Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[S:9][C:10]2[CH2:11][N:12](C(=O)C(F)(F)F)[CH2:13][CH2:14][C:15]=2[N:16]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[S:9][C:10]2[CH2:11][NH:12][CH2:13][CH2:14][C:15]=2[N:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nc2c(s1)CN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1nc2c(s1)CNCC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of [5-(2,2,2-trifluoro-acetyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl]-carbamic acid tert-butyl ester (3.50 g, 9.86 mmol) in MeOH (75 mL) is added a solution of potassium carbonate (13.8 g; 98.6 mmol) in water (125 mL) and the reaction stirred at about 25° C. for 24 hours. The suspension is concentrated and the residue suspended in EtOAc (300 mL). This is washed with sat. NH4Cl (300 mL) then brine (100 mL). Solid product forms in the EtOAc layer. This is filtered off as crop 1. The aqueous layer is extracted with more EtOAc (3×300 mL) and the combined extracts washed with brine and dried (Na2SO4). Concentrate to a white solid and combine with the above precipitate. Triturate this in EtOAc (50 mL) and filter to give the title compound (N).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][C:13]=2[F:20])(=[O:11])=[O:10])[CH:5]=[N:6][CH:7]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[F:20])(=[O:10])=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cncc(Br)c2)c(F)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(Nc1cncc(Br)c1)c1ccc(O)cc1F
Reaction time: 8 h
Yield: 62.1 %

Procedure:
N-(5-Bromopyridin-3-yl)-2-fluoro-4-methoxybenzenesulfonamide (692 mg, 1.92 mmol) was dissolved in DCM (10 ml), the reaction flask was sealed and boron tribromide (5 ml, 1M solution in DCM) was added dropwise under an argon atmosphere. After stirring overnight at reflux, more boron tribromide was added (5 ml) and the mixture was refluxed for 18 h. After cooling in an ice bath, methanol was added dropwise and evaporated under reduced pressure. The mixture was poured into ice and extracted with ethyl acetate. The resulting organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by flash chromatography (0% to 5% DCM/MeOH) to give 414 mg (62% yield) of the title compound as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:6]=1)=[O:4].O1CCOCC1.S(=O)(=O)(O)O>O>[CH3:13][O:12][C:10]([C:8]1[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:9]=1)=[O:11]
Reactant: COC(=O)c1cc(C(=O)OC)n(Cc2ccc(OC)cc2)n1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(C(=O)O)nn1Cc1ccc(OC)cc1
Temperature: 65 °C
Reaction time: 48 h

Procedure:
In a round bottom flask, 1-(4-methoxy-benzyl)-1H-pyrazole-3,5-dicarboxylic acid dimethyl ester (104, 28.5 g, 93.6 mmol) was combined with 100 mL of water and 20 mL of 1,4-dioxane. Sulfuric acid (5.5 mL, 100 mmol) and 2.0 mL of water were added and the reaction was stirred for 2 days at 60-70° C. The reaction was concentrated under vacuum until a precipitate formed. The solid was collected by filtration and washed with cold water several times to provide the desired compound. 1H NMR was consistent with the compound structure.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:40]1[C:52]2[CH:51]([CH2:53][NH2:54])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]=2[CH:43]=[CH:42][CH:41]=1>>[C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2[NH:54][CH2:53][CH:51]1[C:52]2[CH:40]=[CH:41][CH:42]=[CH:43][C:44]=2[C:45]2[C:50]1=[CH:49][CH:48]=[CH:47][CH:46]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: NCC1c2ccccc2-c2ccccc21
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC4c5ccccc5-c5ccccc54)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1

Procedure:
Prepared from ((2R,3R,4S,5S)-4-(benzoyloxy)-2-(6-chloro-2-iodo-9H-purin-9-yi)-5-[(ethylamino)carbonyl]-tetrahydro-3-furanyl benzoate (Preparation 19) and 9H-fluoren-9-ylmethylamine by the same method as Preparation 20. The title compound was obtained as a yellow foam.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([O:37][CH2:38][CH2:39][CH3:40])=[C:16]([C:18]3[NH:19][C:20](=[O:36])[C:21]4[N:22]([C:27]5[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=5)[CH:23]=[N:24][C:25]=4[N:26]=3)[CH:17]=2)(=[O:11])=[O:10])[CH2:5][CH2:4]1)[CH3:2]>C(O)(=O)C.O.[Fe]>[NH2:33][C:30]1[CH:31]=[CH:32][C:27]([N:22]2[C:21]3[C:20](=[O:36])[NH:19][C:18]([C:16]4[CH:17]=[C:12]([S:9]([N:6]5[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:8][CH2:7]5)(=[O:10])=[O:11])[CH:13]=[CH:14][C:15]=4[O:37][CH2:38][CH2:39][CH3:40])=[N:26][C:25]=3[N:24]=[CH:23]2)=[CH:28][CH:29]=1
Reactant: CCCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2ncn(-c3ccc([N+](=O)[O-])cc3)c2c(=O)[nH]1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CCCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2ncn(-c3ccc(N)cc3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
Iron powder (137 mg, 2.45 mmol) was added to a solution of 2-[5-(4-ethylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl]-7-(4-nitrophenyl)purin-6-one (Example 11; 110 mg, 0.19 mmol) in acetic acid (2.2 mL) and water (100 μL), and the reaction stirred vigorously at room temperature for 3 hours. The mixture was filtered through Celite®, washing well with ethyl acetate, and the filtrate concentrated under reduced pressure. The residue was partitioned between ethyl acetate and sodium bicarbonate solution, the layers separated, and the organic phase dried (MgSO4) and evaporated under reduced pressure to give the title compound (80 mg, 79%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[N:18][CH:19]=1.N1(C=O)CC[O:24][CH2:23]C1>C1COCC1>[Cl:13][C:14]1[CH:19]=[N:18][C:17]([F:20])=[C:16]([CH:15]=1)[CH:23]=[O:24]
Reactant: Fc1ccc(Cl)cn1
Reactant: O=CN1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1cc(Cl)cnc1F
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 73.8 %

Procedure:
To a cold (0° C.) solution of diisopropylamine (12.8 mL, 91.2 mmol) in THF (100 mL) was added butyllithium (31.9 mL of 2.5 M, 79.8 mmol) over 5 min. After 5 min, the reaction was cooled to −78° C. for 15 min. Then 5-chloro-2-fluoro-pyridine (10.0 g, 76.0 mmol) was slowly added over 5 min. The reaction was kept at −78° C. for an additional 1.5 hr. Then, morpholine-4-carbaldehyde (17.5 g, 152.1 mmol) was added rapidly. The mixture was stirred for a further 2 min and quenched with 10% citric acid and the mixture was allowed to warm to room temperature. The pH was adjusted to 5-6 with additional citric acid solution. The mixture was extracted with dichloromethane (3×200 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated. Flash chromatography (SiO2, 0-25% EtOAc-Hexanes, gradient elution) provided the desired product as an off-white crystalline solid (8.95 g, 74% yield). LC-MS shows the mass for the desired product and the corresponding hydrate: 1H NMR (300 MHz, CDCl3) δ 10.28 (d, J=8.4 Hz, 1H), 8.41 (t, J=1.4 Hz, 1H) and 8.25 (dd, J=2.7, 7.8 Hz, 1H) ppm; LC/MS Gradient 10-90%, 0.1% formic 5 min, C18/ACN, RT=2.45 min, (M+H) 159.91.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.Cl>C1COCC1>[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]([OH:15])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:12][CH:11]=1
Reactant: CCCCCC[Mg]Br
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCC(O)c1ccc(Br)cc1
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
n-Hexyl magnesium bromide (2.0 M in Et2O, 27 mL, 54 mmol) was added to a solution of 4-bromobenzaldehyde (5.0 g, 27 mmol) in THF (20 mL) at 0° C. under nitrogen. After 1.5 h at 0° C., the reaction was 3 N HCl (20 mL) and concentrated in vacuo. The residue was diluted with water (30 mL) and extracted with Et2O (3×150 mL). Combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (5%→10% EtOAc/Hex) afforded 5.6 g (76%) of 1-(4-bromophenyl)-heptan-1-ol.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH3:16])=[C:11]([CH2:13][CH2:14]Cl)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:24][O:25][C:21]=2[CH:20]=1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH3:16])=[C:11]([CH2:13][CH2:14][N:29]3[CH2:28][CH2:27][CH:26]([C:23]4[C:22]5[CH:32]=[CH:33][C:19]([F:18])=[CH:20][C:21]=5[O:25][N:24]=4)[CH2:31][CH2:30]3)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)N1CCc2c(sc(CCCl)c2C)C1
Agent: Cl
Product: CC(=O)N1CCc2c(sc(CCN3CCC(c4noc5cc(F)ccc45)CC3)c2C)C1

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.0 g of 6-acetyl-2-(2-chloroethyl)-4,5,6,7-tetrahydro-3-methylthieno[2,3-c]pyridine and 1.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 6-acetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-3-methylthieno[2,3-c]pyridine as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][N:13]([CH:17]3[CH2:20][CH2:19][CH2:18]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:21]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]1.C1OCCOCCOCCOCCOCCOC1.[OH-].[K+]>C1(C)C=CC=CC=1.O>[CH:17]1([N:13]2[CH2:14][CH2:15][CH2:16][N:10]([C:8]([C:5]3[CH:6]=[N:7][C:2]([O:27][CH:24]4[CH2:25][CH2:26][O:21][CH2:22][CH2:23]4)=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)[CH2:20][CH2:19][CH2:18]1
Reactant: O=C(c1ccc(Cl)nc1)N1CCCN(C2CCC2)CC1
Reactant: OC1CCOCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(c1ccc(OC2CCOCC2)nc1)N1CCCN(C2CCC2)CC1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a solution of (6-chloro-pyridin-3-yl)-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone (32.7 g, 111.3 mmol) in toluene (470 mL) was added tetrahydro-pyran-4-ol (13.6 g, 133.6 mmol), 18-crown-6 (1.47 g, 5.565 mmol), and then KOH (pulverized solid, 20.6 g, 367.3 mmol). The resulting heterogeneous mixture was warmed to 110° C. and stirred for 3 h. After cooling to room temperature, water (470 mL) was added and the resulting layers were thoroughly mixed and then separated. The organic extract was dried over magnesium sulfate, filtered, and concentrated to yield the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH2:11][CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[C:7]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=1[OH:24])([CH3:4])([CH3:3])[CH3:2].[H][H]>O1CCCC1.[Pd]>[C:20]([C:7]1[CH:8]=[C:9]([CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1cc(CC=Cc2ccccc2)cc(C(C)(C)C)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CCCc2ccccc2)cc(C(C)(C)C)c1O
Yield: 82.8 %

Procedure:
2,6-Di-t-butyl-4-cinnamylphenol (30 g., prepared as described in Example 2) was catalytically hydrogenated at room temperature and pressure in tetrahydrofuran (100 ml.) in the presence of 5% palladium on charcoal. The reaction was allowed to proceed until uptake of hydrogen ceased. The mixture was filtered and the filtrate was evaporated to an oil. Distillation of the oil gave the desired compound (25 g.) as an oil, b.p. 195°-200° C. at 10.5 mm. Hg. The nmr spectrum in CDCl3 at 100 MHz exhibited absorbances as follows: a singlet (9 protons) at δ 1.40, a singlet (9 protons) at δ 1.43, a multiplet (2 protons) at δ 1.75-2.10, a multiplet (4 protons) at δ 2.43-2.82, a singlet (1 proton) at δ 5.00, a singlet (2 protons) at δ 6.98, and a multiplet (5 protons) at δ 7.08-7.40.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[C:3]=1F.O.[NH2:15][NH2:16]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[C:3]=1[NH:15][NH2:16]
Reactant: Fc1cc(C(F)(F)F)cc(F)c1F
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1c(F)cc(C(F)(F)F)cc1F

Procedure:
A mixture of 1,2,3-trifluoro-5-(trifluoromethyl)benzene (300 g, 1.5 mmol) and hydrazine monohydrate (300 g, 6.0 mmol) in ethanol (1200 ml) was heated at reflux overnight. The reaction mixture was concentrated in vacuo and the residue was re-crystallised from 2-propanol to give Preparation 21 (194 g).
Reaction SMILES: ClC1N=CC([CH2:8][N:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3=[N:19][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:21](=[O:22])[C:11]3=[CH:10]2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:36][N:37]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[N:38]1>O1CCCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:20]1[C:21](=[O:22])[C:11]2=[CH:10][N:9]([CH2:8][C:12]3[CH:13]=[C:18]([C:40]4[CH:39]=[N:38][N:37]([CH3:36])[CH:41]=4)[N:9]=[CH:10][CH:11]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]2=[N:19]1
Reactant: O=c1c2cn(Cc3ccc(Cl)nc3)c3ccccc3c-2nn1-c1ccccc1F
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Cn1cc(-c2cc(Cn3cc4c(=O)n(-c5ccccc5F)nc-4c4ccccc43)ccn2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-[(6-Chloropyridin-3-yl)methyl]-2-(2-fluorophenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 225, 40 mg, 0.10 mmol), bis(tri-tert-butylphosphine)palladium(0) (5.0 mg, 0.010 mmol, 0.1 equiv), cesium carbonate (0.20 mL, 1 M aqueous, 0.20 mmol, 2 equiv) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (35 mg, 0.17 mmol, 1.7 equiv) were suspended in tetrahydrofuran (1 mL) and the mixture was irradiated (high setting) for 10 minutes at 140° C. The mixture was cooled to ambient temperature, the organic layer removed, stirred with Quadrapure® (40 mg, 1 wt equiv) for 1 hour, filtered and purified by reverse phase HPLC (80:20 to 5:95; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.16 (1H, s), 8.65 (1H, d, J=2.2 Hz), 829 (1H, s), 8.20 (1H, dd, J=7.8, 1.4 Hz), 7.99 (1H, s), 7.83 (1H, d, J=8.7 Hz), 7.76 (1H, dd, J=8.2, 2.0 Hz), 7.66-7.58 (3H, m), 7.54 (1H, t, J=7.5 Hz), 7.48-7.37 (2H, m), 7.34 (1H, td, J=7.7, 1.5 Hz), 5.76 (2H, s), 3.87 (3H, s) ppm; low resolution mass spectrometry (ES+) m/z 451.0 [(M+H)+; calculated for C26H20FN6O: 451.2].
Reaction SMILES: [NH2:1][C:2]1([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.CCN(CC)CC.[N:22]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:27][CH:26]=1)=[C:23]=[O:24]>C(Cl)Cl>[CH3:8][N:5]1[CH2:4][CH2:3][C:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([NH:1][C:23]([NH:22][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:27][CH:26]=2)=[O:24])[CH2:7][CH2:6]1
Reactant: CCCCCCCCc1ccc(N=C=O)cc1
Reactant: CCOC(=O)CC1(N)CCN(C)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCc1ccc(NC(=O)NC2(CC(=O)OCC)CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
A stirred solution of ethyl 2-(4-amino-1-methylpiperidin-4-yl)acetate (62 mg, 0.308 mmol) in CH2Cl2 (2 mL) was treated with NEt3 (0.13 mL, 0.924 mmol.), and 1-isocyanato-4-octylbenzene (0.071 mL, 0.308 mmol). The reaction was stirred overnight, at room temperature, then the solvent removed in vacuo and the product purified by column chromatography to obtain the title compound (94 mg, 71%). 1H NMR (400 MHz, CDCl3) δ 7.19 (d, 2H, J=8.4 Hz), 7.12 (d, 2H, J=8.4 Hz), 6.45 (bs, 1H), 4.78 (bs, 1H), 4.09 (q, 2H, J=7.2 Hz), 2.90 (s, 2H), 2.58-2.48 (m, 4H), 2.39-2.19 (m, 4H), 2.25 (s, 3H), 1.75-1.70 (m, 2H), 1.60-1.54 (m, 2H), 1.30-1.23 (m, 13H), 0.80 (t, 3H, 6.4 Hz); MS ESI 432.4 [M+H]+, calcd for [C25H41N3O3+H]+ 432.62.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:33])[C@H:21]([CH3:32])[NH:22][C:23](=[O:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[F:34]C1C=CC=CC=1CC(O)=O>>[F:34][C:30]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:24][C:23]([NH:22][C@H:21]([C:20]([NH:19][C@@H:3]1[C:2](=[O:1])[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@@H:4]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:33])[CH3:32])=[O:31]
Reactant: O=C(O)Cc1ccccc1F
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Product: C[C@H](NC(=O)Cc1ccccc1F)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1

Procedure:
A method similar to the one described for (113) was used except that 2-fluorophenylacetic acid (77 mg) was used instead of phenylacetic acid to afford the title compound as a 1:1 mixture with the 2S,3R diastereomer (150 mg), white solid, m.p. 115-135° C. 1H NMR (300 MHz, CDCl3) δ 0.97 (d, 1.5H, J=5 Hz), 1.25 (d, 1.5H, J=5 Hz), 3.49 (m, 2H), 4.63 (p, 0.5H, J=7 Hz), 4.75 (p, 0.5H, J=7 Hz), 4.85 (t, 1H, J=6 Hz), 5.11 (t, 1H, J=6 Hz), 5.80 (dd, 1H, J=7 Hz, J=10 Hz), 6.08 (d, 0.5H, J=8 Hz), 6.27 (d, 0.5 Hz, J=8 Hz), 6.38 (d, 0.5 h, J=6 Hz), 6.66 (d, 0.5H, J=7 Hz), 6.78-7.34 (m, 13H), 8.02 (s, 1H). MS APCI, m/z=484 (M+Na). LC/MS: 2.09 min.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10](Br)[CH:11]=[CH2:12].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:12]([O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH:11]=[CH2:10]
Reactant: N#Cc1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(C#N)cc1

Procedure:
4-Hydroxybenzonitrile (30.0 g, 251.8 mmol), allyl bromide (39.6 g, 327.4 mmol), and cesium carbonate (98.5 g, 302.2 mmol) were dissolved in DMF (900 mL), and 1 mL water was added. After stirring for 12 h at ambient temperature, most of the DMF was removed in vacuo. Water was added and the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with H2O and brine. The organic layer was dried over Na2SO4, filtered, and the solvent was removed in vacuo. The title compound was obtained as a white crystalline material (40 g, 100%). 1H NMR (400 MHz, CDCl3) δ 4.60 (d, 2H), 5.34 (d, 1H), 5.43 (d, 1H), 6.03 (m, 1H), 6.96 (d, 2H), 7.58 (d, 2H).
Reaction SMILES: [Li+].[OH-].[CH3:3][N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([O:12]C)=[O:11])[C:5]1=[O:14].Cl>C1COCC1.CO>[CH3:3][N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([OH:12])=[O:11])[C:5]1=[O:14]
Reactant: COC(=O)c1cccn(C)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cccc(C(=O)O)c1=O
Reaction time: 2 h
Yield: 44.2 %

Procedure:
LiOH (1.3 mL, 1.3 mmol, 1.0 M) was added to a solution of methyl 1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (0.11 g, 0.65 mmol) in a mixture of THF-MeOH (3:1 ratio, 8 mL) at room temperature. After stirring for 2 hours, 1 N HCl (1.3 mL) was added. The reaction mixture was extracted with EtOAc, dried over MgSO4, and concentrated to give the desired product (0.044 g, 44% for 2 step process).
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].CN(C=O)C.[H-].[Na+].[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32][N:1]3[C:12](=[O:13])[C:11]4[N:9]([CH3:10])[CH:8]=[N:7][C:6]=4[N:4]([CH3:5])[C:2]3=[O:3])=[CH:30][CH:29]=2)=[O:27])=[CH:36][CH:37]=1
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cnc2c1c(=O)n(Cc1ccc(C(=O)c3ccc(Cl)cc3)cc1)c(=O)n2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.1 %

Procedure:
To a mixture of theobromine (0.90 g) and DMF (20 ml) was added sodium hydride (240 ml) as well as 4-(4-chlorobenzoyl)benzyl bromide (1.55 g) and the mixture was stirred at room temperature for 18 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was washed with ether to provide the title compound as colorless powder (1.37 g, 67%). 1H-NMR (CDCl3) δ: 3.60(3H,s), 4.00(3H,s), 5.27(2H,s), 7.38-7.79(8H,m)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[CH:15]([OH:18])[CH2:16][CH3:17].Cl[C:20](Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl>>[Cl:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:20](=[O:22])[O:18][CH:15]([CH2:16][CH3:17])[C:3]=3[CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CCC(O)c1cc(-c2cccc(Cl)c2)ccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CCC1OC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21

Procedure:
Prepared according to the procedure of Example 9 from 1-(4-amino-3′-chloro-biphenyl-3-yl)-propanol and triphosgene. White solid: mp 146-148° C.; 1H-NMR (DMSO-d6) δ 10.3 (s, 1H), 7.70 (m, 1H), 7.60 (m, 3H), 7.47 (t, 1H, J=8.22 Hz), 7.39 (d, 1H, J=8.28 Hz), 6.97 (d, 1H, J=8.22 Hz), 5.4 (t, 1H, J=10.9 Hz), 1.9 (m, 2H), 0.97 (t, 3H, J=7.68 Hz); MS (ESI) m/z 286 ([M−H]−, 100%)
Reaction SMILES: O.NN.[CH3:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:30]>C(O)C>[NH2:19][CH2:18][CH2:17][CH2:16][O:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:5]([CH3:4])[C:6](=[O:30])[CH:7]=[CH:8]2
Reactant: Cn1c(=O)ccc2cc(OCCCN3C(=O)c4ccccc4C3=O)ccc21
Agent: NN
Solvent: CCO
Solvent: O
Product: Cn1c(=O)ccc2cc(OCCCN)ccc21
Yield: 77 %

Procedure:
Hydrazine hydrate (6.54 ml) was added to a ethanol solution (250 ml) of 2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]isoindole-1,3-dione (16.28 g), and stirred while heating under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure. A 1N-sodium hydroxide aqueous solution was added to the residue, and stirred for 30 minutes, and extraction with dichloromethane was performed. The organic layer was washed with water and a saturated sodium chloride aqueous solution, in this order. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound(8.04 g) as a colorless oil.
Reaction SMILES: [Cl-].Cl[CH2:3][CH2:4][NH2+:5][CH:6]([CH2:8][CH3:9])[CH3:7].[CH3:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[N:20]=[C:21]=[S:22]>>[CH3:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[N:20]=[C:21]1[N:5]([CH:6]([CH2:8][CH3:9])[CH3:7])[CH2:4][CH2:3][S:22]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CCC(C)[NH2+]CCCl
Agent: [Cl-]
Product: CCC(C)N1CCSC1=Nc1ccc([N+](=O)[O-])cc1C

Procedure:
2-Butylamine was converted to N-(2-hydroxyethyl)-N-(2-butyl)amine according to Method B5a. The amine was reacted with SOCl2 according to Method B7a to give N-(2-chloroethyl)-N-(2-butyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give to give 2-(2-methyl-4-nitrophenylimino)-3-(2-butyl)-1,3-thiazolidine.