Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.C[Si](C)(C)[C:11]#[C:12][CH3:13].C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>C1(C)C=CC=CC=1.[Cu]I.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>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:11]#[C:12][CH3:13])[CH:3]=1
Reactant: Brc1cccc(I)c1
Reactant: CC#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC#Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
To a solution of 1-bromo-3-iodobenzene (3.0 g, 10.6 mmol), copper(I) iodide (0.61 g, 3.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.61 g, 0.53 mmol) in toluene (20 mL) was added 1-(trimethylsilyl)-1-propyne (1.6 mL, 10.6 mmol), triethylamine (4.9 mL, 35.0 mmol) and a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (10.6 mL, 10.6 mmol). The resulting mixture was stirred under a nitrogen atmosphere at r.t. overnight. The mixture was partitioned between water and Et2O and the organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was filtered through a plug of silica and eluted with heptane (4×25 mL) affording the title compound (1.6 g, 80% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 2.05 (s, 3H), 7.30 (t, 1H), 7.39 (d, 1H), 7.52-7.56 (m, 1H), 7.56-7.58 (m, 1H); MS (CI) m/z 195 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
(R)-tert-butyl 3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (4.1 g, 0.01 mol) was dissolved in 20% TFA/CH2Cl2 (40 mL). The reaction mixture was stirred at rt for 2 h, TLC showed the reaction was completed. A solution of sat'd aq Na2CO3 was added dropwise to adjust the pH to 8˜9 and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude (S)-1-(3-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (3.0 g, 97%), which was used without purification.
Reaction SMILES: [CH2:1]([SH:6])[CH:2]([SH:5])[CH2:3][CH3:4].Cl[CH:8]([CH3:12])[C:9](=O)[CH3:10]>>[CH2:3]([CH:2]1[CH2:1][S:6][C:9]([CH3:10])=[C:8]([CH3:12])[S:5]1)[CH3:4]
Reactant: CCC(S)CS
Reactant: CC(=O)C(C)Cl
Product: CCC1CSC(C)=C(C)S1
Yield: 35 %

Procedure:
The procedure of Example 1 (a) is repeated, using 1,2-butanedithiol and 3-chloro-2-butanone to give 2-ethyl-2,3-dihydro-5,6-dimethyl-1,4-dithiin as a colorless oil, bp 68°-81°/0.7, yield 35%, NMR 1.01 (3t), 1.4-2.9 (2m), 1.87 (6s), 2.6- 3.4 (3m). IR, 2910 (sh); 1610 (sh); 1410, 1220 (sh); 1155 (sh); 1070, 735, 700.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:50]1[C:51]([F:68])=[N:52][CH:53]=[CH:54][C:55]=1[C:56]1[C:57]([NH:63][CH2:64][CH:65]2[CH2:67][CH2:66]2)=[N:58][C:59]([NH2:62])=[N:60][CH:61]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:65]1([CH2:64][N:63]2[C:57]3[N:58]=[C:59]([NH2:62])[N:60]=[CH:61][C:56]=3[C:55]3[CH:54]=[CH:53][N:52]=[C:51]([F:68])[C:50]2=3)[CH2:67][CH2:66]1
Reactant: Nc1ncc(-c2ccnc(F)c2Br)c(NCC2CC2)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Nc1ncc2c3ccnc(F)c3n(CC3CC3)c2n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 77.7 %

Procedure:
To a vacuum to argon purged vial containing 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.017 g, 0.030 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.014 g, 0.015 mmol), cesium carbonate (0.19 g, 0.59 mmol) and compound 240 (0.100 g, 0.30 mmol) was added degassed dioxane (2.00 mL). The reaction was stirred at 100° C. After 4 h, the reaction was cooled and applied directly to silica. Silica gel chromatography (gradient elution 40 to 90% ethyl acetate in hexanes) afforded compound 241 (0.060 g, 79% yield). 1H NMR (500 MHz, CDCl3) δ ppm 0.45-0.57 (m, 4 H) 1.34-1.47 (m, 1 H) 4.32 (d, J=7.09 Hz, 2 H) 5.46 (br. s., 2 H) 7.68 (dd, J=5.26, 2.81 Hz, 1 H) 8.02 (dd, J=5.13, 1.71 Hz, 1 H) 8.93 (s, 1 H).
Reaction SMILES: [C:1]1([CH:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:32])[N:12]([CH2:14]/[CH:15]=[CH:16]/[C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4[CH2:26][C:27]([O:29]CC)=[O:28])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([CH:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:32])[N:12]([CH2:14]/[CH:15]=[CH:16]/[C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4[CH2:26][C:27]([OH:29])=[O:28])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cn1ccc2c(/C=C/Cn3cc(C(c4ccccc4)c4ccccc4)ccc3=O)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cn1ccc2c(/C=C/Cn3cc(C(c4ccccc4)c4ccccc4)ccc3=O)cccc21
Reaction time: 5 h

Procedure:
To a solution of ethyl (4-{(1E)-3-[5-(diphenylmethyl)-2-oxo-1(2H)-pyridinyl]-1-propen-1-yl}-1H-indol-1-yl)acetate (70 mg) in MeOH (1.5 mL) was added 1M NaOH aqueous solution (0.2 mL) at ambient temperature. The reaction mixture was stirred at the same temperature for 5 hours. The reaction was quenched with 1M HCl aqueous solution (0.2 mL). The mixture was extracted with EtOAc and washed successively with water and brine. The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:MeOH=100:0-97:3) to give (4-{(1E)-3-[5-(diphenylmethyl)-2-oxo-1(2H)-pyridinyl]-1-propen-1-yl}-1H-indol-1-yl)acetic acid.
Reaction SMILES: N1C=CC=CC=1.ClCCl.[S:10]([O-:14])(=[O:13])(=[O:12])[CH3:11].[OH:15][CH:16]([CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:17][S:18]([CH2:21][CH2:22][CH2:23][N+:24]([CH3:27])([CH3:26])[CH3:25])(=[O:20])=[O:19].[CH2:48]=[C:49]1[O:53][C:51](=[O:52])[CH2:50]1>CO>[S:10]([O-:14])(=[O:13])(=[O:12])[CH3:11].[C:51]([O:15][CH:16]([CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:17][S:18]([CH2:21][CH2:22][CH2:23][N+:24]([CH3:26])([CH3:25])[CH3:27])(=[O:20])=[O:19])(=[O:52])[CH2:50][C:49]([CH3:48])=[O:53]
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)CS(=O)(=O)CCC[N+](C)(C)C
Reactant: C=C1CC(=O)O1
Agent: CS(=O)(=O)[O-]
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOCC(CS(=O)(=O)CCC[N+](C)(C)C)OC(=O)CC(C)=O

Procedure:
In a mixed solvent consisting of 5 ml of pyridine and 20 ml of dichloromethane is dissolved 2.35 g of 3-[(2-hydroxy-3-octadecyloxypropyl)sulfonyl]propyltrimethylammonium mesylate, to which 2.5 ml of diketene is added dropwise with stirring under ice cooling. Thereafter, the mixture is stirred at room temperature for 5 hours, to which is then added 3 ml of methanol. The solvent is distilled off under reduced pressure to leave a residue which in turn is purified by silica gel column chromatography to yield 0.5 g of the captioned compound.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[O:7]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.I[C:24]1[C:25]([NH2:32])=[N:26][CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>COCCOC.O.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>[CH3:31][O:30][C:29]1[CH:28]=[CH:27][N:26]=[C:25]([NH2:32])[C:24]=1[C:17]1[CH:18]=[CH:19][C:14]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: COc1ccnc(N)c1I
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
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: O
Solvent: COCCOC
Product: COc1ccnc(N)c1-c1ccc(Oc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
A mixture of sodium carbonate (122 mg), tetrakis(triphenylphosphine)palladium(0) (33.2 mg), 4-phenoxyphenylboronic acid (160 mg) and 3-iodo-4-methoxypyridin-2-amine (144 mg) in DME (10 mL) and water (3 mL) was stirred at 80° C. overnight. The mixture was added with silica gel, concentrated in vacuo, and purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (124 mg) as a pale yellow solid.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([N:8]([CH3:28])[C:9]2[C:10]3[CH:17]=[CH:16][N:15]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:50][C:51]1[CH:52]=[C:53]([NH:58][CH2:59][C:60](O)=[O:61])[CH:54]=[C:55]([Cl:57])[CH:56]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.CO.C(Cl)Cl>[Cl:50][C:51]1[CH:52]=[C:53]([NH:58][CH2:59][C:60]([N:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([N:8]([CH3:28])[C:9]3[C:10]4[CH:17]=[CH:16][N:15]([S:18]([C:21]5[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=5)(=[O:19])=[O:20])[C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:2]2)=[O:61])[CH:54]=[C:55]([Cl:57])[CH:56]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C4CCCCNC4)ncnc32)cc1
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C4CCCCN(C(=O)CNc5cc(Cl)cc(Cl)c5)C4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a solution of N-(azepan-3-yl)-N-methyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (200 mg, 0.5 mmol), in DMF (4 mL) was added EDCI (144 mg, 0.75 mmol), HOBt (101 mg, 0.75 mmol), 2-(3,5-dichlorophenylamino)acetic acid (109 mg, 0.5 mmol) and DIEA (129 mg, 1.0 mmol) at 0° C. The reaction mixture was stirred at rt overnight and diluted with EtOAc (100 mL) and washed with water (50 mL). The aqueous layer was extracted with the EtOAc (50 mL), the combined organic layer was dried over Na2SO4 and evaporated in vacuo to give a residue that was subjected to flash column chromatography using 0-4% MeOH in CH2Cl2 as an eluent to give (235 mg, 77%) of the titled compound. LC-MS: m/z [M+1]=601.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]([O:9]CC2C=CC=CC=2)=[O:8])[CH2:2]1>CO.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]([OH:9])=[O:8])[CH2:2]1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCOC1
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@H]1CCCOC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
Pd/C (10%, 1 g) was added to a solution of (S)-benzyl tetrahydro-2H-pyran-3-carboxylate (1.1 g, 5 mmol) in MeOH (10 mL). The suspension was stirred under hydrogen atmosphere at ambient temperature for 2 h. The catalyst was filtered off and washed with MeOH (5 mL). The filtrate and washings were combined and concentrated to dryness to afford (S)-tetrahydro-2H-pyran-3-carboxylic acid (0.6 g, 92% yield). (R)-Tetrahydro-2H-pyran-3-carboxylic acid was made in a similar manner.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11]O)[CH:5]=[CH:6][C:7]=1[Cl:8].CS(Cl)(=O)=O.Cl.[C-:19]#[N:20].[K+]>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][C:19]#[N:20])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [C-]#N
Reactant: OCCCc1ccc(Cl)c(Cl)c1
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: N#CCCCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 253.1 %

Procedure:
Intermediate 17A (2.0 g, 9.8 mmol) was dissolved in pyridine (20 mL) and treated with methane sulfonyl chloride (0.84 mL, 10 mmol) drop wise while maintaining the temperature below 20° C. The reaction mixture was stirred at rt for 3 h and added to concentrated HCl (10 mL) in crushed ice. The layers were separated and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with saturated NaHCO3 twice and brine and the organic portion dried over Na2SO4, filtered and concentrated. The resulting light yellow sulfonate ester was immediately dissolved in DMF (20 mL) and water (4 mL) and cooled to 0° C. Solid potassium cyanide (0.95 g, 15 mmol) was added to the reaction mixture and the mixture was stirred at rt for 72 h. The reaction mixture was then diluted with water and the aqueous phase extracted with ethyl acetate twice. The combined organic layers were washed with H2O twice, brine twice, dried over Na2SO4, filtered and concentrated. The residue was purified by ISCO chromatography (EtOAc/Hexanes 0-80%, column 80 g) to give Intermediate 17B (1.06 g, 24.8 mmol, 51.0%) as a white solid. HPLC/MS (Method L) RT=1.952 min, [M+1]+=214.0.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8](=[O:19])OC1C=CC([N+]([O-])=O)=CC=1.[CH3:20][N:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[NH2:22].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH3:20][N:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[NH:22][C:8](=[O:19])[NH:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1cccs1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CN(C)N
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(C)NC(=O)NCc1cccs1
Reaction time: 4.5 h
Yield: 46.2 %

Procedure:
To the solution of 4-nitrophenyl thiophen-2-ylmethylcarbamate (Compound XII-1) 3.14 g (11 mmol) in dichloromethane 20 ml, ethyl 2-(1-methylhydrazinyl)acetate (Compound XV-2) 2.98 g (22.6 mmol) and triethylamine 2.36 ml (17 mmol) was added at 0° C. and stirred at additional 4.5 hours. The reaction mixture was diluted with ethyl acetate 100 ml and washed with water 10 ml and brine 75 ml. The organic phase was dried with magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was submitted to silcagel chromatography to obtain the title compound 1.38 g (45%).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]1[CH2:7][CH2:6][CH2:5][N+:4]=1[CH3:8].[CH3:10][O:11]S([O-])(=O)=O.C[O-].[Na+]>C(OCC)C>[CH3:1][N:2]([CH3:9])[C:3]1([O:11][CH3:10])[CH2:7][CH2:6][CH2:5][N:4]1[CH3:8]
Reactant: CN(C)C1=[N+](C)CCC1
Reactant: COS(=O)(=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: COC1(N(C)C)CCCN1C
Yield: 27.1 %

Procedure:
Add (dropwise, at room temperature, with stirring) 50.0 g of 2-dimethylamino-1-methyl-1-pyrrolinium-methylsulfate to 12.65 g of sodium methylate, suspended in 120 ml of absolute diethyl ether and boil the resulting reaction mixture under reflux for 1 hour. After cooling the refluxed material, filter the precipitated salt therefrom. Draw off the ether from the filtrate and distil under a vacuum what remains of the filtrate to obtain 9.0 g of the title compound as a liquid (with a very marked tendency to decomposition) of b.p. 45° to 47° at 11 mm of Hg.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.Cl.[C:55](Cl)(=[O:62])[C:56]1[CH:61]=[CH:60][CH:59]=[N:58][CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:55]([C:56]2[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=2)=[O:62])[CH2:51][CH2:52]1
Reactant: O=C(Cl)c1cccnc1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cccnc1)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 50 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-12-(2-piperidin-4-ylethoxy)-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-nonaene tris(trifluoroacetate) and nicotinoyl chloride hydrochloride as the starting materials in 50% yield. LCMS for C30H31ClN7O2 (M+H)+: m/z=556.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH:12]=[C:13]([C:19]([O:21]CC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:10][O:9][C:8]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[NH:11][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]2=[O:21]
Reactant: CCOC(=O)C(=CNc1ccc(OC)c(OC)c1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2cc(OC)c(OC)cc2c1=O
Temperature: 50 °C
Yield: 65.2 %

Procedure:
[[(3,4-Dimethoxyphenyl)amino]methylene]malonic acid, diethyl ester (60 g, 188.5 mmol) was added to hot diphenylether (bath temperature 275° C.) under stirring. After stirring for 15 minutes, the mixture was allowed to cool to 50° C. The resulting crystals were collected by suction, washed thoroughly with ether and dried in vacuo to yield 34.1 g of the title compound having a melting point of 297° C.
Reaction SMILES: [C:1](OO)(C)(C)C.[CH2:7]([OH:18])[C@@H:8](O)[C@H:9]1[O:14][C:12](=[O:13])[C:11](O)=[C:10]1O.N>O>[C:12]([O:14][CH2:9][CH:8]1[O:18][CH2:7]1)(=[O:13])[C:11]([CH3:10])=[CH2:1]
Reactant: CC(C)(C)OO
Reactant: O=C1O[C@H]([C@H](O)CO)C(O)=C1O
Agent: N
Solvent: O
Product: C=C(C)C(=O)OCC1CO1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
The initiator solution consisted of 2.5 g of 70% t-butyl hydroperoxide dissolved in 25 g of water and the reducing agent solution consisted of 1.4 g of erythorbic acid, 0.5 g of aqua ammonia, and 25 g of water. The reactor contents were heated to 50° C. and 52.8 g of monomer mixture #1 was added to the reactor. Two ml of the initiator solution and 1 ml of the reducing agent solution were separately added to the reactor. Polymerization was started. The remaining monomer mixture #1 was added over a 60 minute period followed by a 30 minute addition of monomer mixture #2. The remaining initiator and reducing agent solutions were added over a 105 minute period. After completion of the additions, the polymer dispersion was held at 70° C. for 30 minutes. The polymer dispersion was checked by gas chromatographic analysis for residual unreacted monomer. The monomer content was less than 1000 ppm. The dispersion was cooled to room temperature and the physical properties determined.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C@H:17]([CH3:20])[CH2:18][OH:19]>CC(CC)=O>[Br:1][C:2]1[C:7]([O:8][CH2:16][C@H:17]([CH3:20])[CH2:18][OH:19])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Br
Reactant: C[C@H](CO)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C[C@H](CO)COc1cccnc1Br
Temperature: 100 °C
Yield: 80 %

Procedure:
2-bromo-3-pyridinol (230 mg) and potassium carbonate (216 mg) was dissolved in methylethylketone (10 ml) and reacted for 30 minutes. Then, (R)-3-bromo-2-methyl-1-propanol (0.21 ml) was added to the solution and refluxed for 3 hours at 100° C. Potassium carbonate was filtered out and separated by flash chromatography under a silica gel phase (ethyl acetate:normal hexane=1:1). As a result, (R)-3-(2-bromopyridine-3-yloxy)-2-methyl-1-propanol (260 mg, yield: 80%) was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])[CH:15]=3)=[CH:10][CH:9]=2)=[N:5][N:4]=1.[C:27]1([CH2:33][S:34](Cl)(=[O:36])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>N1C=CC=CC=1.C(Cl)Cl>[CH2:33]([S:34]([NH:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])[CH:15]=3)=[CH:12][CH:13]=2)=[N:5][N:4]=1)(=[O:36])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN)o2)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CNS(=O)(=O)Cc3ccccc3)o2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4′-[5-(Aminomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Example 53) (30 mg) was mixed with α-toluenesulphonyl chloride (33 mg) in pyridine (6 ml) at 0° C. and the reaction stirred at room temperature for 72 hours. Further α-toluenesulphonyl chloride (66 mg) in pyridine (3 ml) was added and stirring continued for 18 hours. The reaction was diluted with DCM and washed with hydrochloric acid (2N, 4×5 ml) and then water (5 ml). The organic phase was reduced to dryness under vacuum and the residue purified by HPLC to give after evaporation of the solvents 4′-(5-{[(benzylsulfonyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1O)(=[O:10])[CH3:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(=O)ON=NOC(=O)OCC)C>C1COCC1>[CH:1]1([O:7][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:8](=[O:10])[CH3:9])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: OC1C=CCCC1
Reactant: CC(=O)Nc1ccccc1O
Agent: CCOC(=O)ON=NOC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccccc1OC1C=CCCC1
Yield: 19.4 %

Procedure:
2-Cyclohexenol (491 mg, 0.49 ml, 5.00 mmol, 1.0 equiv.), 2-acetamidophenol (756 mg, 5.00 mmol, 1.0 equiv.) and triphenylphosphine (1.44 g, 5.50 mmol, 1.1 equiv.) were dissolved in THF (10 ml) and kept at ambient temperature by a water bath. After dropwise addition of diethyl azodicarbonic acid (871 mg, 0.78 ml, 5.00 mmol, 1.0 equiv.), dissolved in THF (3 ml), the reaction mixture was stirred over night. Extractive work-up and flash chromatography on silica gel (heptane/tertbutyl(methyl)ether=1:1) afforded 224 mg (19%) the title compound as a yellow oil.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH:35]([CH3:37])[CH3:36])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[N:8]2[CH2:2][CH2:3][N:4]([CH:35]([CH3:37])[CH3:36])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)N(CCO)C(=O)c1nc(CC2(c3ccccc3)CCCCC2)nc(O)c1OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)N1CCn2c(CC3(c4ccccc4)CCCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Reaction time: 2 h
Yield: 43.6 %

Procedure:
To a mixture of 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclohexylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (258) (0.43 g, 0.85 mmol) and triphenyl phosphine (0.45 g, 1.71 mmol) in dry dichloromethane (10.0 mL) was added diethyl azidocarboxylate (0.34 mL, 2.13 mmol) at room temperature and the reaction stirred for 2 h. After completion of the reaction, the solvent was evaporated and the crude product was purified by normal silica gel column chromatography (using 2% methanol in dichloromethane) to get 9-benzyloxy-2-isopropyl-6-(1-phenyl-cyclohexylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (259) (0.18 g, 43.0%) as a white solid.