Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2I)[C:5]1=[O:15].[NH2:16][CH2:17][C:18]1([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[O:26]1CCOC[CH2:27]1>CO>[OH:25][C:18]1([CH2:17][NH:16][C:27]([C:10]2[C:11]3[CH:12]=[CH:13][N:4]([CH2:3][CH2:2][OH:1])[C:5](=[O:15])[C:6]=3[CH:7]=[CH:8][CH:9]=2)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NCC1(O)CCCCCC1
Reactant: C1COCCO1
Reactant: O=c1c2cccc(I)c2ccn1CCO
Solvent: CO
Product: O=C(NCC1(O)CCCCCC1)c1cccc2c(=O)n(CCO)ccc12
Temperature: 80 °C

Procedure:
Into a 5 ml microwave reaction vial was combined 2-(2-hydroxyethyl)-5-iodoisoquinolin-1(2H)-one (200 mg, 0.000635 mol), 1-(aminomethyl)cycloheptanol (273 mg, 0.00190 mol) molybdenum hexacarbonyl (168 mg, 0.000635 mol) palladium acetate (10 mg, 0.00006 mol) 1,8-diazabicyclo[5.4.0]undec-7-ene (0.285 mL, 0.00190 mol) and 1,4-dioxane (3 mL, 0.03 mol). The mixture was subjected to microwave heating at 80° C. for 10 minutes. Methanol (1.5 ml) was added and the reaction mixture was filtered through a syringe filter and the filtrate concentrated. The mixture was purified by prep HPLC using a Phenomenex C18 Axia packed xolumn at PH 12. The combined pure fractions were reduced in vacuo to yield the title compound as a white solid. LC/MS M+H=359.3. 1H NMR (DMSO-d6) δ: 8.36-8.26 (m, 2H), 7.81-7.78 (dd, 1H) 7.52 (t, 1H), 7.48 (d, 1H) 6.813 (d, 1H), 4.892 (t, 1H), 4.325 (t, 1H), 4.016 (t, 1H), 3.66 (t, 1H), 3.285 (d, 1H), 1.69-1.44 (m, 10H), 1.414-1.317 (m, 2H)
Reaction SMILES: [CH:1]1([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:11]COC)[CH2:4][CH2:3][CH2:2]1.C([Li])(CC)C.C1CCCCC1.CN(C)[CH:28]=[O:29].Cl>O1CCCC1>[CH:1]1([C:5]2[C:6]([OH:11])=[C:7]([CH:8]=[CH:9][CH:10]=2)[CH:28]=[O:29])[CH2:2][CH2:3][CH2:4]1
Reactant: COCOc1ccccc1C1CCC1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: O=Cc1cccc(C2CCC2)c1O
Reaction time: 2 h

Procedure:
1-cyclobutyl-2-methoxymethoxybenzene (1.18 g) was dissolved in tetrahydrofuran (11 mL), and a 1.01M s-butyllithium-cyclohexane solution (8.7 mL) was added to the solution at −60° C. over 15 minutes under an argon gas flow, and then the mixture was stirred for 2 hours. N,N-dimethylformamide (0.90 mL) was added and the mixture was stirred at the same temperature for 2 hours. 4N hydrochloric acid (15 mL) was added at room temperature, and then the mixture was stirred at 60° C. for 20 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1) to obtain the title compound (0.95 g) as a colorless oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:19][CH2:20][CH2:21][CH2:22][CH3:23].CC(Br)CCC>>[CH3:19][CH:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13])=[CH:15][CH:16]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCOC(=O)NCCOc1ccc(O)cc1
Reactant: CCCCC
Agent: CCCC(C)Br
Agent: [H-]
Agent: [Na+]
Product: CCCC(C)Oc1ccc(OCCNC(=O)OCC)cc1

Procedure:
In the same manner, ethyl N-{2-(4-hydroxyphenoxy]ethyl}carbamate (1.25 g, 5.5 mmol) and sodium hydride, prewashed with pentane, (0.132 g, 5.5 mmol) are reacted together, followed by addition of 1-methylbutyl bromide. The mixture is heated at 50° for 20 hours, then worked up and purified by prep. TLC to give ethyl N-{2-[4-(1-methylbutoxy)phenoxy]ethyl}carbamate (compound 14, Table A).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[C:13]([NH2:16])[S:14][CH:15]=3)=[C:9]([CH3:17])[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[CH2:21][CH2:20]1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.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>[CH3:17][C:9]1[NH:8][C:5]2=[N:6][CH:7]=[C:2]([C:29]3[CH:28]=[CH:27][C:26]([CH2:25][N:22]4[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]4)=[CH:31][CH:30]=3)[CH:3]=[C:4]2[C:10]=1[C:11]1[N:12]=[C:13]([NH2:16])[S:14][CH:15]=1
Reactant: CN1CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1[nH]c2ncc(Br)cc2c1-c1csc(N)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1[nH]c2ncc(-c3ccc(CN4CCN(C)CC4)cc3)cc2c1-c1csc(N)n1
Temperature: 175 °C

Procedure:
In a personal chemistry microwave reaction vial 4-(5-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-ylamine (0.2 g, 0.64 mmol) and 1-Methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperazine (0.23 g, 0.71 mmol), bis(triphenylphosphine)-palladium(II) dichloride (0.004 g, 0.006 mmol) in acetonitrile (2 mL), and 1 M Na2CO3 (2 mL) were added. The resulting mixture was de-gassed with N2 for 10 min, after which it was heated at 175° C. for 30 min in a Personal Chemistry Optimizer. The mixture was diluted with DMF (3 mL), and concentrated in vacuo and purified on silica gel column using dichloromethane and methanol to afford 4-{2-Methyl-5-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-thiazol-2-ylamine.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][CH2:20][CH2:21]Br.O>CN(C)C=O>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([O:11][CH2:21][CH2:20][O:19][CH3:18])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(O)ccc(F)c1F
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(F)c(F)c1C=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 2,3-difluoro-6-hydroxybenzaldehyde (0.63 g) and potassium carbonate (0.83 g) in N,N-dimethyl -formamide (4 mL) was added 2-methoxyethyl bromide (0.45 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=85/15−60/40) to give 2,3-difluoro-6-(2-methoxyethoxy)benzaldehyde (0.62 g). This material was dissolved in tetrahydrofuran (6 mL). To the solution were added water (0.6 mL) and sodium borohydride (0.12 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (0.61 g).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][S:12]([C:15]1[CH:27]=[CH:26][C:18]([C:19]([NH:21][CH2:22][C:23](O)=[O:24])=[O:20])=[CH:17][CH:16]=1)(=[O:14])=[O:13].C(OC(=O)[NH:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(C)(C)C>>[ClH:1].[NH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:23](=[O:24])[CH2:22][NH:21][C:19](=[O:20])[C:18]2[CH:26]=[CH:27][C:15]([S:12](=[O:13])(=[O:14])[NH:11][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][C:3]3[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:2]=3[Cl:1])=[CH:16][CH:17]=2)[CH2:42][CH2:41]1
Reactant: O=C(O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: Cl
Product: NC1CCN(C(=O)CNC(=O)c2ccc(S(=O)(=O)Nc3ccccc3Oc3ccc(Cl)cc3Cl)cc2)CC1

Procedure:
The title compound was prepared from {4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-benzoylamino}-acetic acid (Example 1.1/e) and piperidin-4-yl-carbamic acid tert-butyl ester (Aldrich) according to the method described in Example 11.1. MS (EI) 577.2 (MH±).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][CH:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([OH:15])=O)=[O:10])[C:5](=[O:22])[C:4]1=[O:23])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:39][C@H:40]1[C@H:43]([CH3:44])[N:42]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]1=[O:53].C1(C)C(S([O-])(=O)=O)=CC=CC=1.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][CH:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([NH:39][C@H:40]2[C@H:43]([CH3:44])[N:42]([O:45][CH2:46][C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:41]2=[O:53])=[O:15])=[O:10])[C:5](=[O:22])[C:4]1=[O:23])[CH3:2]
Reactant: C[C@H]1[C@H](N)C(=O)N1OCc1ccccc1
Reactant: CCN1CCN(C(=O)NC(C(=O)O)c2ccccc2)C(=O)C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccccc1S(=O)(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCN(C(=O)NC(C(=O)N[C@@H]2C(=O)N(OCc3ccccc3)[C@H]2C)c2ccccc2)C(=O)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of α-[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]benzeneacetic acid (0.879 g) hydroxybenzotriazole (0.42 g), and dicyclohexylcarbodiimide (0.56 g), in dimethylformamide (15 ml) is stirred at 26° C. for one hour, at which point a solution of (3S-trans)-3-amino-4-methyl-1-(phenylmethoxy)-2-azetidinone, toluenesulfonate (0.95 g) and diisopropylethylamine (0.44 ml) in dimethylformamide (5 ml) is added. The reaction mixture is stirred at room temperature for about 16 hours, then poured into water (100 ml) and extracted with ethyl acetate (three 100 ml portions). The combined organic extracts are washed with water (three 100 ml portions) and aqueous sodium bicarbonate solution (one 100 ml portion), then dried over sodium sulfate and concentrated under reduced pressure to a semi-solid residue. Liquid chromatography (ethyl acetate) affords the desired product as a foam (0.599 g). Recrystallization from chloroform/isopropyl ether yields the title compound, melting point 100°-105° C.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1>C(O)C>[CH2:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:21][CH:13]1[NH:12][C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1csc2ncnc(Cl)c12
Reactant: NC1Cc2ccccc2C1
Solvent: CCO
Product: Cc1csc2ncnc(NC3Cc4ccccc4C3)c12
Yield: 100 %

Procedure:
4-chloro-5-methylthieno[2,3-d]pyrimidine (92 mg, 0.50 mmol) (see J. Pharm. Soc. JAPAN, 109, 464 (1989)) and 2-aminoindan (330 mg, 2.5 mmol) in dry ethanol (1 ml) were heated to reflux under an argon atmosphere for 40 minutes. The solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to obtain the title compound (140 mg, 0.50 mmol) having the following physical properties:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]#[C:10][Si](C)(C)C)=[C:7]([C:15]([F:18])([F:17])[F:16])[N:6]=[C:5]([CH3:19])[N:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[C:9]([C:8]1[C:3]([O:2][CH3:1])=[N:4][C:5]([CH3:19])=[N:6][C:7]=1[C:15]([F:18])([F:16])[F:17])#[CH:10]
Reactant: COc1nc(C)nc(C(F)(F)F)c1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1c(OC)nc(C)nc1C(F)(F)F
Yield: 49.3 %

Procedure:
5-Iodo-4-methoxy-2-methyl-6-trifluoromethylpyrimidine (5.0 g) was dissolved in DMF (50 ml) and N,N-diisopropylethylamine (6.5 g), copper(I) iodide (0.3 g), dichlorobis(triphenylphosphine)palladium(II) (1.12 g) and trimethylsilylacetylene (15.4 g) was added at room temperature with stirring. The mixture was heated (50° C.) in nitrogen atmosphere for 7 hr and cool to room tempeature. The reaction mixture was added methyl tert-butyl ether (MTBE) (200 ml). The insoluble matter was removed by filtration through Celite and the filtrate was washed with water and brine, respectively. The MTBE solution was dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give crude 4-methoxy-2-methyl-6-trifluoromethyl-5-trimethylsilylethynylpyrimidine (5.3 g) as pale yellow oil. This crude 4-methoxy-2-methyl-6-trifluoromethyl-5-trimethylsilylethynylpyrimidine (5.2 g) was dissolved in THF (100 ml) and tetrabutylammonium fluoride (1M THF solution, 18 ml) was added under ice cooling with stirring. After stirring 30 min at this temperature, the reaction mixture was added water in one portion under ice cooling and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, respectively and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane ethyl acetate) to give 5-ethynyl-4-methoxy-2-methyl-6-trifluoromethylpyrimidine (1.92 g) as colorless crystalline solid, mp 77° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][CH2:13]O)[O:7][CH2:6][CH2:5]2.Cl.[Br:16][C:17]1[CH:18]=[C:19]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:20]=[CH:21][C:22]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.BrC1C=C(OC)C=CC=1N1CCNCC1.N1(C2C=CC(S(N)(=O)=O)=CC=2)CCNCC1>>[Br:16][C:17]1[CH:18]=[C:19]([S:29]([NH2:32])(=[O:30])=[O:31])[CH:20]=[CH:21][C:22]=1[N:23]1[CH2:28][CH2:27][N:26]([CH2:13][CH2:12][C@H:8]2[C:9]3[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=3)[CH2:5][CH2:6][O:7]2)[CH2:25][CH2:24]1
Reactant: NS(=O)(=O)c1ccc(N2CCNCC2)c(Br)c1
Reactant: OCCC1OCCc2cc(Br)ccc21
Agent: COc1ccc(N2CCNCC2)c(Br)c1
Agent: Cl
Agent: NS(=O)(=O)c1ccc(N2CCNCC2)cc1
Product: NS(=O)(=O)c1ccc(N2CCN(CC[C@@H]3OCCc4cc(Br)ccc43)CC2)c(Br)c1

Procedure:
Following the general procedure of EXAMPLE 49 and making non-critical variations, 2-(6-bromoisochroman-1-yl)ethanol (LXXIX, 0.399 g) and 3-bromo-4-(piperazin-1-yl)-benzenesulfonamide hydrochloride (VIII, Chart C, 0.544 g; prepared by the method of EXAMPLE 37 but using 4-(piperazin-1-yl)benzenesulfonamide (IV) in place of 1-(4-methoxyphenyl)piperazine) are combined to give the title compound; mp 206°-208°; MS (m/z) 557 and 559; IR (mineral oil) 1165, 1338, 1450, 616, 1586 and 731 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]([CH3:20])[C:12](=[O:19])[CH:13]=[CH:14][C:15]=1C(O)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:28])C=CC=CC=1.C([N:40]([CH2:43]C)CC)C>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2[N:11]([CH3:20])[C:12](=[O:19])[CH:13]=[CH:14][C:15]=2[NH:40][C:43]1=[O:28]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)O)ccc1=O
Solvent: CC#N
Product: Cn1c(=O)ccc2[nH]c(=O)n(-c3ccc(I)cc3F)c21
Temperature: 60 °C
Reaction time: 5 h

Procedure:
2-[(2-fluoro-4-iodophenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (5.840 g, 15 mmol) was suspended in acetonitrile (117 ml) and diphenylphosphoryl azide (1.2 eq., 4 ml, 18 mmol) as well as triethylamine (1.2 eq., 2.5 ml, 18 mmol) were added. The mixture was stirred at 60° C. for 5 hours. A suspension was formed. The precipitate was filtered off and washed once with acetonitrile and dried in vacuo. The residue delivered the title product (4.20 g, 69%) sufficient purity (95% UV) and was used for the next transformation without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:35]I)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:35][O:14][C:11]2[CH:12]=[N:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]
Reactant: Oc1ccc(-c2ccc(Cl)cc2)nc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OC)C1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(Cl)cc3)nc2)CCN(C(=O)c2ccccc2OC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 6-(4-chloro-phenyl)-pyridin-3-ol (Preparation 23) and 3-iodomethyl-1-(2-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 15) to afford the racemate as a white solid (116 mg, 47.7%)
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[O:8])[CH:3]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53].FC(F)(F)C(O)=O.[F:64][C:65]1[CH:66]=[N:67][C:68]2[NH:69][C:70]3[CH:71]=[N:72][CH:73]=[C:74]([CH:87]=3)[CH2:75][CH2:76][C:77]3[CH:85]=[C:81]([NH:82][C:83]=1[N:84]=2)[CH:80]=[CH:79][C:78]=3[NH2:86]>CN(C)C=O.C(N(CC)C(C)C)(C)C>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53].[F:64][C:65]1[CH:66]=[N:67][C:68]2[NH:69][C:70]3[CH:71]=[N:72][CH:73]=[C:74]([CH:87]=3)[CH2:75][CH2:76][C:77]3[CH:85]=[C:81]([NH:82][C:83]=1[N:84]=2)[CH:80]=[CH:79][C:78]=3[NH:86][C:16](=[O:18])[CH2:15][CH:12]1[CH2:11][CH2:10][N:9]([C:7]([C:4]2[CH:3]=[C:2]([CH3:1])[O:6][N:5]=2)=[O:8])[CH2:14][CH2:13]1
Reactant: Cc1cc(C(=O)N2CCC(CC(=O)O)CC2)no1
Reactant: Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(F)c(n1)N2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(F)c(n3)N4)CC2)no1
Reaction time: 8 h
Yield: 8.2 %

Procedure:
A solution of {1-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4-yl}acetic acid (2.0 mg, 0.0079 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (8.1 mg, 0.021 mmol) in N,N-dimethylformamide (0.1 mL) and N,N-diisopropylethylamine (3.2 uL) was stirred for 15 minutes. A solution of 6-fluoro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate) (2.5 mg, 0.0078 mmol) in N,N-dimethylformamide (0.04 mL) and was added to the previous solution and stirred overnight. The reaction mixture was purified by preparative HPLC (pH 2) to give the desired product (0.5 mg, 14%). LCMS for C29H30FN8O3 (M+H)+: m/z=557.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:15]O)[CH2:9][CH2:10][C:11](OC)=[O:12])=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:15][C:11](=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(=NO)c1ccc(Br)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1CCC(c2ccc(Br)cc2)N1
Temperature: 80 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
To a suspension of methyl 4-(4-bromophenyl)-4-(hydroxyimino)butanoate (5.0 g, 17 mmol) in acetic acid (60 mL) was added Zn (2.3 g, 35 mmol). The resulting mixture was stirred at 80° C. overnight under N2 atmosphere. The reaction was cooled to room temperature and filtered. The filtrate was neutralized with saturated NaHCO3 solution and extracted with ethyl acetate (30 mL×3). The combined organics were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The solid was washed with ether to afford 5-(4-bromophenyl)-pyrrolidin-2-one (0.82 g, 20%). 1H NMR (CDCl3, 400 MHz) δ 7.50 (d, J=8.4, 1 H), 7.18 (d, J=8.4, 2H), 5.87 (br s, 1H), 4.72 (t, J=6.8, 2H), 2.63-2.50 (m, 1H), 2.48-2.38 (m, 2H), 1.98-1.89 (m, 1H). MS (ESI) m/z 240.1 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[C:19]([F:20])=[C:18]([F:21])[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28](C)(C)[O:29][SiH2]C(C)(C)C)=[CH:24][CH:23]=4)=[C:16]([F:37])[C:15]=3[F:38])[NH:10][C:9]=2[CH:8]=[C:7]([CH3:39])[CH:6]=1)=[O:4].Cl>O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[C:15]([F:38])=[C:16]([F:37])[C:17]([C:22]4[CH:23]=[CH:24][C:25]([CH2:28][OH:29])=[CH:26][CH:27]=4)=[C:18]([F:21])[C:19]=3[F:20])[NH:10][C:9]=2[CH:8]=[C:7]([CH3:39])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(C)cc2[nH]c(-c3c(F)c(F)c(-c4ccc(C(C)(C)O[SiH2]C(C)(C)C)cc4)c(F)c3F)nc12
Agent: Cl
Solvent: O
Product: COC(=O)c1cc(C)cc2[nH]c(-c3c(F)c(F)c(-c4ccc(CO)cc4)c(F)c3F)nc12
Yield: 75.4 %

Procedure:
2-[4′-(tert-butyl-dimethyl-silanyloxymethyl)-2,3,5,6-tetrafluoro-biphenyl-4-yl]-6-methyl-1H-benzoimidazole-4-carboxylic acid methyl ester (2.0 g, 3.58 mmol) was suspended in an q. solution of 4 N HCl (100 mL) and stirred at room temperature for 4 h. TLC shows completion of the reaction. The reaction mixture was diluted with water and extracted with ethyl acetate (100 mL×3). Ethyl acetate layer washed with water (50 mL×2) and brine. Dried over anhydrous sodium sulphate and concentrated to get off white solid (1.2 g, 75.9%) which was directly taken to next step.
Reaction SMILES: COP([CH2:7][C:8](=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:14]=1)(=O)OC.[CH3:30][C:31]1[N:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][N:32]=1.[OH-].[Na+]>C1COCC1>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][NH:19][C:15]2[N:14]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][C:8](=[O:29])[CH:7]=[CH:37][C:34]3[CH:33]=[N:32][C:31]([CH3:30])=[N:36][CH:35]=3)[CH:18]=[CH:17][CH:16]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc(CNc2cccc(CCCCC(=O)CP(=O)(OC)OC)n2)cc1
Reactant: Cc1ncc(C=O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(CNc2cccc(CCCCC(=O)C=Cc3cnc(C)nc3)n2)cc1
Reaction time: 0.17 h
Yield: 65.2 %

Procedure:
To a solution of 6-7 (42.8 g, 102 mmol) and 2-methyl-pyrimidine-5-carbaldehyde (12.45 g, 102 mmol) in THF (250 mL) at 0° was added 4M NaOH (26.7 mL, 107 mmol) dropwise. After 15 minutes the ice bath was removed and the mixture stirred for an additional 10 minutes. The solution was diluted with water, extracted with ethyl acetate, and dried (Na2SO4). Following concentration, the residue was triturated with ether to give 27.7 g (61%) of 16-1 as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(S(F)(F)[F:17])CC)C>ClCCl>[F:17][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCCCc1ccccc1
Solvent: ClCCl
Product: FCCCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
3-Phenyl-1-propanol (1 mL) and (diethylamino)sulfur trifluoride (1.2 mL) were dissolved in dichloromethane (10 mL). The reaction solution was stirred at rt for 3 d. The reaction mixture was passed through a short silica gel column and washed with dichloromethane. The collected solution was evaporated to give 1-fluoro-3-phenylpropane as light yellow oil. 1H NMR (DMSO-d6): δ 1.84-2.02 (m, 2H), 2.65 (t, J=7.5 Hz, 2H), 4.34 (t, J=5.7 Hz, 1H), 4.50 (t, J=5.7 Hz, 1H), 7.20 (m, 5H); 19F NMR (282 MHz, DMSO-d6): δ−79.22.
Reaction SMILES: [NH2:1][C:2]1([C:8]#[N:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:10][C:11]([CH2:14][C@H:15]([NH2:19])[C:16]([OH:18])=O)([CH3:13])[CH3:12].[C:20]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)(=[O:22])[CH3:21]>>[C:20]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:19][CH:15]([C:16](=[O:18])[NH:1][C:2]2([C:8]#[N:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]2)[CH2:14][C:11]([CH3:10])([CH3:12])[CH3:13])=[O:29])=[CH:26][CH:25]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)C[C@H](N)C(=O)O
Reactant: N#CC1(N)CCOCC1
Product: CC(=O)Nc1ccc(C(=O)NC(CC(C)(C)C)C(=O)NC2(C#N)CCOCC2)cc1

Procedure:
The title compound was prepared from 4-amino-4-cyano-tetrahydropyran, L-neopentyl glycine and 4-acetylaminobenzoic acid analogous to the procedure described in Example 24.