Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[NH:11][C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[N:15]=[C:14]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:13]=2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CN(C=O)C.CCOC(C)=O>[CH3:8][O:9][C:10]1[N:11]([CH2:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[N:15]=[C:14]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:13]=2
Reactant: CCCCCNc1nc(N)c2nc(OC)[nH]c2n1
Reactant: BrCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCNc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.6 %

Procedure:
To a solution of 8-methoxy-N2-pentyl-9H-purine-2,6-diamine trifluoroacetic acid salt (223 mg) in dry DMF (3.85 mL) was added potassium carbonate (339 mg) at 60° C. and the mixture was stirred for 90 mins. The mixture was cooled to room temperature and 4-(bromomethyl)tetrahydro-2H-pyran (121 mg) was added in one portion. The reaction was stirred at 50° C. overnight and was then cooled and taken up in EtOAc (20 mL). The organics were washed with water (2×10 mL), separated, dried over MgSO4, filtered and concentrated in vacuo to give an off-white solid. The crude material was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluent (20-60%) to afford the title compound as an off-white solid (140 mg).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.O>CN(C=O)C>[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([N:8]([CH:9]2[CH2:10][CH2:11]2)[S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1NC1CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(c2ccc(Cl)cc2[N+](=O)[O-])C2CC2)cc1
Temperature: 25 °C
Yield: 60.9 %

Procedure:
To a suspension of sodium hydride (60%, 0.10 g (2.50 mmol)) in DMF (3.0 ml), 4-chloro-N-cyclopropyl-2-nitroaniline (0.40 g (1.88 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, p-toluenesulfonyl chloride (0.38 g (1.99 mmol)) was added. After one hour's stirring at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography with ethyl acetate-hexane (1:3) as eluent, to give 0.42 g (61%) of the title compound as yellow crystals
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Cl:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][CH:20]2[CH3:25]>>[Cl:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][N:19]([C:11]([C:9]1[CH:10]=[C:5]3[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]3[N:8]=1)=[O:13])[CH:20]2[CH3:25]
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2c(Cl)cccc21
Product: CC1c2cccc(Cl)c2CCN1C(=O)c1cc2ncc(Cl)cn2n1
Yield: 61 %

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Chloro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Reaction SMILES: [C:1]([O-:14])(=[O:13])[CH2:2][CH2:3][CH2:4]CCCCCCCC.[C:15]([O-:28])(=[O:27])[CH2:16]CCCCCCCCCC.C([Sn+2]CCCC)CCC.C1C=CC(C(N=C=O)N=C=O)=CC=1.C1C(CC2C=CC(N=C=O)=CC=2)=CC=C(N=C=O)C=1.[O:70]1[CH2:74][CH2:73][CH2:72][CH2:71]1>>[CH2:4]([OH:27])[CH2:3][CH2:2][CH2:1][OH:14].[C:74]([OH:70])(=[O:13])[CH2:73][CH2:72][CH2:71][CH2:16][C:15]([OH:28])=[O:27]
Reactant: C1CCOC1
Reactant: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: O=C=NC(N=C=O)c1ccccc1
Agent: O=C=Nc1ccc(Cc2ccc(N=C=O)cc2)cc1
Product: O=C(O)CCCCC(=O)O
Product: OCCCCO
Temperature: 60 °C

Procedure:
0.5 g of dibutyltin dilaurate was added to a 60% strength by weight solution of 112.0 g of toluylene diisocyanate and 158.3 g of diphenylmethane 4,4'-diisocyanate in tetrahydrofuran, and the mixture was then heated to 60° C. At this temperature, a 60% strength by weight solution of 390 g of a polyesterol obtained from 1,4-butanediol and adipic acid and having a molecular weight of 1000, 167.5 g of a polyesterol obtained from 1,6-hexanediol, adipic acid and terephthalic acid, 29.4 g of polydimethylsiloxane having hydroxyl functional groups and a molecular weight of 900, 3.17 g of trimethylolpropane, 3.13 g of methyldiethanolamine, 72 g of diethoxylated bisphenol A and 27 g of 1,6-hexanediol in tetrahydrofuran was metered in over 2 hours.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8].[C:17]([O-])([O-])=O.[K+].[K+].CI>CN(C)C=O.O>[CH3:17][NH:8][C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[CH2:5][O:4][C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[CH3:1]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccccc1OCc1ccccc1N
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CNc1ccccc1COc1ccccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A mixture of 5 g (23 mmol) of 2-(2'-methylphenoxymethyl)-aniline (Example 1b), 5 g (36 mmol) of K2CO3 and 3.4 g (24 mmol) of methyl iodide in 50 ml of dimethylformamide is stirred overnight at room temperature. The reaction mixture is diluted with water and the aqueous phase is extracted three times with methyl tert-butyl ether. The combined organic phases are extracted with water, dried over MgSO4 and evaporated down. The residue is purified chromatographically using mixtures of hexane and methylene chloride. There is obtained 3.0 g (70% purity, about 40% yield) of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=2)[N:3]=1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(=O)C.CO>[CH:17](=[N:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=2)[N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)c1cccc(N2CCC(N)=N2)c1
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)c1cccc(N2CCC(N=Cc3ccccc3)=N2)c1
Reaction time: 4 h

Procedure:
3-Amino-1-(3-t-butylphenyl)-2-pyrazoline (500 mg) was reacted with benzaldehyde (500 mg) in boiling methanol (5 ml) in the presence of glacial acetic acid (1 drop). After some 4 hours, the mixture was cooled and 3-benzylideneamino-1-(3-t-butylphenyl)-2-pyrazoline separated in crystals m.p. 140°-141°, (yield 500 mg).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:14]([CH2:15][OH:16])[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:7])(C)(C)C.ClC(Cl)(Cl)C(=N)O[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.FC(F)(F)S(O)(=O)=O>C1CCCCC1.ClCCl>[CH2:32]([O:16][CH2:15][CH:14]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:8]1[C:6]([OH:5])=[O:7])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1ccc(S(=O)(=O)N2CCCCC(CO)C2C(=O)OC(C)(C)C)cc1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: COc1ccc(S(=O)(=O)N2CCCCC(COCc3ccccc3)C2C(=O)O)cc1
Temperature: 0 °C

Procedure:
To a solution of 3-Hydroxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid tert-butyl ester (110 mg, 0.275 mmoL) in 3.9 mL cyclohexane and 1.95 mL of dichloromethane was added benzyl trichloracetimidate (0.1 mL, 0.55 mmoL). The solution was cooled to 0° C. and trifluoromethane sulfonic acid (0.008 mL, 0.091 mmoL) was added in. After 2.5 hours the reaction was filtered and the cake was washed with a 2:1 solution of cyclohexane and dichloromethane, the solvent was evaporated under reduced pressure and the residue was taken up in ethyl acetate. The solution was washed sequentially with dilute sodium bicarbonate and brine. The organic layer was dried over anhyrous magnesium sulfate, filtered, and the solvent evaporated under reduced pressure. The residue was purified by column chromatography (silica: 30% ethyl acetate in hexanes to 5% methanol in dichloromethane) to yield 3-Benzyloxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid; MS: (M+H)+ =434, (M-H)- =432.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][C:5]2=[C:8]([O:23][CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[N:4]2[N:3]=1.CN(C)C=O.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.[NH2:58][C:59]1[CH:64]=[CH:63][C:62]([CH:65]2[CH2:70][CH2:69][N:68]([CH2:71][C:72]([NH2:74])=[O:73])[CH2:67][CH2:66]2)=[CH:61][C:60]=1[O:75][CH3:76]>>[CH3:21][S:18]([N:17]([CH3:22])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[N:4]2[C:5]([CH:6]=[N:7][C:2]([NH:58][C:59]3[CH:64]=[CH:63][C:62]([CH:65]4[CH2:70][CH2:69][N:68]([CH2:71][C:72]([NH2:74])=[O:73])[CH2:67][CH2:66]4)=[CH:61][C:60]=3[O:75][CH3:76])=[N:3]2)=[C:8]([O:23][CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[CH:9]=1)(=[O:20])=[O:19]
Reactant: COc1cc(C2CCN(CC(N)=O)CC2)ccc1N
Reactant: CN(c1ccccc1-c1cc(OCOCC[Si](C)(C)C)c2cnc(O)nn12)S(C)(=O)=O
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1cc(C2CCN(CC(N)=O)CC2)ccc1Nc1ncc2c(OCOCC[Si](C)(C)C)cc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
1259h. Into a 8-dram vial, N-{2-[2-Hydroxy-5-(2-trimethylsilanyl-ethoxymethoxy)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methanesulfonamide (9.0E1 mg, 0.19 mmol), N,N-Dimethylformamide (0.70 mL, 9.0 mmol) N,N-Diisopropylethylamine (0.101 mL, 0.581 mmol) and N-Phenylbis(trifluoromethanesulphonimide) (83.0 mg, 0.232 mmol) were added. The reaction mixture was stirred at room temperature for one hour. 2-[4-(4-Amino-3-methoxy-phenyl)-piperidin-1-yl]-acetamide (102 mg, 0.387 mmol) was added. The reaction was heated at 120° C. for 3 hours. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with DCM and NH3 in methanol as eluant (2 to 15% NH3 in methanol). The collected fractions afforded 2-(4-{4-[7-[2-(Methanesulfonyl-methyl-amino)-phenyl]-5-(2-trimethylsilanyl-ethoxymethoxy)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-3-methoxy-phenyl}-piperidin-1-yl)-acetamide as a red oil (89 mg, 65%)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[NH2:16])=[O:14])[CH3:2].CO.[CH:21](=O)[CH3:22]>O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[N:16]=[CH:21][CH3:22])=[O:14])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Reactant: CC=O
Solvent: O
Solvent: CO
Product: CC=NN(C)C(=O)C(=O)c1c(CC)cc(C)cc1CC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a test tube (outside diameter 21 mmφ×overall length 160 mm), 100 mg of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39), 380 mg of methanol and 45 μl of acetaldehyde were added and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and the resultant was extracted with chloroform three times. The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 103 mg of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-ethylidene-1-methylhydrazine ((40-b)-(15)-2).
Reaction SMILES: CCOP(O/[N:10]=[C:11](/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)\C#N)(OCC)=S.C(N(C(C)C)CC)(C)C.[CH3:29][C:30]1[N:35]=[CH:34][C:33]([C:36]([N:38]2[CH2:42][CH2:41][C@@H:40]([NH2:43])[CH2:39]2)=[O:37])=[CH:32][CH:31]=1.C(N)C1C=CC=CC=1.[N-]=[C:53]=[O:54]>>[CH2:11]([NH:10][C:53]([NH:43][C@@H:40]1[CH2:41][CH2:42][N:38]([C:36]([C:33]2[CH:34]=[N:35][C:30]([CH3:29])=[CH:31][CH:32]=2)=[O:37])[CH2:39]1)=[O:54])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1ccc(C(=O)N2CC[C@@H](N)C2)cn1
Reactant: CCOP(=S)(OCC)O/N=C(\C#N)c1ccccc1
Reactant: [N-]=C=O
Solvent: NCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N2CC[C@@H](NC(=O)NCc3ccccc3)C2)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Phoxime resin (Aldrich Chemical Co.) (0.077 g, 0.14 mmol) was added to a glass reaction vessel and treated with diisopropylethylamine (0.016 g, 0.12 mmol, in 0.75 mL of methylene chloride) and (3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-amine (0.013 g, 0.06 mmol, in 1.3 mL of methylene chloride). The mixture was shaken for 18 hours at room temperature to afford a resin-bound oximecarbamate intermediate that was washed with methylene chloride (3 mL). Benzylamine (0.14 mmol, in 0.6 mL of toluene) and diisopropylethylamine (0.14 mmol, in 0.75 mL of toluene) were added to the resin which was then heated to 80° C. and shaken for 18 hours. The reaction mixture was filtered and the filtrate was treated with PS-isocyanate resin (Argonaut Technologies, 0.148 g, 0.18 mmol) for 4 hours at room temperature to remove unreacted benzylamine. The product was separated from the resin by filtration and purified by HPLC as described above.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)([CH3:16])[C:12]([O:14]C)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)([CH3:16])[C:12]([OH:14])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(C)(CCNC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCC(C)(C(=O)O)c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 98.9 %

Procedure:
Methyl 4-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)-2-methylbutanoate (720 mg, 2.11 mmol) was dissolved in THF (4.2 mL) and water (1.8 mL). The mixture was treated with LiOH—H2O (265 mg, 6.32 mmol) and allowed to stir overnight to completion by LCMS analysis. The mixture was diluted with water and washed twice with diethyl ether (discarded). The aqueous was treated with 3M HCl solution until a pH of about 2 to about 3 (white ppt) and extracted with ethyl acetate several times. The combined organic portions were washed with water, then brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to afford 4-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)-2-methylbutanoic acid as a colorless oil (684 mg, 99%). LCMS (APCI+) [M+H]+ 326.0; Rt: 2.26 min.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12](O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:16]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:17]1[O:19][CH2:18]1>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[OH:19][CH:17]([CH2:16][O:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:18][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:18][CH:17]([OH:19])[CH2:16][O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cc2ccc(O)cc2)cc1
Reactant: CCCCOCC1CO1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Product: CCCCOCC(O)Cc1ccc(Cc2ccc(CC(O)COCCCC)cc2)cc1

Procedure:
bis(p-Hydroxyphenyl)methane (153 g; 67% pure, containing polynuclear homologues), butyl glycidyl ether (232.5 g), and benzyltrimethylammonium chloride (3.85 g) were stirred and heated slowly to 100°, when a mildly exothermic reaction commenced and the temperature rose to 110°. The mixture was kept at 110° for 41/2 hours, 120° for 1 hour, and 150° for 11/2 hours. The product had an epoxy value of 0.19 equiv./kg.
Reaction SMILES: [H-].[Na+].[C:3]1(C(Cl)=O)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)C=[CH:5][CH:4]=1.O.C[CH2:18][O:19][C:20]([CH3:22])=[O:21].C[N:24](C=O)C>>[CH3:5][C:4]1[NH:24][C:7]2[C:12]([C:3]=1[CH2:22][C:20]([O:19][CH3:18])=[O:21])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CCOC(C)=O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)Cc1c(C)[nH]c2ccccc12
Reaction time: 16 h
Yield: 43 %

Procedure:
The compound of step 1 (1.13g; 5.56 mmol) in 6 mL of DMF was treated with NaH 80% (0.18 g; 5.99 mmol) at 25° C. After 30 min a solution of 1-naphthoyl chloride in 5 mL of DMF was added dropwise The reaction mixture was left stirring for 16 h and poured into cold water-EtOAc. The organic phase was washed with H2O (2×15 mL) and brine, dried over Na2SO4 and the solvent removed. Chromatography on silica gel (eluted with 2% EtOAc in toluene) yielded 0.86 g (43%) of the title compound. 1H NMR (CDCL3, 400 MHZ) Δ2.20 (S, 3H), 3.67 (S, 3H), 7.0 (M, 1H), 7.10-7.26 (M, 3H), 7.45-7.60 (M, 5H), 7.95 (M, 1H) AND 8.07 (M, 3H).
Reaction SMILES: IC1C=CN(CC[C@@](C)(S(C)(=O)=O)C(NO[C@@H]2CCCCO2)=O)C(=O)C=1.CC1(C)C(C)(C)OB(C2C=CC(OC[C@H]3CC[C@H](OC4CCCCO4)CC3)=CC=2)O1.[CH3:57][C@@:58]([S:99]([CH3:102])(=[O:101])=[O:100])([CH2:69][CH2:70][N:71]1[CH:76]=[CH:75][C:74]([C:77]2[CH:82]=[CH:81][C:80]([O:83][CH2:84][C@H:85]3[CH2:90][CH2:89][C@@H:88]([O:91][CH:92]4[CH2:97][CH2:96][CH2:95][CH2:94][O:93]4)[CH2:87][CH2:86]3)=[CH:79][CH:78]=2)=[CH:73][C:72]1=[O:98])[C:59]([NH:61][O:62][CH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][O:64]1)=[O:60]>>[CH3:57][C@@:58]([S:99]([CH3:102])(=[O:100])=[O:101])([CH2:69][CH2:70][N:71]1[CH:76]=[CH:75][C:74]([C:77]2[CH:82]=[CH:81][C:80]([O:83][CH2:84][C@H:85]3[CH2:90][CH2:89][C@H:88]([O:91][CH:92]4[CH2:97][CH2:96][CH2:95][CH2:94][O:93]4)[CH2:87][CH2:86]3)=[CH:79][CH:78]=2)=[CH:73][C:72]1=[O:98])[C:59]([NH:61][O:62][CH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][O:64]1)=[O:60]
Reactant: C[C@@](CCn1ccc(-c2ccc(OC[C@H]3CC[C@@H](OC4CCCCO4)CC3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: CC1(C)OB(c2ccc(OC[C@H]3CC[C@H](OC4CCCCO4)CC3)cc2)OC1(C)C
Agent: C[C@@](CCn1ccc(I)cc1=O)(C(=O)NO[C@@H]1CCCCO1)S(C)(=O)=O
Product: C[C@@](CCn1ccc(-c2ccc(OC[C@H]3CC[C@H](OC4CCCCO4)CC3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O

Procedure:
The title compound (489 mg, 49.7%) was prepared from (2R)-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-[(2R)-tetrahydro-2H-pyran-2-yloxy]butanamide (742 mg, 1.49 mmol) and 2-[(trans-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclohexyl)oxy]tetrahydro-2H-pyran (620 mg, 1.49 mmol) by a procedure analogous to that described for (2R)-2-methyl-2-(methylsulfonyl)-4-[2-oxo-4-(4-{[cis-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}phenyl)pyridin-1(2H)-yl]-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, Example 8, Step E. LCMS m/z 659.8 (M−1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.O[CH2:23][C:24]1[N:25]([S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2>C(Cl)Cl>[Br:20][CH2:23][C:24]1[N:25]([S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2
Reactant: BrBr
Reactant: Cc1ccc(S(=O)(=O)n2c(CO)cc3ccccc32)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2c(CBr)cc3ccccc32)cc1
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution of triphenylphosphine (20.2 g, 77 mmol) in dry CH2Cl2 (80 mL) was added dropwise a solution of bromine (11.9 g, 77 mmol) in dry CH2Cl2 (40 mL). The stirring was continued for one hour and then a solution of compound of step 2 (23.2 g, 77 mmol) in dry CH2Cl2 (40 mL) was added dropwise. The resulting mixture left stirring for 12 hours. After removing the solvent the residue was taken up in ethyl acetate and washed with water. The organic extract was dried over MgSO4 and the solvent evaporated in vacuo. The residue was chromatographed over silica gel using toluene as eluant to give a yellow oil (21.0 g, 75%); IR (film) 1600 cm-1, MS ((70 eV): m/z 363 (M+,12.6), 129 (100).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[O:6]=[C:7]1[CH2:27][CH2:26][C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9][CH2:8]1.[Cl:28][CH2:29]Cl>CN(C)C=O.C(OCC)(=O)C>[Cl:28][C:29]1[CH2:8][CH2:9][C:10]2([CH2:11][CH2:12][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:14][CH2:15]2)[CH2:26][C:27]=1[CH:7]=[O:6]
Reactant: ClCCl
Reactant: O=C1CCC2(CC1)CCN(C(=O)OCc1ccccc1)CC2
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: O=CC1=C(Cl)CCC2(CCN(C(=O)OCc3ccccc3)CC2)C1
Reaction time: 8 h

Procedure:
Phosphorus oxychloride (2.33 mL) was added dropwise to a cooled (0° C.) solution of EXAMPLE 265D (7.5 g) in N,N-dimethylformamide (10 mL) and dichloromethane (30 mL). The mixture was then stirred overnight before it was diluted with ethyl acetate (300 mL) and washed with aqueous sodium acetate, water (3×), and brine and dried over Na2SO4. After filtration and concentration, the crude product was used directly in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].F[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:23][C:21]1[CH:20]=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([CH:22]=1)[NH:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2ccccc12
Temperature: 50 °C
Reaction time: 1.17 h
Yield: 44.9 %

Procedure:
Ethyl 2-aminobenzo[b]thiophene-3-carboxylate (69.3 g) and 2,4-difluoronitrobenzene (50 g) were dissolved in dimethyl sulfoxide (550 Ml) and heated to 50° C. Thereto was added potassium carbonate (63 g) and the mixture was stirred at 100° C. for 70 min. After cooling, the reaction mixture was allowed to cool to 70° C. and poured into water (2.5 L). The reaction mixture was allowed to stand still, and filtered. The filtrated orange crystals were washed with ethyl acetate to give ethyl 2-(5-fluoro-2-nitroanilino)benzo[b]thiophene-3-carboxylate (50.7 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([OH:12])=O)[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.ClC(OCC)=O.[C:26]1([CH:32]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:33]2[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH2:35][CH2:34]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][N:36]2[CH2:37][CH2:38][N:33]([CH:32]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:34][CH2:35]2)=[O:12])[CH:5]=[N:6][CH:7]=1
Reactant: NCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=C(O)C=Cc1cncc(F)c1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(C=Cc1cncc(F)c1)NCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 2 h
Yield: 36.6 %

Procedure:
To a stirred suspension of 0.29 g of 3-(5-fluoro-3-pyridyl)acrylic acid in 15 ml of dry tetrahydrofuran, 0.24 g of triethylamine is added at room temperature. The resulting solution is cooled to between -10° C. and -5° C., and a solution of 0.25 g of ethyl chloroformate in 2 ml of tetrahydrofuran is added slowly. After the mixture is stirred at the same temperature for 2 hours, a solution of 0.75 g of 4-(4-diphenylmethyl-1-piperazinyl)butylamine in 2 ml of dry tetrahydrofuran is added. The mixture is stirred for 1 hour at between -10° C. and -5° C. and then at room temperature overnight. The insoluble materials are filtered off, and the filtrate is concentrated. The residue is chromatographed on silica gel with chloroform-methanol (40:1) to give 0.3 g of the title compound. m.p. 128°-129° C. (recrystallized from toluene-hexane)