/[C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[C:25]/[CH:26]=[CH:27]/[CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][C@H:37]([NH:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[C:49](=[O:56])[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:38]([O:40]C)=[O:39])=[CH:32][CH:31]=3)=[CH:20][CH:19]=2)=[CH:8][CH:7]=1.[OH-].[Na+]>C1COCC1.C(O)C>[C:64]([C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=1[NH:57][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[CH:15]/[C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[C:25]/[CH:26]=[CH:27]/[CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][C@H:37]([NH:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[C:49](=[O:56])[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:38]([OH:40])=[O:39])=[CH:32][CH:31]=3)=[CH:20][CH:19]=2)=[CH:8][CH:7]=1)[C:3]([OH:72])=[O:2])(=[O:71])[C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1
Reactant: COC(=O)[C@H](Cc1ccc(OC/C=C/C#Cc2ccc(C#C/C=C/COc3ccc(C[C@H](Nc4ccccc4C(=O)c4ccccc4)C(=O)OC)cc3)cc2)cc1)Nc1ccccc1C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(c1ccccc1)c1ccccc1N[C@@H](Cc1ccc(OC/C=C/C#Cc2ccc(C#C/C=C/COc3ccc(C[C@H](Nc4ccccc4C(=O)c4ccccc4)C(=O)O)cc3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (E)(E)(S)(S) 2-(2-benzoyl-phenylamino)-3-(4-{5-[4-(5-{4-[2-(2-benzoyl-phenylamino)-2-methoxycarbonyl-ethyl]-phenoxy}-pent-3-en-1-ynyl)-phenyl]-pent-2-en-4-ynyloxy}-phenyl)-propionic acid methyl ester (example 9) (370 mg 0.39 mmol) in THF (3 mL) and ethanol (3 mL) was added 1N sodium hydroxide (2 mL). After stirring at room temperature for 1 h, the reaction mixture was concentrated in vacuo, added water and 1N hydrochloride acid to pH 1. The product was extracted with dichloromethane (×3) and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to give the title compound as a crystalline product. The product was recrystallised from ethyl acetate and petroleum ether to give 200 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>C(COC)OC>[C:18]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)(=[O:20])[CH3:19]
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCOCC1
Reactant: CC(=O)OC(C)=O
Solvent: COCCOC
Product: CC(=O)Nc1cc(C(F)(F)F)ccc1N1CCOCC1
Temperature: 25 °C
Yield: 96 %

Procedure:
A mixture of 40 g. (16 mmoles) of 4-(2-amino-4-trifluoromethylphenyl)morpholine and 2.2 g. (22 mmoles) of acetic anhydride in 40 ml. of dry dimethoxyethane was heated at 70° C. for 10 hours. The reaction mixture was cooled to room temperature and then the solvent removed by evaporation under reduced pressure. The residue was dissolved in 100 ml. of methylene chloride and the solution washed with 5% sodium bicarbonate solution. After drying over anhydrous sodium sulfate, the solution was filtered and evaporated under reduced pressure. The residue was dissolved in n-hexane from which it crystallized to give 4.4 g. (96%) of the desired product melting at 85° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.N1C=CC=CC=1.[C:16]1([CH:23]=[CH:22][C:20]([OH:21])=[CH:19][CH:18]=1)[OH:17].[OH-].[Na+]>CS(C)=O>[Cl:8][C:7]1[C:2]([O:17][C:16]2[CH:23]=[CH:22][C:20]([OH:21])=[CH:19][CH:18]=2)=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1

Procedure:
In procedures similar to those in Example 1 above, except that a 2,3,5-trichloropyridine was used in place of the bis reactant, it was found that reaction of equimolar amounts of the pyridine reactant, hydroquinone and 50% NaOH in dimethylsulfoxide (DMSO) at 100°-116° C. for about 11/2 hours gave product yields of 33% 1,4-((bis(3,5-dichloro-2-pyridinyl)oxy))benzene and about 49% of the desired mono compound, i.e., 4-(3,5-dichloro-2-pyridinyloxy)phenol. Reaction of 0.1 mole of the pyridine reactant with 0.2 mole of the hydroquinone and 0.15 mole of the 50% NaOH (added portionwise to the reaction mixture over a period of about 20 minutes) in 80 ml of DMSO at 90°-100° C. for about 5.5 hours resulted in a product yield of about 16.6% of the bis compound named above and about 75.9% of the desired mono compound. Further operations using equimolar amounts of pyridine reactant to hydroquinone reactant (0.4 mole each) and a mole ratio of base to hydroquinone of 2:1 (0.8 mole 50% caustic, 0.4 mole hydroquinone) in 250 ml of DMSO at temperatures of 100°-113° C. for about 2.5 hours resulted in a product yield of only 4% of the bis compound and 84.4% of the desired mono compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH:9]([Mg]Cl)([CH3:11])[CH3:10].[CH3:14][N:15]([CH3:28])[C:16]1(C#N)[CH2:25][CH2:24][C:19]2([O:23]CCO2)[CH2:18][CH2:17]1.[Cl-].[NH4+]>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2([N:15]([CH3:14])[CH3:28])[CH2:17][CH2:18][C:19]([CH2:10][CH2:9][C:11]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)([OH:23])[CH2:24][CH2:25]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: CC(C)[Mg]Cl
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C1(c2ccc(Br)cc2)CCC(O)(CCc2ccccc2)CC1
Reaction time: 8 h

Procedure:
26.6 g 4-bromoiodobenzene were placed in 150 ml diethylether and 47 ml 2.0 molar isopropyl magnesium chloride solution were added dropwise at ambient temperature. After one further hour, 18 g 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile, dissolved in 250 ml diethylether, were added dropwise and stirred overnight. To work up the mixture with ice cooling, 20 ml ammonium chloride solution (20% by weight) were added, extracted three times with 100 ml diethylether in each case, the combined organic phases were dried over sodium sulfate, filtered, concentrated and substantially freed of solvent residues under vacuum. The crude product (21.8 g) obtained was chromatographed with diethylether over silica gel. 7.49 g 4-(4-bromophenyl)-4-dimethylamino-1-phenethylcyclohexanol were obtained as a colorless liquid.
Reaction SMILES: [OH-].[Na+].Cl[C:4]([O:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[C:15]([O:19][C:20](=[O:41])[CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][NH2:40])([CH3:18])([CH3:17])[CH3:16]>O.C(OCC)(=O)C>[C:15]([O:19][C:20](=[O:41])[CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][NH:40][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOCCN
Reactant: O=C(Cl)OC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOCCNC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 487.8 %

Procedure:
Sodium hydroxide (2.0 mL of a 3M in water, 6.0 mmol) and benzoyl chloroformate (0.52 mL, 0.36 mmol) were added in portions to compound 5 (0.90 g, 2.3 mmol) in ethyl acetate (10 mL) and the resulting mixture was stirred overnight. The reaction mixture was concentrated in vacuo, water (20 mL) was added, and the slurry was extracted with CH2Cl2 (3×100 mL), and the combined organic solutions were washed with saturated aq. NaHCO3 (20 mL) and brine (20 mL), and dried over anhydrous MgSO4. The solution was concentrated in vacuo and the residue was loaded onto a silica gel gravity column (100 g) and eluted with CH2Cl2:MeOH 100:1 to 10:1 (v/v) to afford compound 6 as a colorless oil (0.93 g, 76%).
Reaction SMILES: [C:1]1([CH:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:8]2[C:16]3[CH:15]=[C:14]4[O:17][CH2:18][CH2:19][O:20][C:13]4=[CH:12][C:11]=3[CH:10]([C:21]3[C:22]([OH:30])=[CH:23][C:24]4[O:28][CH2:27][CH2:26][C:25]=4[CH:29]=3)[C:9]2=[O:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:38]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:32]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[CH:15]=[C:14]4[O:17][CH2:18][CH2:19][O:20][C:13]4=[CH:12][C:11]=3[C:10]3([CH2:38][O:30][C:22]4[CH:23]=[C:24]5[C:25](=[CH:29][C:21]3=4)[CH2:26][CH2:27][O:28]5)[C:9]2=[O:31])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: O=C1C(c2cc3c(cc2O)OCC3)c2cc3c(cc2N1C(c1ccccc1)c1ccccc1)OCCO3
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2cc3c(cc2C12COc1cc4c(cc12)CCO4)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 6-(diphenylmethyl)-8-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 6′-(diphenylmethyl)-2′,3′,5,6-tetrahydrospiro[benzo[1,2-b:5,4-b′]difuran-3,8′-[1,4]dioxino[2,3-f]indol]-7′(6′H)-one was obtained (67%) as a colorless solid: MS (ES+) m/z 504.0 (M+1).
Reaction SMILES: [C:1]([S@@:5]([NH2:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[Br:8][C:9]1[N:14]=[C:13]([C:15](=O)[CH2:16][CH2:17][O:18][CH3:19])[C:12]([F:21])=[C:11]([Si:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:10]=1>C1COCC1.C(OCC)(=O)C.[Cl-].[Na+].O>[Br:8][C:9]1[N:14]=[C:13](/[C:15](=[N:7]/[S@:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[O:6])/[CH2:16][CH2:17][O:18][CH3:19])[C:12]([F:21])=[C:11]([Si:22]([CH2:27][CH3:28])([CH2:23][CH3:24])[CH2:25][CH3:26])[CH:10]=1
Reactant: CC[Si](CC)(CC)c1cc(Br)nc(C(=O)CCOC)c1F
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC[Si](CC)(CC)c1cc(Br)nc(/C(CCOC)=N/[S@@](=O)C(C)(C)C)c1F
Temperature: 60 °C
Reaction time: 34 h
Yield: 63.5 %

Procedure:
A mixture of titantetraethoxide (11.03 g, 48.4 mmol), (S)-tert.-butylsulfinamide (3.52 g, 29 mmol) and 1-(6-Bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-3-methoxy-propan-1-one (9.1 g, 24.18 mmol) in THF (100 ml) was stirred at 60° C. under a nitrogen atmosphere for 34 hours. The cold reaction mixture was diluted with ethyl acetate and poured onto icecold brine (200 ml) with gentle stirring. The precipitate was filtered through a pad of hyflo and washed with ethyl acetate. The filtrate was diluted with ethyl acetate and washed with brine, dried over sodium sulfate, filtered and evaporated. The crude yellowish-brown oil (10.67 g) was chromatographed over silica gel (Redisep column 120 g, cyclohexane/ethyl acetate 95:5) to give the title compound as a yellow-orange oil. 7.51 g (63.5% yield).
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C:10]([C:12]2([C:15]([F:18])([F:17])[F:16])[CH2:14][CH2:13]2)=[O:11])[CH2:4][CH2:3]1.C1CCN2C(=NCCC2)CC1.Cl[Si:32]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34]>C1COCC1>[F:1][C:2]1([F:19])[CH2:3][CH2:4][CH:5]([CH2:8][CH:9]=[C:10]([C:12]2([C:15]([F:16])([F:17])[F:18])[CH2:13][CH2:14]2)[O:11][Si:32]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34])[CH2:6][CH2:7]1
Reactant: O=C(CCC1CCC(F)(F)CC1)C1(C(F)(F)F)CC1
Reactant: CC[Si](Cl)(CC)CC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC[Si](CC)(CC)OC(=CCC1CCC(F)(F)CC1)C1(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
3-(4,4-Difluorocyclohexyl)-1-(1-trifluoromethylcyclopropyl)propan-1-one (0.200 g, 0.704 mmol) obtained in step 3 was dissolved in THF (2.0 mL). Under ice-cooled condition, DBU (0.117 mL, 0.774 mmol) and chlorotriethylsilane (0.130 mL, 0.774 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with heptane after adding a saturated sodium hydrogen carbonate aqueous solution. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5→90/10) to give {3-(4,4-difluorocyclohexyl)-1-(1-trifluoromethylcyclopropyl)prop-1-enyloxy}triethylsilane (0.253 g, yield 90%).
Reaction SMILES: BrC[CH2:3][C:4]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][C:5]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:21]1([CH2:3][C:4]2[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][C:5]=2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCOC(=O)c1ccc(-c2ccccc2)c(CCBr)c1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccccc2)c(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 50 ml of DMF was dissolved 13.6 g of ethyl 2-(bromoethyl)biphenyl-4-carboxylate, and then a suspension of 50 ml of DMF, 6.2 ml of piperidine, and 9.2 g of potassium carbonate were added thereto under ice cooling, followed by 3 hours of stirring at room temperature. Water was added to the reaction solution, the whole was extracted with ethyl acetate, and the resulting organic layer was dried over anhydrous magnesium sulfate, followed by removal of the solvent by evaporation. The obtained residue was purified by silica gel column chromatography (chloroform:methanol:aqueous ammonia) to obtain 12.6 g of ethyl 2-(piperidin-1-ylmethyl)biphenyl-4-carboxylate as a pale yellow oil.