Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.[OH:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][C:14]2=[O:25])[CH:7]([C:26]([NH:28][CH3:29])=[O:27])[CH2:6]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17]([N:16]=[CH:15][C:14](=[O:25])[N:13]2[CH2:12][CH2:11][N:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH:7]2[C:26]([NH:28][CH3:29])=[O:27])=[CH:18][CH:19]=1
Reactant: CNC(=O)C1CC(O)CCN1CCn1c(=O)cnc2ccc(OC)cc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CNC(=O)C1CC(=O)CCN1CCn1c(=O)cnc2ccc(OC)cc21
Reaction time: 1 h

Procedure:
To 2 mL of a dichloromethane solution containing 11 mg of 4-hydroxy-1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)-N-methylpiperidine-2-carboxamide, 13 mg of Dess-Martin periodinane was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was added with an aqueous saturated sodium hydrogen carbonate solution and chloroform. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 12 mg of a yellow oily substance, 1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)-N-methyl-4-oxopiperidine-2-carboxamide.
Reaction SMILES: C[N:2](C)CC=C.O.[S:8]([C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[S:20])=[CH:14][CH:13]=1)([OH:11])(=[O:10])=[O:9].[Na:21]>O>[S:8]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH2:2])=[S:20])=[CH:16][CH:17]=1)([OH:11])(=[O:9])=[O:10].[Na:21]
Reactant: O=S(=O)(O)c1ccc(N=C=S)cc1
Reactant: C=CCN(C)C
Agent: [Na]
Solvent: O
Product: NC(=S)Nc1ccc(S(=O)(=O)O)cc1

Procedure:
Trifluoroacetic acid (4 ml) was added to a suspension of BHAlyslys2lys4lys8DBL16 (0.73 g; 0.1 mmol) in dry dichloromethane (4 ml) under nitrogen. A vigorous evolution of gas was observed for a short time and the resulting solution was stirred at room temperature for two hours and then concentrated. The residual syrup was dissolved in water (5 ml), the solution passed through a column of Amberlite IRA-401(OH) and the filtrate concentrated to give BHAlyslys2lys4lys8lys16 as a viscous oil (0.49 g). The oil was redissolved in water (5 ml) and N,N-dimethyl-N-allylamine buffer (pH 9.5; 3 ml) added. Solid sodium 4-sulfophenylisothiocyanate monohydrate (1.30 g; 5.1 mmol) was then added and the resulting solution heated under nitrogen at 53° for two hours and then cooled. The solution was concentrated and the brownish solid residue purified by gel filtration (Sephadex LH20; water). The pure fractions were combined, passed through a column of Amberlite IR 120(Na) and freeze dried to give the sodium 4-sulfophenylthiourea terminated BHAlyslys2lys4lys8lys16 dendrimer as a fluffy white solid (374 mg). 1H nmr (D2O): δ 1.40; 1.72; 3.08; 3.42; 4.24; 4.60; 7.30; 7.40 (d, J=9 Hz); 7.78 (d, J=9 Hz). 13C nmr (D2O): δ 27.3; 32.5; 35.9; 43.7; 48.9; 58.6; 63.3; 128.8; 131.0; 143.7; 144.7; 145.1; 177.7; 178.1; 183.8; 185.2.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([N:21]1[CH:25]=[CH:24][N:23]=[N:22]1)=[CH:6][NH:7][NH:8][C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:12]=[CH:11][N:10]=1)C.C[O-].[Na+].[ClH:30]>C(O)C.CO>[ClH:30].[N:15]1([C:13]2[N:12]=[CH:11][N:10]=[C:9]([N:8]3[C:4](=[O:3])[C:5]([N:21]4[CH:25]=[CH:24][N:23]=[N:22]4)=[CH:6][NH:7]3)[CH:14]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)C(=CNNc1cc(N2CCOCC2)ncn1)n1ccnn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: O=c1c(-n2ccnn2)c[nH]n1-c1cc(N2CCOCC2)ncn1
Temperature: 10 °C

Procedure:
Batch 2: A further amount of the title compound is obtained as follows: The residue (2.4 g) obtained from the mother liquor during the synthesis of Example Compound 71, which contains the open-ring intermediate state of the cyclization, 3-[2-(6-morpholin-4-ylpyrimidin-4-yl)hydrazino]-2-(1H-1,2, 3-triazol-1-yl)prop-2-enoic acid ethyl ester, is dissolved in 12 ml ethanol and 1.5 ml 30% strength sodium methylate solution in methanol are added at RT, while stirring. The mixture is subsequently stirred at RT for 45 min, then adjusted to pH 5 with 2 N hydrochloric acid and subsequently stirred at RT for a further 16 h. The mixture is cooled to 10° C. and the solid is filtered off and washed with 3.5 ml dioxane. The mixture is dried under a high vacuum for 16 h, 5 ml methanol are then added and the mixture is subsequently stirred at RT for 1 h. The solid is filtered off, washed with 2 ml methanol and dried under a high vacuum to give a further 997 mg of the title compound in this way.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)O)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].CN(C)C1C=CC=CC=1.S(Br)([Br:40])=O>C(Cl)(Cl)Cl>[CH3:8][C@@H:7]([C@@H:9]1[C@@:27]2([CH3:28])[CH2:26][CH2:25][C@@H:24]3[C@@:22]4([CH3:23])[CH2:21][CH2:20][C@H:18]([Br:40])[CH2:17][C:16]4=[CH:15][CH2:14][C@H:13]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=S(Br)Br
Solvent: CN(C)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](Br)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Cholesterol, (25 g, 64.6 mmol) was dissolved in 10 ml of dimethylaniline (78.9 mmol) and 5 ml of chloroform. While stirring on ice; small quantities of thionyl bromide (6 ml, 77.6 mmol) dissolved in 20 ml of cold chloroform was added slowly over a period of 15 minutes. After the addition of thionyl bromide was complete, the mixture was stirred for an additional 2 hours at room temperature. The resulting solution was poured into 200 ml of ice cold 95% ethanol and left on ice for 2 hour until crystallization was complete. The product was filtered and washed with 25 ml of ice cold 95% ethanol. A small amount of product was recovered from the filtrate with the addition of 75 ml distilled water followed by refrigeration. Finally, the product was recrystallized from 120 ml of acetone giving 21.8 g of cholesteryl bromide (yield, 75%) with a melting point of 93-95° C. (lit 97-98° C.). The identity of the product was confirmed with mass spectrometry (EI) which showed an intense peak with an m/z of 448, corresponding to the molecular ion (M+°) of cholesteryl bromide. Also, the bromide molecular weight pattern characteristic of the two different isotopes of bromine (79Br:81-Br,1:1) was observed.
Reaction SMILES: [N:1]([C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:11])=[N+:2]=[N-:3].C[Si](C)(C)[C:14]#[C:15][CH2:16][OH:17]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:4]=1[N:1]1[C:15]([CH2:16][OH:17])=[CH:14][N:3]=[N:2]1
Reactant: [N-]=[N+]=Nc1c(Cl)cccc1Cl
Reactant: C[Si](C)(C)C#CCO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: OCc1cnnn1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 44 %

Procedure:
A solution of 2-azido-1,3-dichloro-benzene (4.00 g, 1 equiv) and 3-trimethylsilanyl-prop-2-yn-1-ol (6.29 mL, 2 equiv) in toluene (10 mL) is heated to 120° C. for 23 h. The reaction mixture is allowed to cool to room temperature and is diluted with 100 mL methylene chloride. The solution is adsorbed onto diatomaceous earth and is purified via flash chromatography eluting with hexanes/ethyl acetate (85:15 to 20:80) to give [3-(2,6-Dichloro-phenyl)-3H-[1,2,3]triazol-4-yl]-methanol (2.30 g, 44%) as an off-white solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[C:12]([CH3:25])=[N:13][NH:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:24])[CH3:23])[CH:17]=1>>[CH3:24][N:22]([CH3:23])[C:18]1[CH:17]=[C:16]([C:15]2[NH:14][N:13]=[C:12]([CH3:25])[C:11]=2[NH:10][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1n[nH]c(-c2cccc(N(C)C)c2)c1N
Reactant: O=C(Cl)c1ccccc1
Product: Cc1n[nH]c(-c2cccc(N(C)C)c2)c1NC(=O)c1ccccc1
Reaction time: 16 h

Procedure:
The preparation was carried out as in Example 22A, using 460 mg of benzoyl chloride and 700 mg of 4-amino-5-(3-dimethylamino-phenyl)-3-methylpyrazole, except the reaction mixture was stirred for 16 h and the residue was purified by MPLC (ethyl acetate as eluant) to give the title compound as a tan solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][CH:15]=[CH:14][C:13]=3[CH:17]=2)O1.I[C:20]1[C:28]2[C:23](=[N:24][CH:25]=[N:26][C:27]=2[NH2:29])[N:22]([CH:30]([CH3:32])[CH3:31])[N:21]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:16]1[C:12]2[CH:11]=[CH:10][C:9]([C:20]3[C:28]4[C:23](=[N:24][CH:25]=[N:26][C:27]=4[NH2:29])[N:22]([CH:30]([CH3:32])[CH3:31])[N:21]=3)=[CH:17][C:13]=2[CH:14]=[CH:15]1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: CC1(C)OB(c2ccc3occc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2ccc3occc3c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 64.8 %

Procedure:
A solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran (56 mg, 0.23 mmol) in EtOH (1.65 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.1 mmol) in DME (6 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (0.95 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA96 (19 mg, 72% yield). ESI-MS (M+H)+ m/z calcd 296.1, found 296.1.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:12][OH:13])[CH:7]=[C:8]([F:11])[C:9]=1[F:10].[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17].Cl[C:22]1[CH:32]=[C:26]2[N:27]([CH3:31])[CH2:28][CH2:29][CH2:30][N:25]2[C:24](=[O:33])[N:23]=1>CN(C=O)C>[CH3:31][N:27]1[CH2:28][CH2:29][CH2:30][N:25]2[C:24](=[O:33])[N:23]=[C:22]([O:13][CH2:12][C:6]3[CH:5]=[C:4]([F:3])[C:9]([F:10])=[C:8]([F:11])[CH:7]=3)[CH:32]=[C:26]12.[C:16]([OH:18])([C:15]([F:20])([F:19])[F:14])=[O:17]
Reactant: OCc1cc(F)c(F)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CN1CCCn2c1cc(OCc1cc(F)c(F)c(F)c1)nc2=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of NaH (38.3 mg, 0.956 mmol) in DMF (2 mL) was added (3,4,5-trifluorophenyl)methanol (65 mg, 0.401 mmol) at rt. The reaction mixture was stirred for 5 mins at rt, and then 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one trifluoroacetic acid salt (100 mg, 0.319 mmol) was added. The reaction mixture was stirred for another 1 h at rt, quenched with water and then filtered to give clear solution. The solution was purified by MDAP (0.3% TFA in water/MeCN) to afford the title compound as its TFA salt (16 mg, 0.036 mmol, 11.42%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O.CN(C=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(I)c(F)cc1F
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc(I)c(F)cc1F
Temperature: 60 °C

Procedure:
To a solution of 11 (74.0 g, 260 mmol) in toluene (370 mL) was added thionyl chloride (95 mL, 1300 mmol) in DMF (2.5 mL, 26 mmol) and the mixture was heated to reflux for 4 h. The mixture was cooled to approximately 60° C. and filtered to remove insoluble material. The filtrate was concentrated under reduced pressure and residual thionyl chloride was co-evaporated with toluene (2×120 mL) to give crude 12 which was used without purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C@H:7]([NH2:13])[C:8]2([CH3:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[C:20]([C:21]([N:23]([CH3:25])[CH3:24])=[O:22])=[C:19]([OH:26])[C:18]([NH:27][C:28]2[C:31](=O)[C:30](=[O:33])[C:29]=2[O:34]CC)=[CH:17][CH:16]=1>CO>[Cl:14][C:15]1[C:20]([C:21]([N:23]([CH3:25])[CH3:24])=[O:22])=[C:19]([OH:26])[C:18]([NH:27][C:28]2[C:29](=[O:34])[C:30](=[O:33])[C:31]=2[NH:13][C@@H:7]([C:5]2[O:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:8]2([CH3:12])[CH2:9][O:10][CH2:11]2)=[CH:17][CH:16]=1
Reactant: Cc1ccc([C@H](N)C2(C)COC2)o1
Reactant: CCOc1c(Nc2ccc(Cl)c(C(=O)N(C)C)c2O)c(=O)c1=O
Solvent: CO
Product: Cc1ccc([C@H](Nc2c(Nc3ccc(Cl)c(C(=O)N(C)C)c3O)c(=O)c2=O)C2(C)COC2)o1
Temperature: 25 °C
Reaction time: 72 h
Yield: 53 %

Procedure:
A mixture of 412 mg (2.27 mmol, 1.1 eq) of C—(R)-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine (prepared in EXAMPLE 50, steps 1 to 4) and 700 mg (2.07 mmol, 1 eq) of 6-chloro-3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N,N-dimethylbenzamide in 45 ml of methanol was stirred at ambient temperature for 3 days. The methanol was evaporated off and the residue was taken up with ethyl acetate and washed with a 1 M aqueous sodium dihydrogen phosphate solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue (0.90 g) was chromatographed on silica gel (80 g prepacked column, eluent dichloromethane/methanol, from 0 to 10% of methanol). 520 mg of 6-chloro-2-hydroxy-N,N-dimethyl-3-(2-{[(R)-(5-methylfuran-2-yl)-(3-methyloxetan-3-yl)methyl]amino}-3,4-dioxocyclobut-1-enylamino)benzamide were obtained in the form of an ochre solid. Yield=53%. Mp=165-167° C.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:21](=[O:28])[CH:22]=[C:23]([CH2:26][OH:27])[O:24][CH:25]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:38][S:39]([O:27][CH2:26][C:23]1[O:24][CH:25]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:1])([F:29])[F:30])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)[C:21](=[O:28])[CH:22]=1)(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: O=c1cc(CO)occ1OCCCCCOc1ccnc2ccc(C(F)(F)F)cc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cc(=O)c(OCCCCCOc2ccnc3ccc(C(F)(F)F)cc23)co1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.5 %

Procedure:
To a solution of 5-(5-(6-(trifluoromethyl)quinolin-4-yloxy)pentyloxy)-2-(hydroxymethyl)-4H-pyran-4-one 11 (93 mg, 0.22 mmol) in CH2Cl2 (5 mL) was added at 0° C. triethylamine (37 μL, 0.26 mmol), methanesulfonyl chloride (20.5 μL, 0.26 mmol). The solution was stirred at RT for 1.5 h. Dichloromethane (50 mL) was added and the solution was washed with water (2×100 mL), dried over MgSO4, filtered and evaporated. (5-(5-(6-(Trifluoromethyl)quinolin-4-yloxy)pentyloxy)-4-oxo-4H-pyran-2-yl)methyl methanesulfonate 16 was obtained (100 mg, 90.5% yield) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][CH:10]([CH2:11]3)[N:9]3[C:5](=[N:6][C:7]([C:17]([NH2:19])=[O:18])=[CH:8]3)[C:4]=2[CH:3]=1.[C:20]([C:22]1([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23]1)#[CH:21]>>[OH:27][C:22]1([C:20]#[C:21][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][CH:15]=2)[CH:12]2[CH2:16][CH:10]([CH2:11]2)[N:9]2[C:5]3=[N:6][C:7]([C:17]([NH2:19])=[O:18])=[CH:8]2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1C1CC2C1
Reactant: C#CC1(O)CCCC1
Product: NC(=O)c1cn2c(n1)-c1cc(C#CC3(O)CCCC3)ccc1C1CC2C1

Procedure:
9-Bromo-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7(12),8,10-pentaene-4-carboxamide (30 mg) was reacted with 1-ethynylcyclopentanol similar to as described in Procedure E to afford 8.9 mg of 9-[2-(1-hydroxycyclopentyl)ethynyl]-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene-4-carboxamide following reverse phase hplc purification. MS (Q1) 348 (M)+. 1H NMR (400 MHz, DMSO) δ 8.61 (d, J=11.1 Hz, 1H), 7.82 (s, 1H), 7.52 (s, 1H), 7.26 (s, 2H), 7.09 (s, 1H), 5.33 (s, 1H), 4.92 (q, J=4.5 Hz, 1H), 3.75-3.66 (m, 1H), 3.12-3.03 (m, 2H), 1.96-1.88 (m, 4H), 1.81-1.62 (m, 7H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:3][CH2:2]1.CS(O[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[F:34])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[F:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][CH2:26][N:1]1[CH2:2][CH2:3][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:5][CH2:6]1
Reactant: c1ccc2c(c1)Cn1cccc1C(C1CCNCC1)O2
Reactant: CS(=O)(=O)OCCc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccccc1CCN1CCC(C2Oc3ccccc3Cn3cccc32)CC1
Temperature: 85 °C

Procedure:
A mixture of 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (5.0 g, 0.019 mole), (2-fluorophenyl)-ethyl methanesulfonate (4.47 g, 0.02 mole), K2CO3 (11 g) and 150 ml dimethylformamide was heated at 85° C. for 9 hours.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][CH2:24][C:25]([F:47])([F:46])[CH2:26][C@@H:27]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)(=[O:31])=[O:30])=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[CH3:48][CH:49](O)[CH3:50].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][CH2:24][C:25]([F:47])([F:46])[CH2:26][C@@H:27]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[N:28]([S:29]([C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)(=[O:30])=[O:31])[CH:49]([CH3:50])[CH3:48])=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: CC(C)O
Reactant: CCOC(=O)[C@H](CC(F)(F)CCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CC(F)(F)CCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)N(C(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
To a solution of the material from Step 9 (150 mg, 0.222 mmol), 2-propanol (0.034 mL, 0.443 mmol) and Ph3P (116 mg, 0.443 mmol) in THF (1 mL) at 0° C. was slowly added diisopropyl azodicarboxylate (0.086 mL, 0.443 mmol). The reaction mixture was stirred at room temperature overnight. LCMS showed about 50% conversion, more 2-propanol (0.034 mL, 0.443 mmol), Ph3P (116 mg, 0.443 mmol) and diisopropyl azodicarboxylate (0.086 mL, 0.443 mmol) were added, stirred for 8 hours, LCMS showed no progress. It was concentrated to dryness and the residue was purified by column chromatography on silica gel using ethyl acetate-hexanes (0:100 to 90:10) to afford 81 mg of the title compound as a colorless foam. LCMS (M+1)=719.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]=O)=[CH:2]1.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1>N1C=CC=CC=1>[S:1]1[CH:2]=[C:3]([CH:10]=[CH:13][C:14]([OH:16])=[O:15])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2
Reactant: O=Cc1csc2ccccc12
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1csc2ccccc12
Temperature: 110 °C

Procedure:
A suspension of 1-benzothiophene-3-carbaldehyde (4.9 g, 0.03 mol), malonic acid (6.6 g, 0.06 mol) and piperidine (1 mL) in 100 mL anhydrous pyridine was heated at 110° C. overnight. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was taken up in 100 mL of water and 1 N hydrochloric acid was added to adjust the pH of this solution to ca. 3. The suspension was filtered and the yellow solid was collected, washed with water (3×50 mL) and concentrated in vacuo to give the indicated product with 95% purity (5.65 g, 91%).
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([S:16]([CH:19]=[CH2:20])(=[O:18])=[O:17])[CH3:15]>>[CH2:14]([S:16]([CH2:19][CH2:20][P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:18])=[O:17])[CH3:15]
Reactant: C=CS(=O)(=O)CC
Reactant: c1ccc(Pc2ccccc2)cc1
Product: CCS(=O)(=O)CCP(c1ccccc1)c1ccccc1
Reaction time: 1.75 h
Yield: 69 %

Procedure:
A mixture of 64 g (0.34 mole) of diphenyl phosphine and 40.2 g (0.33 mole) of highly reactive, freshly distilled vinyl ethyl sulfone monomer was irradiated in the usual manner. To suppress polymer forming side reactions the temperature of the reaction mixture was kept below 5° C. by an ice-water bath and the u.v. irradiation was limited to 105 minutes. The adduct formed crystallized from the liquid mixture by the end of the reaction period. Consequently, the reaction mixture was filtered with suction to recover the crude, crystalline product, i.e. 2-ethylsulfonylethyl diphenyl phosphine. The crude, dried product (94 g, 94%) was recrystallized from 670 ml methanol to yield 69 g (69%) of the compound (of unpleasant odor) as a white crystalline solid (Table 4).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[F:20])[NH2:16]>>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1ccc(F)c(Cl)c1
Product: O=C(O)Cc1ccccc1Nc1ccc(F)c(Cl)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-chloro-4-fluoroaniline to yield 2-[(3-chloro-4-fluorophenyl)amino]phenylacetic acid.
Reaction SMILES: [Si]([O:18][C:19]1[CH:59]=[CH:58][C:22]([O:23][CH2:24][C@@H:25]([OH:57])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:56]=[CH:55][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38](C(NC(NCCCCCCCC)=O)=O)[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][C:20]=1[F:60])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)(Cl)Cl.[CH3:65][OH:66]>>[CH2:28]([NH:27][C:65]([N:38]1[CH2:39][CH2:40][CH:35]([NH:34][C:33]2[CH:55]=[CH:56][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:57])[CH2:24][O:23][C:22]3[CH:58]=[CH:59][C:19]([OH:18])=[C:20]([F:60])[CH:21]=3)=[CH:31][CH:32]=2)[CH2:36][CH2:37]1)=[O:66])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:55][CH3:56]
Reactant: CCCCCCCCNC(=O)NC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)c(F)c3)cc2)CC1
Reactant: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)c(F)c3)cc2)CC1

Procedure:
N-({4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}-3-fluorophenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-1-piperidinyl}carbonyl)-N′-octylurea (0.228 g, 0.271 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 2% triethylamine) to give the title compound (0.126 g, 0.223 mmol).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[CH3:12])=[O:4].[CH3:13][C:14]([CH3:19])([CH2:17]O)[CH2:15][OH:16].O>C1(C)C(C)=CC=CC=1>[Cl:1][CH2:2][C:3]1([C:5]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=2[CH3:12])[O:16][CH2:15][C:14]([CH3:19])([CH3:17])[CH2:13][O:4]1
Reactant: Cc1ccc(C)c(C(=O)CCl)c1
Reactant: CC(C)(CO)CO
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1ccc(C)c(C2(CCl)OCC(C)(C)CO2)c1

Procedure:
0.5 mol of 2-chloro-1-(2,5-dimethylphenyl)ethanone, 104 g [1 mol] of 2,2-dimethyl-1,3-propanediol (neopentyl glycol) and 9.5 g [0.05 mol] of p-TsOH hydrate are boiled in 500 ml of xylene with a water trap until the formation of water ceases (about 4 hours). 200 ml of water and 30 ml of xylene are added to the reaction mixture at room temperature. A better phase separation is achieved by adding 50 ml of saturated aqueous NaCl solution. The organic phase is then extracted again with 100 ml of water and 100 ml of saturated aqueous NaCl solution, dried and concentrated.