Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:16][CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH:23]([N:26]=[C:27]=[O:28])([CH3:25])[CH3:24]>ClCCl>[CH:23]([NH:26][C:27]([N:20]1[CH2:21][CH2:22][CH:17]([O:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH:1]4[CH2:2][CH2:3][CH2:4]4)[CH2:11][CH2:10][C:9]=3[CH:12]=2)[CH2:18][CH2:19]1)=[O:28])([CH3:25])[CH3:24]
Reactant: c1cc2c(cc1OC1CCNCC1)CCN(C1CCC1)CC2
Reactant: CC(C)N=C=O
Solvent: ClCCl
Product: CC(C)NC(=O)N1CCC(Oc2ccc3c(c2)CCN(C2CCC2)CC3)CC1

Procedure:
A solution of 3-cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) (150 mg, 0.5 mmol) and isopropyl isocyanate (60 μL, 0.6 mmol) in dichloromethane (5 ml) was stirred at room temperature for 16 hours. The solution was concentrated in vacuo and the residue was purified by column chromatography eluting with dichloromethane then a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title product (E66). MS (ES+) m/e 386 [M+H]+.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][NH2:5].[SH:6][C:7]1[S:8][CH2:9][CH2:10][N:11]=1>C1C=CC=CC=1>[ClH:2].[ClH:1].[NH2:5][CH2:4][CH2:3][S:6][C:7]1[S:8][CH2:9][CH2:10][N:11]=1
Reactant: SC1=NCCS1
Reactant: NCCCl
Agent: Cl
Solvent: c1ccccc1
Product: NCCSC1=NCCS1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
In 100 ml of benzene, 0.1 mol of 2-chloroethylamine hydrochloride and 0.1 mol of 2-mercaptothiazoline were dispersed, gradually heated to 80° C., and stirred for reaction at this temperature for 30 minutes. After completion of the reaction, the reaction mixture was filtered to obtain white 2-(2-aminoethylthio)-thiazoline dihydrochloride powder in a yield of 99.7%. In 100 ml of 36 wt % hydrochloric acid, 23.5 g (0.1 mol) of 2-(2-aminoethylthio)-thiazoline dihydrochloride was dissolved. The resultant solution was refluxed for 30 hours, to obtain cysteamine hydrochloride. Then, the cysteamine hydrochloride was concentrated to dryness under a vacuum and then thoroughly dissolved by heating to a temperature above 80° C. The solution was aspired with a Pasteur pipet 2 mm in mouth diameter and dropped onto a tetrafluoroethylene plate having the opposite side thereof cooled with water to 30° C. The white solid cysteamine hydrochloride heaps consequently deposited on the plate were hemispheres 3 to 5 mm in diameter and 2 to 3 mm in height.
Reaction SMILES: [F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4](O)=[O:5].C(Cl)(=O)C([Cl:13])=O>CN(C=O)C>[F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4]([Cl:13])=[O:5]
Reactant: O=C(O)CC(F)=C(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CC(F)=C(F)F

Procedure:
Reaction of 3,4,4-trifiuoro-3-butenoic acid (IV) with oxalyl chloride in the presence of DMF as a catalyst without any solvent to give 3,4,4-trifluoro-3-butenoyl chloride (V).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:32])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.C[Sn](C)(C)[C:35]1[S:36][CH:37]=[CH:38][N:39]=1>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:35]3[S:36][CH:37]=[CH:38][N:39]=3)[CH:3]=2)=[O:32])=[CH:12][CH:13]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2cccc(I)c2)cc1
Reactant: C[Sn](C)(C)c1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2cccc(-c3nccs3)c2)cc1
Yield: 19.5 %

Procedure:
A mixture of 10 g of N-[3-iodophenyl)-4-(tetradecyloxy)benzeneacetamide, 4.96 g of 2-(trimethylstannyl)thiazole, and 638.62 mg of dichlorobis(triphenylphosphine)palladium (II) in 100 ml of tetrahydrofuran is refluxed under argon for 6 hours. The solvent is evaporated and the residue is partitioned between chloroform and 1N sodium hydroxide. The organic layer is dried and evaporated to a yellow solid residue. The residue is purified by chromatography on silica gel using chloroform. A total of 3.5 g of starting material is recovered as well as impure pro duct which is crystallized from hexane:carbon tetrachloride to give 1.8 g of the desired product as a tan solid, m.p. 128°-131° C.
Reaction SMILES: Br[CH2:2][C:3]([CH3:20])=[CH:4][CH2:5][C:6]1[C:14]([OH:15])=[C:13]2[C:9]([CH2:10][O:11][C:12]2=[O:16])=[C:8]([CH3:17])[C:7]=1[O:18][CH3:19].[P:21]([O:26]C)([O:24][CH3:25])[O:22][CH3:23]>>[CH3:23][O:22][P:21]([CH2:2][C:3]([CH3:20])=[CH:4][CH2:5][C:6]1[C:14]([OH:15])=[C:13]2[C:9](=[C:8]([CH3:17])[C:7]=1[O:18][CH3:19])[CH2:10][O:11][C:12]2=[O:16])(=[O:26])[O:24][CH3:25]
Reactant: COP(OC)OC
Reactant: COc1c(C)c2c(c(O)c1CC=C(C)CBr)C(=O)OC2
Product: COc1c(C)c2c(c(O)c1CC=C(C)CP(=O)(OC)OC)C(=O)OC2
Yield: 55.7 %

Procedure:
A solution of 6-(4-bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one (33 mg, 0.097 mmol) in trimethyl phosphite (1.0 mL, 8.5 mmol) was heated to 100° C. for 1 hour, whereupon complete reaction was indicated by LCMS. The reaction was worked up by removal of the excess of trimethyl phosphite under reduced pressure and the residue was purified by silica gel chromatography using EtOAc-hexanes (20-100%) to provide 20 mg (60%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 1.90 (s, 3H), 2.09 (s, 3H), 2.48 (d, 2H, J=22 Hz), 3.38 (t, 2H, J=6 Hz), 3.64 (d, 6H, J=11 Hz), 3.72 (s, 3H), 5.14 (s, 2H), 5.33 (q, 1H, J=6 Hz), 7.65 (br s, 1H); MS (m/z) 371 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](O)=[O:18])[CH2:15][C:8]=3[CH:7]=[C:6]([Cl:26])[C:5]=2[NH:4][N:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[NH:60]1[CH2:65][CH2:64][CH:63]([N:66]2[C:74]3[C:69](=[N:70][CH:71]=[CH:72][CH:73]=3)[NH:68][C:67]2=[O:75])[CH2:62][CH2:61]1>CN(C)C=O>[Cl:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:23])[F:24])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](=[O:18])[N:60]4[CH2:61][CH2:62][CH:63]([N:66]5[C:74]6[C:69](=[N:70][CH:71]=[CH:72][CH:73]=6)[NH:68][C:67]5=[O:75])[CH2:64][CH2:65]4)[CH2:15][C:8]=3[CH:7]=[C:6]([Cl:26])[C:5]=2[NH:4][N:3]=1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]nc(Cl)c3c2CN(CC(F)(F)F)C1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C[C@@H]1Cc2cc(Cl)c3[nH]nc(Cl)c3c2CN(CC(F)(F)F)C1=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
(S)-2-(1,4-Dichloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (110 mg, 0.268 mmol) was dissolved in N,N-dimethylformamide (2.0 ml). N,N-Diisopropylethylamine (150 μl, 0.861 mmol) was added to the mixture followed successively by TBTU (92 mg, 0.287 mmol) and 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one dihydrochloride (92 mg, 0.316 mmol). Reaction stirred at room temperature for 5 hours. Reaction was quenched with 50% acetonitrile-water. Material was purified by prep HPLC (water-acetonitrile-trifluoroacetic acid). Acetonitrile was removed from the fractions by roto-vap. Remaining aqueous was made basic with aqueous sodium bicarbonate. Material was extracted twice with ethyl acetate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 70% yield. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.89 (s, 1H) 11.55 (s, 1H) 7.90 (dd, J=5.19, 1.22 Hz, 1 H) 7.64 (dd, J=70.19, 7.93 Hz, 1H) 7.35 (s, 1H) 6.99 (dd, J=7.78, 5.34 Hz, 0.4H) 6.90 (dd, J=7.93, 5.19 Hz, 0.6H) 5.44 (d, J=4.88 Hz, 2H) 4.35-4.62 (m, 3H) 3.95-4.32 (m, 3H) 3.15-3.28 (m, 2H) 2.85-3.12 (m, 2H) 2.61-2.76 (m, 1H) 2.20-2.47 (m, 2H) 1.93-2.12 (m, 1H) 1.64-1.87 (m, 2H). High resolution MS m/e (M+H)+=610.1328.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][NH2:16].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:16][CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CCCC1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCC1CCCN1C(=O)OC(C)(C)C
Reaction time: 72 h
Yield: 88.8 %

Procedure:
To a suspension of 2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.68 g) in methanol (30 mL) was added a solution of methylamine (0.83 g) in methanol (3 mL). The reaction mixture was stirred for 72 hours and then sodium borohydride (0.76 g) and molecular sieves were added. After stirring for 2 hours, the reaction mixture was filtered and the filtrate reduced in vacuo. The residue was re-dissolved in dichloromethane (30 mL), washed with saturated sodium bicarbonate solution (30 mL), brine (30 mL), dried (MgSO4) and reduced in vacuo to give 2-methylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.56 g). To a solution of 2-methylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.50 g) in dichloromethane (10 mL) was added triethylamine (0.36 mL) followed by methanesulfonyl chloride (0.20 mL). After stirring for 3 hours the reaction mixture was diluted with dichloromethane, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to yield 2-[(methanesulfonyl-methyl-amino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a white solid (0.63 g). Treatment of this compound with HCl in dichloromethane/methanol yielded N-methyl-N-pyrrolidin-2-ylmethyl-methanesulfonamide hydrochloride (0.49 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:12]=[C:13]([OH:23])[C:14]3[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=3[N:16]=1)[N:6]=[C:5]2[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31].[F:32][C:33]([F:38])([F:37])[CH2:34][CH2:35]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:12]=[C:13]([O:23][CH2:35][CH2:34][C:33]([F:38])([F:37])[F:32])[C:14]3[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=3[N:16]=1)[N:6]=[C:5]2[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31]
Reactant: OCCC(F)(F)F
Reactant: CC1(C)C(=O)Nc2nc(-n3nc(Cc4ccccc4F)c4cc(F)ccc43)nc(O)c21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)C(=O)Nc2nc(-n3nc(Cc4ccccc4F)c4cc(F)ccc43)nc(OCCC(F)(F)F)c21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Under argon, 80 mg (0.19 mmol) of the compound from example 31 was largely dissolved in 2 ml THF, 32.5 mg (0.29 mmol) of 3,3,3-trifluoropropan-1-ol, 75 mg (0.29 mmol) of triphenyl phosphine and 56 μl (0.29 mmol) of diisopropyl azodicarboxylate were added and it was stirred for 3 d at RT. A further 11 mg (0.01 mmol) of 3,3,3-trifluoropropan-1-ol, 25 mg (0.01 mmol) of triphenyl phosphine and 19 μl (0.01 mmol) of diisopropyl azodicarboxylate were added and it was stirred for 1 d at RT. The reaction mixture was concentrated by evaporation and the residue was purified by preparative HPLC (Reprosil C18, gradient of acetonitrile/0.01% aq. formic acid). Yield: 48 mg (49% of theor.)
Reaction SMILES: [CH3:1][C:2]([C:4]1[O:8][CH:7]=[CH:6][C:5]=1O)=[O:3].P(Cl)(Cl)(Cl)(Cl)[Cl:11].O>C(Cl)Cl>[C:2]([C:4]1[O:8][CH:7]=[CH:6][C:5]=1[Cl:11])(=[O:3])[CH3:1]
Reactant: CC(=O)c1occc1O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1occc1Cl
Reaction time: 1 h

Procedure:
Isomaltol (6.3 g, 0.05 moles) in 60 ml of CH2Cl2 was added dropwise over 10 minutes to a solution of PCl5 (10.4 g, 0.05 moles) in 125 ml of CH2Cl2 at 4° C. After stirring at 4°-5° C. for 1 hour, the reaction was allowed to come to room temperature, poured into 350 ml of water and the CH2Cl2 layer separated. The aqueous layer was then extracted with CH2Cl2, the CH2Cl2 layers combined and then concentrated to yield a dark oil, 7.0 g. Pure 2-acetyl-3-chloro-furan was obtained by chromatography from silica gel, NMR (CDCl3, δ) 7.5 (1H, d, J=2Hz), 6.56 (1H, d, J=2Hz), 2.53 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:13]=[N:12]1.[NH2:22][C:23]1[C:24]([O:38][CH3:39])=[C:25]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:26]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:28]=1>>[C:29]([C:27]1[CH:26]=[C:25]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:24]([O:38][CH3:39])=[C:23]([NH:22][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]([N:11]3[CH:15]=[C:14]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:13]=[N:12]3)[CH:4]=2)[CH:28]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: O=C(O)c1ccc(F)c(-n2cc(-c3cccnc3)nn2)c1
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COc1c(NC(=O)c2ccc(F)c(-n3cc(-c4cccnc4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 5 was prepared by coupling 4-fluoro-3-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzoic acid with N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide in the same manner as Example 1. ESI MS m/z 539 [C26H27FN6O4S+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])=[CH:10][CH:9]=2)[C:5]2[CH:22]=[C:23]([C:26]3[N:30]([CH3:31])[C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[N:27]=3)[CH:24]=[CH:25][C:4]=2[N:3]=1.[N-:36]=[N+:37]=[N-:38].[Na+]>CN(C)C=O>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[NH:38][N:37]=[N:36][N:21]=3)=[CH:12][CH:13]=2)[C:5]2[CH:22]=[C:23]([C:26]3[N:30]([CH3:31])[C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[N:27]=3)[CH:24]=[CH:25][C:4]=2[N:3]=1
Reactant: Cc1nc2ccc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2ccc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 41 from 4'-[[2-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12](=[O:26])[CH:11]([CH3:27])[CH2:10]1.Br[CH2:29][CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:32]([O:31][CH2:30][CH2:29][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:17][CH:16]=2)[C:12](=[O:26])[CH:11]([CH3:27])[CH2:10]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC1CC(c2c(O)cccc2F)N(Cc2ccc(OC(F)(F)F)cc2)C1=O
Reactant: BrCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CC(c2c(F)cccc2OCCOCc2ccccc2)N(Cc2ccc(OC(F)(F)F)cc2)C1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 5-(2-fluoro-6-hydroxyphenyl)-3-methyl-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one (preparation described in example 413; 50 mg; 0.13 mmol), ((2-bromoethoxy)methyl)benzene (28 mg; 0.13 mmol), potassium carbonate (36 mg; 0.26 mmol), and cesium carbonate (8.5 mg; 0.026 mmol) in anh. DMF (0.7 ml) was stirred at rt, under nitrogen, for 17 h. Water was added, and the separated aq. layer was extracted with Et2O. The mixed organic layers were washed with water, dried over anh. MgSO4, filtered and concentrated to dryness under reduced pressure affording 5-(2-(2-(benzyloxy)ethoxy)-6-fluorophenyl)-3-methyl-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one. LC-MS (conditions A): tR=1.04 min.; [M+H]+: 518.47 g/mol. A mixture of 5-(2-(2-(benzyloxy)ethoxy)-6-fluorophenyl)-3-methyl-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one 55 mg; 0.10 mmol), and platinum (IV) oxide hydrate PtO2 (24 mg; 0.10 mmol) in anh. MeOH (2 ml) was stirred at rt, under hydrogen atmosphere (1 atm), for 16 h. Filtration over a pad of celite, concentration to dryness under reduced pressure, and subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 427.92 g/mol.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[F:32])[S:15]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([S:15]([CH:14]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8])(=[O:17])=[O:16])=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCCCCO)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In tetrahydrofuran (30 ml) was dissolved 2-[6-(t-butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]hexyl]-1,4-difluorobenzene (0.70 g, 1.4 mmol). Under ice cooling, a tetrahydrofuran solution (1.0M, 4.2 ml, 4.2 mmol) of tetrabutylammonium fluoride was added and the mixture was stirred at room temperature for 1 hour. After addition of water (1.0 ml) to the reaction mixture, the mixture was concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=3:2) to yield a white solid. The resulting white solid was washed with hexane, whereby the title compound (0.47 g, 86%) was obtained as a white powder.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH:10]([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12])[CH2:5]1.[H][H].O>CN(C)C=O>[CH2:7]([C:10]([CH:6]1[CH2:7][CH2:8][CH2:9][CH:4]([CH3:3])[CH2:5]1)([C:11]([O:13][CH3:14])=[O:12])[C:15]([O:17][CH3:18])=[O:16])[CH2:8][CH2:9][CH2:4][CH:5]=[CH2:6]
Reactant: COC(=O)C(C(=O)OC)C1CCCC(C)C1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCCCC(C(=O)OC)(C(=O)OC)C1CCCC(C)C1

Procedure:
To a slurry of sodium hydride (2.53 g, 0.06 mol) in anhydrous N,N-dimethylformamide (50 mL) was added dropwise dimethyl 2-(3-methylcyclohexyl)-malonate (14.46 g, 0.06 mol). After complete addition, the reaction was stirred until no more hydrogen gas was evolved. To the reaction was then added dropwise 1-bromo-6-hexene (10.33 g, 0.06 mol) followed by stirring. The progress of the reaction was followed by analytical chromatography using silica plates and ethyl acetate:hexanes (40:60). After complete reaction, water (20 mL) was added and most of the solvents removed under high vacuum. The remaining material was partitioned between water and ether and the ether layer washed twice with water. The ether solution was dried with MgSO4 and evaporated to give a thick yellow oil. The product was then distilled at 127-134° C. and 0.4 mm pressure to give clear oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:21](Br)[C:22]#[CH:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:11]=2)=[CH:3][C:2]=1[O:1][CH2:23][C:22]#[CH:21]
Reactant: C#CCBr
Reactant: COC(=O)Cc1cccc(-c2ccc(OC)c(O)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#CCOc1cc(-c2cccc(CC(=O)OC)c2)ccc1OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
207 mg methyl (3′-hydroxy-4′-methoxybiphenyl-3-yl)acetate was dissolved in 3 ml N,N-dimethylformamide, 0.17 ml propargyl bromide and 150 mg potassium carbonate were added thereto, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate and washed with 1 N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography, to give 221 mg of the title compound in the 4:1 hexane-ethyl acetate fraction.
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]=O)=[CH:15][CH:16]=1.[BH4-].[Na+]>CCO>[CH2:1]([NH:8][CH2:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C=CCCCCCN
Reactant: COc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C=CCCCCCNCc1ccc(OC)cc1
Temperature: 25 °C
Yield: 57.6 %

Procedure:
A solution of hept-6-enylamine (2.0 g, 13.4 mmol) and anisaldehyde (1.79 mL, 14.7 mmol) in EtOH (50 mL) was stirred at room temperature for 1 h. Then, NaBH4 (556 mg, 14.7 mmol) was added at 0° C. under nitrogen. The resulting solution was allowed to warm up to room temperature for 4 h. Then, the reaction mixture was partitioned between ice-cold water and CH2Cl2, washed with brine, dried (Na2SO4) and evaporated. The residue was purified by chromatography (gradient AcOEt/CH2Cl2 0:1 to 2:8, then CH2Cl2/MeOH 9:1) to give 1.8 g (34%) of the title product 86 as a colorless oil: m/z=234 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:8]([C:9]([O:11]C)=O)=[CH:7][N:6]=[CH:5][CH:4]=1.[C:15](=[N:20]O)([NH2:19])[CH:16]([CH3:18])[CH3:17].[O-]CC.[Na+]>C(O)C>[CH:16]([C:15]1[N:20]=[C:9]([C:8]2[CH:7]=[N:6][CH:5]=[CH:4][C:3]=2[C:2]([F:1])([F:14])[F:13])[O:11][N:19]=1)([CH3:18])[CH3:17]
Reactant: COC(=O)c1cnccc1C(F)(F)F
Reactant: CC(C)C(N)=NO
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)c1noc(-c2cnccc2C(F)(F)F)n1
Temperature: 0 °C

Procedure:
2 g of methyl 4-trifluoromethylnicotinate and 1.56 g of isobutyramide oxime were initially charged in 15 ml of ethanol and cooled to 0° C. 10 ml of a 1.2 molar sodium ethoxide solution were added dropwise to this solution. The mixture was allowed to warm to room temperature over a period of two hours and stirring was then continued at this temperature until the reaction, according to TLC, had ended. The reaction mixture was concentrated and the residue was taken up in saturated ammonium chloride solution and extracted with diethyl ether. Chromatographic purification of the crude product gave the desired compound as a yellowish oil.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:7][C@@H:6]2[C@@H:8]([OH:11])[CH2:9][O:10][C@@H:5]2[C@@H:4]1[OH:12].[CH:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=1>CN(C=O)C>[CH2:19]([O:12][CH:4]1[CH:5]2[O:10][CH2:9][CH:8]([OH:11])[CH:6]2[O:7][CH2:3]1)[C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC1COC2C(OCc3ccccc3)COC12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
To a suspension of NaH (60% mineral oil suspension, 3.28 g, 82.1 mmol) in DMF (135 mL) at 0° C. was added a solution of isobide (10.00 g, 68.4 mmol) in DMF (10 mL) dropwise. After addition, the reaction mixture was stirred at 0° C. for 30 min, then BnBr (14.04 g, 82.1 mmol) was added too. The resulting mixture was allowed to stir at rt overnight and concentrated in vacuo. The residue was dissolved in water (100 mL), and extracted with EtOAc (200 mL×3). The combined organic phases were washed with brine (200 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/10) to give the title compound as yellow oil (10.36 g, 64.1%).