Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].[Cs+].CC1C=CC(S([O:13][CH2:14][C@@H:15]2[O:17][CH2:16]2)(=O)=O)=CC=1.[Cl:18][C:19]1[C:24]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][C:32](F)=[CH:33][C:34]=3OC3CCOCC3)[N:29]=[CH:28][N:27]=2)=[C:23]2[O:44][CH2:45][O:46][C:22]2=[CH:21][CH:20]=1.CN([CH:50]=[O:51])C>>[Cl:18][C:19]1[C:24]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:13][CH2:14][C@@H:15]4[O:17][CH2:16]4)=[CH:33][CH:34]=3)[N:29]=[C:28]([O:44][CH:23]3[CH2:24][CH2:50][O:51][CH2:21][CH2:22]3)[N:27]=2)=[C:23]2[O:44][CH2:45][O:46][C:22]2=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: Fc1cc(OC2CCOCC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Reactant: CN(C)C=O
Agent: [Cs+]
Agent: [F-]
Product: Clc1ccc2c(c1Nc1nc(OC3CCOCC3)nc3cc(OC[C@H]4CO4)ccc13)OCO2
Temperature: 70 °C

Procedure:
Caesium fluoride (0.46 g) and (2R)-(−)-glycidyl tosylate (0.275 g) were added in turn a solution of 4-(6-chloro-2,3-methylenedioxyanilino)-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline (0.416 g) in DMF (5 ml) and the reaction mixture was stirred and heated to 60° C. for 2 hours and to 70° C. for a further 1.5 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with water and with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 49:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.36 g); NMR Spectrum: (CDCl3) 1.9-2.1 (m, 2H), 2.2-2.3 (m, 2H), 2.8 (m, 1H), 2.98 (m, 1H), 3.42 (m, 1H), 3.6-3.7 (m, 2H), 3.954.1 (m, 3H), 4.45 (m, 1H), 4.8 (m, 1H), 6.02 (s, 2H), 6.59 (m, 12H), 6.72 (d, 1H), 6.81 (d, 1H), 6.97 (d, 1H), 8.5 (s, 1H), 9.27 (s, 1H); Mass Spectrum: M+H+ 472 and 474.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.O[CH2:81][CH2:82][N:83]1[CH2:87][CH2:86][CH2:85][C:84]1=[O:88]>CN(C=O)C.C(O)=O>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19](=[O:20])[N:21]3[CH2:22][CH2:23][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([O:36][CH2:81][CH2:82][N:83]5[CH2:87][CH2:86][CH2:85][C:84]5=[O:88])=[O:35])[CH2:29][CH2:28]4)[CH2:25][CH2:26]3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1
Reactant: O=C1CCCN1CCO
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)O)CC3)CC2)cc(C)c1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O=CO
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)OCCN4CCCC4=O)CC3)CC2)cc(C)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 80 mg (0.12 mmol) (R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 45 mg (0.14 mmol) TBTU and 32 μL (0.23 mmol) triethylamine in 1.2 mL DMF was stirred for 1 h at RT. Then 26 mg (0.23 mmol) 1-(2-hydroxy-ethyl)-pyrrolidin-2-one were added and the reaction mixture was stirred overnight at RT. The reaction solution was mixed with 5 drops of formic acid, filtered through a syringe filter and purified directly by HPLC without any further working up. The fractions containing the product were combined, extracted with 30 mL EtOAc, the organic phase was made alkaline with 5% NaHCO3 solution, separated off and dried on Na2SO4. After the elimination of the desiccant and solvent the residue was triturated with DIPE, suction filtered and dried.
Reaction SMILES: [O:1]([CH2:11][CH:12]=[CH2:13])[CH:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@H:3]1[OH:4].[C:14]1(C)[C:15]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=1.N1C=CC=C[CH:26]=1>>[C:18]1([CH3:26])[CH:19]=[CH:14][C:15]([S:20]([O:10][CH2:9][C@H:7]2[O:8][CH:2]([O:1][CH2:11][CH:12]=[CH2:13])[C@H:3]([OH:4])[C@@H:5]2[OH:6])(=[O:21])=[O:22])=[CH:16][CH:17]=1
Reactant: c1ccncc1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: C=CCOC1O[C@H](CO)[C@@H](O)[C@H]1O
Product: C=CCOC1O[C@H](COS(=O)(=O)c2ccc(C)cc2)[C@@H](O)[C@H]1O
Temperature: 25 °C

Procedure:
A solution of allyl α,β-D-ribofuranoside 1 (18.6 g) in dry pyridine (100 mL) was cooled in an ice bath and p toluenesulfonyl chloride (22.4 g, 1.2 eq) was added portion-wise keeping the reaction temperature <5° C. The resulting solution was allowed to warm slowly to RT overnight and then was concentrated to dryness. 1,4-Dioxane (100 mL) was added to the residue and it was again concentrated to dryness. Chromatography of the residue afforded an anomeric mixture of the title compounds 3 as a syrup (17.6 g, 52%). 1H NMR (CDCl3) δ 7.80 (2H, d, J=8.3 Hz), 7.34 (2H, d, J=8.0 Hz), 5.85-5.72 (1H, m), 5.25-5.11 (2H, m), 4.94 (1H, s), 4.27-3.98 (6H, m), 3.87-3.80 (1H, m), 2.44 (3H, s); 13C NMR δ 145.5, 134.1, 133.0, 130.3, 128.4, 117.9, 106.6, 80.8, 75.2, 72.3, 71.0, 68.6, 22.0.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]1[C:10]([N+:11]([O-])=O)=[CH:9][N:8]=[C:7]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH:6]=1.[H][H]>C(O)C.[Pt]=O>[N:14]1([C:7]2[CH:6]=[C:5]3[CH:4]=[CH:3][NH:11][C:10]3=[CH:9][N:8]=2)[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: CN(C)C=Cc1cc(-n2cncn2)ncc1[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: c1ncn(-c2cc3cc[nH]c3cn2)n1
Yield: 50.3 %

Procedure:
N,N-Dimethyl-2-(5-nitro-2-(1,2,4-triazol-1-yl)pyridin-4-yl)ethenamine (8 g, 31 mmol) was hydrogenated over platinum oxide (1.6 g) in ethanol (150 mL) at 30 psi of hydrogen for 1 hour. The catalyst was removed by filtration and the solvent evaporated in vacuo. The residue was chromatographed on silica eluting with ethyl acetate to afford an orange/brown solid. This was triturated with ether and the precipitate collected by filtration to give the title compound (2.89 g, 51%) as a pink solid. mp 203°-205° C. 1H NMR (360 MHz, d6 -DMSO) δ 6.67 (1H, d, J=3.0Hz), 7.76 (1H, d, J=2.9Hz), 8.01 (1H, s), 8.23 (1H, s), 8.70 (1H, s), 9.25 (1H, s) and 11.86 (1H, br s).
Reaction SMILES: O[CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:15]O)[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.CCOC(C)=O.[H][H]>[Pd].CC(O)=O>[CH3:15][C:10]1[C:9]2[C:8]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:2][C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: [H][H]
Reactant: OCc1cccc2c1-c1ccccc1C2O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cccc2c1-c1ccccc1C2
Yield: 77.3 %

Procedure:
A solution of 9-hydroxyfluoren-4-methanol (2.6 g, 12.2 mmol) in 1.1 EtOAc:AcOH was charged with catalytic amount of 10% palladium on charcoal. The mixture was treated with hydrogen under 1600 psi, at room temperature for three days. The catalyst was removed and the solvent was evaporated under reduced pressure. Recrystalyzation from MeOH afforded 1.7 g (77.0%) of the product as a light yellow solid.
Reaction SMILES: C(O[CH2:5][CH3:6])(=O)C.Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3[C:20]([C:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[C:22]4[C:27]=2[CH:26]=[CH:25][CH:24]=[CH:23]4)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=1.[CH3:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>>[C:20]1([C:21]2[C:28]3[C:33]([C:14]([C:11]4[CH:12]=[CH:13][C:8]([C:36]5[CH:35]=[CH:34][C:39]([C:36]6([C:6]7[CH:5]=[CH:13][CH:8]=[CH:9][CH:10]=7)[C:35]7[CH:27]=[CH:14][CH:11]=[CH:12][C:34]=7[C:16]7[C:37]6=[CH:38][CH:39]=[CH:20][CH:15]=7)=[CH:38][CH:37]=5)=[CH:9][CH:10]=4)=[C:27]4[C:22]=2[CH:23]=[CH:24][CH:25]=[CH:26]4)=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCCCC
Reactant: Brc1ccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)cc1
Reactant: CCOC(C)=O
Product: c1ccc(-c2c3ccccc3c(-c3ccc(-c4ccc(C5(c6ccccc6)c6ccccc6-c6ccccc65)cc4)cc3)c3ccccc23)cc1

Procedure:
The Rf value of the obtained pale yellow powder by silica gel thin layer chromatography (TLC) (with a developing solvent containing ethyl acetate and hexane in a 1:5 ratio) was 0.63, and that of 9-(4-bromophenyl)-10-phenylanthracene was 0.78.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Br[CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:14][C:13]([CH3:15])=[CH:12][CH2:11][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cccc(O)c1
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCOc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
3-Hydroxybenzonitrile (1.19 g, 10 mmol) and 4-bromo-2-methyl-2-butene (1.66 g, 10 mmol) were dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (1.66 g, 12 mmol) was added, and the solution was stirred at room temperature for 2 hours. Water (50 mL) was added to the reaction solution, which was then extracted with ethyl acetate (50 mL). The extract was washed, then, dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5), and the title compound (1.71 g, 10 mmol, 99.4%) was obtained as a colorless oil.
Reaction SMILES: [NH3:1].[CH3:2][O:3][C:4](=[O:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.ClCCl>C(#N)C>[CH3:2][O:3][C:4](=[O:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12]([NH2:1])(=[O:14])=[O:13])[CH:7]=1
Reactant: COC(=O)Cc1cccc(S(=O)(=O)Cl)c1
Reactant: N
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)Cc1cccc(S(N)(=O)=O)c1
Temperature: 22 °C
Reaction time: 2 h

Procedure:
0.880 Ammonia (0.027 ml) was added to a stirred solution of methyl[3-(chlorosulfonyl)phenyl]acetate (0.35 g) in a 1:1 mixture of dichloromethane and acetonitrile (1.75 ml), and the mixture was stirred at 22° C. for 2 h. The mixture was allowed to stand for a further 18 h, and the solvent was evaporated in vacuo. The residue was re-dissolved in dichloromethane and applied to a silica gel cartridge (10 g Varian Bond Elut, pre-conditioned with dichloromethane). The cartridge was eluted with dichloromethane, chloroform, ether, ethyl acetate, acetone, acetonitrile and methanol (1 column volume each), the fractions containing the product evaporated in vacuo, and the residue passed down a 5 g silica gel cartridge which was prepared and eluted in an identical manner. The product containing fractions were evaporated in vacuo to give a residue which was further purified using mass-directed preparative HPLC, to give the title compound as a colourless gum (0.018 g).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:13]([N:15]1[CH2:19][CH:18]([O:20][C:21]2[C:30]3[C:25](=C(Cl)[CH:27]=[CH:28][CH:29]=3)[N:24]=[C:23]([O:32][CH2:33][CH:34]([O:37][CH3:38])[O:35][CH3:36])[CH:22]=2)[CH2:17][CH:16]1[C:39](=[O:57])[NH:40][C:41]1([C:46]([NH:48][S:49]([O:52][C:53]2([CH3:56])[CH2:55][CH2:54]2)(=[O:51])=[O:50])=[O:47])[CH2:43][CH:42]1[CH2:44][CH3:45])=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O.[F:66][C:67]([F:85])([F:84])[C:68]([O:71][C:72](=[O:83])OC1C=CC([N+]([O-])=O)=CC=1)([CH3:70])[CH3:69].C(N(C(C)C)CC)(C)C.[CH2:95]([Cl:97])Cl>CO>[F:85][C:67]([F:66])([F:84])[C:68]([O:71][C:72](=[O:83])[NH:7][CH:8]([C:13]([N:15]1[CH2:19][CH:18]([O:20][C:21]2[C:30]3[C:25](=[C:95]([Cl:97])[CH:27]=[CH:28][CH:29]=3)[N:24]=[C:23]([O:32][CH2:33][CH:34]([O:35][CH3:36])[O:37][CH3:38])[CH:22]=2)[CH2:17][CH:16]1[C:39](=[O:57])[NH:40][C:41]1([C:46]([NH:48][S:49]([O:52][C:53]2([CH3:56])[CH2:54][CH2:55]2)(=[O:50])=[O:51])=[O:47])[CH2:43][CH:42]1[CH2:44][CH3:45])=[O:14])[C:9]([CH3:10])([CH3:11])[CH3:12])([CH3:69])[CH3:70]
Reactant: ClCCl
Reactant: CCC1CC1(NC(=O)C1CC(Oc2cc(OCC(OC)OC)nc3c(Cl)cccc23)CN1C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)C(=O)NS(=O)(=O)OC1(C)CC1
Reactant: CC(C)(OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCC1CC1(NC(=O)C1CC(Oc2cc(OCC(OC)OC)nc3c(Cl)cccc23)CN1C(=O)C(NC(=O)OC(C)(C)C(F)(F)F)C(C)(C)C)C(=O)NS(=O)(=O)OC1(C)CC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 47 %

Procedure:
(1-{4-[8-chloro-2-(2,2-dimethoxy-ethoxy)-quinolin-4-yloxy]-2-[2-ethyl-1-(1-methyl-cyclopropoxysulfonylaminocarbonyl)-cyclopropylcarbamoyl]-pyrrolidine-1-carbonyl}-2,2-dimethyl-propyl)-carbamic acid tert-butyl ester (444 mg, 0.520 mmol) was dissolved in CH2Cl2 (2.6 mL) and MeOH (0.21 mL, 5.20 mmol), and treated with TFA (2.6 mL). After stirring for 25 min at room temperature, MeOH (7 mL) was added and the solvents were removed in vacuo. The crude mixture was partitioned with saturated NaHCO3 and DCM. The layers were separated and the organic layer was dried over Na2SO4 and concentrated. The resultant residue was dissolved in DCM (5.2 mL) to which carbonic acid 4-nitro-phenyl ester 2,2,2-trifluoro-1,1-dimethyl-ethyl ester (183 mg, 0.624 mmol) and diisopropylethylamine (362 μL, 2.08 mmol) were added sequentially. After stirring for 24 h at 35° C., the reaction was purified by column chromatography on silica (3-7% MeOH/DCM) to provide (1-{4-[8-chloro-2-(2,2-dimethoxy-ethoxy)-quinolin-4-yloxy]-2-[2-ethyl-1-(1-methyl-cyclopropoxysulfonylaminocarbonyl)-cyclopropylcarbamoyl]-pyrrolidine-1-carbonyl}-2,2-dimethyl-propyl)-carbamic acid 2,2,2-trifluoro-1,1-dimethyl-ethyl ester (222 mg, 47% yield). LCMS found 908.0 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([CH2:13][C:14]#[N:15])[N:6]=1.[H][H].Cl[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][CH3:27])[C:20]=1[N+:28]([O-:30])=[O:29].Cl>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][CH3:27])[C:20]=2[N+:28]([O-:30])=[O:29])[C:14]#[N:15])[N:6]=1
Reactant: COCc1cccc(Cl)c1[N+](=O)[O-]
Reactant: COc1cc(OC)nc(CC#N)n1
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cccc(C(C#N)c2nc(OC)cc(OC)n2)c1[N+](=O)[O-]
Temperature: 10 °C
Yield: 64.8 %

Procedure:
11.2 g (0.28 M) of 60% sodium hydride was suspended in 100 ml of N,N-dimethylformamide. While the suspension was cooled to 10° C. or lower in an ice water bath and stirred, thereto was dropwise added a solution of 25 g (0.14 M) of 2-(4,6-dimethoxypyrimidine-2-yl)acetonitrile dissolved in 100 ml of N,N-dimethylformamide. After the completion of the dropwise addition, the mixture was stirred at room temperature until there was no evolution of hydrogen. While the mixture was cooled to 10° C. or lower in an ice water bath and stirred, thereto was dropwise added a solution of 28 g (0.14 M) of 2-chloro-6-methoxymethylnitrobenzene dissolved in 100 ml of dimethylformamide. Then, the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water. The mixture was acidified with 10% hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and water, dried and concentrated under reduced pressure. The resulting crystals were washed with a mixed solvent of ethanol and isopropyl ether to obtain 31 g (yield: 64%) of 2-(4,6-dimethoxypyrimidine-2-yl)-2-(3-methoxymethyl-2-nitrophenyl)acetonitrile as a reddish brown powder (melting point: 112 to 113° C).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:24]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:25]=1)=[O:11])([OH:6])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCCCCCCCCCOc1ccccc1CC(=O)OCC
Product: CCCCCCCCCCOc1ccc(C(=O)c2ccccc2C(=O)O)cc1CC(=O)OCC
Yield: 8 %

Procedure:
Following the procedure of Examples 30 and 31, phthalic anhydride and ethyl 2-decyloxybenzene acetate were reacted to provide the title product in 8% yield. The product was an oil.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)(=O)=O)=CC=1.[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[C:36](=[O:40])[NH:35][CH2:34]2>S1(CCCC1)(=O)=O.O>[Cl:29][C:26]1[CH:27]=[N:28][C:23]([N:20]2[CH2:19][CH2:18][CH:17]([C@H:15]3[CH2:16][C@H:14]3[CH2:13][CH2:12][NH:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[C:36](=[O:40])[NH:35][CH2:34]4)[CH2:22][CH2:21]2)=[N:24][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Reactant: Nc1ccc2c(c1)CNC2=O
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: O=C1NCc2cc(NCC[C@@H]3C[C@@H]3C3CCN(c4ncc(Cl)cn4)CC3)ccc21
Temperature: 120 °C
Reaction time: 2 h

Procedure:
2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl 4-methylbenzenesulfonate from step 1 of Example 5 (100 mg, 0.23 mmol) was dissolved in sulfolane and 5-aminoisoindolin-1-one (68 mg, 0.46 mmol) from step 3 of this example added. The mixture was at stirred 110° C. for 3 and at 120° C. for 2 hours. The mixture was cooled to RT, diluted with 4:1 water:saturated sodium bicarbonate (40 ml), extracted with EtOAc (3×30 ml), the organic fractions combined, washed with brine, dried over Na2SO4, filtered, the volatiles removed in vacuum. The product was purified by chromatography on SiO2 eluting with 80% acetone:hexanes to give the titled compound. LRMS calc: 411.18; obs: 412.08 (M+1). Compounds reported in Table 7 are prepared by a general procedure analogous to that described in Example 44 above.
Reaction SMILES: CON(C)[C:4](=[O:19])[CH2:5][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:21][C:22]1[CH:27]=[C:26](I)[C:25]([CH3:29])=[CH:24][N:23]=1>>[F:21][C:22]1[CH:27]=[C:26]([C:4](=[O:19])[CH2:5][CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:25]([CH3:29])=[CH:24][N:23]=1
Reactant: Cc1cnc(F)cc1I
Reactant: CON(C)C(=O)CC(c1ccccc1)c1ccccc1
Product: Cc1cnc(F)cc1C(=O)CC(c1ccccc1)c1ccccc1

Procedure:
In analogy to example 55, step 2, the title compound was prepared from N-methoxy-N-methyl-3,3-diphenyl-propionamide and 2-fluoro-4-iodo-5-picoline (CAS RN: [153034-94-7]) as a yellow liquid, MS (ESI+): m/z=320.1 ([M+H]+).
Reaction SMILES: ClCCl.[CH3:4][C:5]1[CH:37]=[CH:36][CH:35]=[CH:34][C:6]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH2:22][NH:21][CH:20]([CH3:24])[CH:19]2[C:25]23[O:32][CH2:31][C:28]([CH3:33])([CH2:29][O:30]2)[CH2:27][O:26]3)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[CH3:38][N:39]=[C:40]=[O:41]>C(OCC)(=O)C>[CH3:38][NH:39][C:40]([N:21]1[CH2:22][CH2:23][N:18]([S:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]3[CH:34]=[CH:35][CH:36]=[CH:37][C:5]=3[CH3:4])=[CH:14][CH:13]=2)(=[O:16])=[O:17])[CH:19]([C:25]23[O:32][CH2:31][C:28]([CH3:33])([CH2:29][O:30]2)[CH2:27][O:26]3)[CH:20]1[CH3:24])=[O:41]
Reactant: CN=C=O
Reactant: Cc1ccccc1COc1ccc(S(=O)(=O)N2CCNC(C)C2C23OCC(C)(CO2)CO3)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNC(=O)N1CCN(S(=O)(=O)c2ccc(OCc3ccccc3C)cc2)C(C23OCC(C)(CO2)CO3)C1C
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a dichloromethane (5 ml) solution of 1-[4-(2-methyl-benzyloxy)-benzenesulfonyl]-3-methyl-2-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-piperazine (compound of formula XLV, 1.78 g, 3.64 mmol) at about 0° C. was added methyl isocyanate (0.24 ml, 4.0 mmol). The reaction was allowed to stir for about 0.5 hour at about 23° C., was diluted with ethyl acetate and extracted with water. The organic layer was dried with sodium sulfate and then was concentrated to give 1.927 g of a compound of formula XLIV.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][N:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:25](I)[CH2:26][CH2:27][CH3:28].CN(C=O)C>C1COCC1.O>[C:1]([O:5][C:6]([N:8]([CH2:25][CH2:26][CH2:27][CH3:28])[CH:9]1[CH2:10][N:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)C1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCN(C(=O)OC(C)(C)C)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 19 h
Yield: 48.7 %

Procedure:
A solution of benzyl 3-[(tert-butoxycarbonyl)amino]azetidine-1-carboxylate obtained in Example (227a) (500 mg, 1.63 mmol) in THF (6 mL) was added to a suspension of sodium hydride (55%) (142 mg, 3.26 mmol) in THF (10 mL) at 0° C. Subsequently, butyl iodide (0.93 mL, 8.15 mmol) was added at 0° C., and the mixture was stirred at room temperature for 19 hours. DMF (2 mL) was added, followed by stirring for four hours. Then, sodium hydride (55%) (36 mg, 0.82 mmol) and butyl iodide (0.37 mL, 3.26 mmol) were added, followed by stirring for 2.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. Thereafter, the combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. Following filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=2/1) to obtain 288 mg of the title compound as a colorless oily substance (49%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[C:8]([Br:11])=[C:7]([NH:12][C@@H:13]2[CH2:18][C@@H:17]3[CH2:19][C@@H:15]([C:16]3([CH3:21])[CH3:20])[C@H:14]2[CH3:22])[CH:6]=[N:5]1.C(N(CC)CC)C.[N:30]1[CH:35]=[CH:34][C:33]([C:36](Cl)=[O:37])=[CH:32][CH:31]=1.O>ClCCl>[Br:11][C:8]1[C:9](=[O:10])[N:4]([CH2:3][CH2:2][NH:1][C:36]([C:33]2[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=2)=[O:37])[N:5]=[CH:6][C:7]=1[NH:12][C@@H:13]1[CH2:18][C@@H:17]2[CH2:19][C@@H:15]([C:16]2([CH3:21])[CH3:20])[C@H:14]1[CH3:22]
Reactant: O=C(Cl)c1ccncc1
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CCN)c(=O)c1Br)C2(C)C
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CCNC(=O)c3ccncc3)c(=O)c1Br)C2(C)C
Yield: 52.8 %

Procedure:
2-(2-Aminoethyl)-4-bromo-5-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one (28 mg, 0.0758 mmol) and triethylamine (21 μL, 0.152 mmol) in dichloromethane (1 mL) were stirred with pyridine-4-carbonyl chloride (20 mg, 0.112 mmol) at room temperature for 5 hours. After completion of the reaction, the reaction solution was mixed with water and extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol=9/1) to give the desired product (19 mg, 52% yield).