Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)=[O:19])=[CH:15][C:14]([C:34]([CH3:37])([CH3:36])[CH3:35])=[N:13]2)=[CH:8][CH:7]=1)C.[Li+].[OH-]>C1COCC1.O.CCO.Cl>[C:34]([C:14]1[CH:15]=[C:16]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)=[O:19])[N:12]([C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C:4]([OH:38])=[O:3])=[CH:11][CH:10]=2)[N:13]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CCOC(=O)Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(CC(=O)O)cc2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.6 %

Procedure:
To a suspension of ethyl(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]-amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)acetate (2.42 g, 4.72 mmol) in THF/H2O/EtOH (3:1:1, 50 mL) was added LiOH (0.34 g, 14.15 mmol) and the resulting reaction mixture was stirred at room temperature for 2.5 h. The mixture was evaporated at reduced pressure to afford a syrup-type residue. The residue was dissolved in 1N HCl, and then the acidity was adjusted to pH ˜7. The mixture was washed with EtOAc, and then the aqueous phase was acidified to pH 5-6. The white precipitate that formed was collected by filtration, washed with water and hexane, and air-dried to afford the product as a white solid (2.1 g) in 92% yield. 1H-NMR (DMSO-d6) δ 12.45 (broad, 1H), 9.64 (broad, 1H), 8.98 (broad, 1H), 8.38 (dd, JJ=1.6 Hz, 4.7 Hz, 2H), 7.51-7.42 (m, 4H), 7.36 (d, J=8.3 Hz, 2H), 7.05 (dd, JJ=2.1 Hz, 6.9 Hz, 2H), 6.84 (dd, JJ=1.6 Hz, 4.7 Hz, 2H), 6.31 (s, 1H), 3.58 (s, 2H), 1.27 (s, 9H); MS LC-MS [M+H]+=486.2, RT=2.39 min.
Reaction SMILES: [Br-].[K+].[C:3]([O:7][C:8](=[O:15])[NH:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])([CH3:6])([CH3:5])[CH3:4].C(=O)(O)[O-].[Na+].Cl[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.CC1CCC[N+]([O-])(C)C1(C)C>[C:3]([O:7][C:8](=[O:15])[NH:9][C:10]([CH3:14])([CH3:13])[CH:11]=[O:12])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Agent: CC1CCC[N+](C)([O-])C1(C)C
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC(C)(C=O)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
0.94 g of tetramethylpiperidine N-oxide (6.0 mmol) and 3.57 g of potassium bromide (30 mmol) were added to a solution of 56.78 g of (2-hydroxy-1,1-dimethylethyl)carbamic acid t-butyl ester obtained in Reference Example (3a) (300 mmol) in a mixture of methylene chloride (500 ml) and a saturated sodium bicarbonate aqueous solution (525 ml) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. 534 ml of a 5% sodium hypochlorite aqueous solution (360 mmol) was added to the reaction mixture under ice-cooling over 1.5 hours, and the mixture was stirred at the same temperature for 20 minutes. A saturated sodium thiosulfate aqueous solution was added to the reaction mixture, and the reaction mixture was returned to room temperature, followed by extraction with methylene chloride. Then, the organic layer was washed with brine and then dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. Hexane was added to the residue, and the solid was collected by filtration to obtain 42.32 g of the title compound (yield: 79%).
Reaction SMILES: [N:1]1[C:8]([F:9])=[N:7][C:5](F)=[N:4][C:2]=1[F:3].[NH2:10][C:11]1[C:12]([OH:45])=[C:13]([N:21]=[N:22][C:23]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N:24][NH:25][C:26]2[CH:31]=[C:30]([S:32]([OH:35])(=[O:34])=[O:33])[CH:29]=[CH:28][C:27]=2[C:36]([OH:38])=[O:37])[CH:14]=[C:15]([S:17]([OH:20])(=[O:19])=[O:18])[CH:16]=1.[OH-].[Na+].Cl>O>[F:9][C:8]1[N:1]=[C:2]([F:3])[N:4]=[C:5]([NH:10][C:11]2[C:12]([OH:45])=[C:13]([N:21]=[N:22][C:23]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[N:24][NH:25][C:26]3[CH:31]=[C:30]([S:32]([OH:35])(=[O:33])=[O:34])[CH:29]=[CH:28][C:27]=3[C:36]([OH:38])=[O:37])[CH:14]=[C:15]([S:17]([OH:20])(=[O:19])=[O:18])[CH:16]=2)[N:7]=1
Reactant: Fc1nc(F)nc(F)n1
Reactant: Nc1cc(S(=O)(=O)O)cc(N=NC(=NNc2cc(S(=O)(=O)O)ccc2C(=O)O)c2ccccc2)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(S(=O)(=O)O)cc1NN=C(N=Nc1cc(S(=O)(=O)O)cc(Nc2nc(F)nc(F)n2)c1O)c1ccccc1
Reaction time: 0.25 h

Procedure:
9.65 parts of cyanuric fluoride are added to a neutral solution of 35.80 parts of the copper complex of 5-amino-3-[3-phenyl-5-(2-carboxy-5-sulfophenyl)-1-formazano]-4-hydroxybenzenesulfonic acid in 350 parts of water at 0 to 2° C. in the course of 10 minutes. During the addition the pH is kept at 5.8 to 6 with a 15% sodium hydroxide solution. After the addition the mixture is stirred for about 15 minutes, the pH is brought to 3.5 to 3.8 with 32% hydrochloric acid and the mixture is stirred again for about 15 minutes. The pH is then brought to about 5.8 to 6 with a 15% sodium hydroxide solution. A solution of 5-[4,6-difluoro-1,3,5-triazin-2-ylamino]-3-[3-phenyl-5-(2-carboxy-5-sulfophenyl)-1-formazano]-4-hydroxybenzenesulfonic acid is obtained.
Reaction SMILES: C([Li])CCC.[Li+].CC([N-]C(C)C)C.[S:14]1[C:18]2[C:19]([C:22]([OH:24])=[O:23])=[CH:20][S:21][C:17]=2[N:16]=[N:15]1.[Cl:25]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1.O>[Cl:25][C:20]1[S:21][C:17]2[N:16]=[N:15][S:14][C:18]=2[C:19]=1[C:22]([OH:24])=[O:23]
Reactant: O=C(O)c1csc2nnsc12
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1c(Cl)sc2nnsc12
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 98.7 %

Procedure:
79 ml (201.6 mmol) of n-butyllithium (1.6M in hexane) are added at -30° C., under nitrogen, to a solution of 20.4 g (201.6 mmol) of diusopropylamine in 200 ml of tetrahydrofuran (THF). After 20 minutes' stirring at -20° C., the LDA solution so prepared is added dropwise at -90° C., under nitrogen, by means of a capillary, to a suspension of 15.0 g (80.6 mmol) of thieno[2,3-d]1,2,3-thiadiazole-6-carboxylic acid in 150 ml of THF. After 90 minutes' stirring at -50° C., a solution of 42.0 g (177.2 mmol) of hexachloroethane in 70 ml of THF is added at -90° C. and the reaction mixture is heated to room temperature within a period of 2 hours. Then the reaction mixture is poured onto 2 litres of water, the aqueous phase is extracted with diethyl ether and acidified with concentrated hydrochloric acid, and the product is isolated by filtration. There are obtained 17.55 g of light-brown solid having a melting point of 255°-265° C. (decomposition).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=1>>[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH:16]=1
Reactant: Brc1cncc2cccnc12
Reactant: COC(=O)c1ccc(C#N)c(B2OC(C)(C)C(C)(C)O2)c1
Product: COC(=O)c1ccc(C#N)c(-c2cncc3cccnc23)c1

Procedure:
Using, 8-bromo-[1,6]naphthyridine (1 mol. eq.) and 4-cyano-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (2.0 mol. eq.) as starting materials, the product was prepared using General procedure L (Suzuki) to give the title compound. MS(ESI) m/z 290.1 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1.C1C[O:32]CC1>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]=1[CH2:19][CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][OH:32])=[CH:26][CH:27]=1
Reactant: Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Lithium aluminum hydride (61 mL of a 1.0 M solution in THF) is added to a solution of the title A compound, 5-methyl-2-phenyl-4-(2-p-tolyloxy-ethyl)-oxazole (8.22 g, 24.36 mmol) in THF (200 mL) at 0° C. The mixture is stirred at 0° C. for 5 h, then at RT overnight. The reaction mixture is then cooled in an ice-water bath and quenched with saturated aqueous sodium bicarbonate and concentrated under vacuum to remove some of the THF. The residue is extracted with EtOAc, and the resulting organic phase is washed with brine, dried with magnesium sulfate, and concentrated under vacuum to give {4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-methanol as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([O:29]C)=[O:28])=[N:25][CH:26]=3)[O:18][N:17]=2)[N:3]=1.[OH-].[Na+]>CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([OH:29])=[O:28])=[N:25][CH:26]=3)[O:18][N:17]=2)[N:3]=1
Reactant: COC(=O)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(C(=O)O)nc3)n2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of (methyl 5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)pyridine-2-carboxylate) (prepared in an analogous manner to Example 279, 500 mg, 1.23 mmol) in MeOH (20 mL) was added a 1M sodium hydroxide aq. solution (1.85 mL, 1.85 mmol). The solution was stirred at room temperature overnight and evaporated to dryness. The resulting solid was dissolved in water (20 mL) and the solution acidified to pH 3 with a 1M HCl aq. solution. The resulting solid was filtered and dried to afford the desired product as a beige solid (418 mg, 87%). Method C HPLC-MS: MH+ requires m/z=391. Found: m/z=390.9, Rt=1.16 min (95%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:10]=[C:9]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH:23]([CH3:25])[CH3:24])=[CH:4][CH:3]=1.[CH3:26][S:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28].C([O-])([O-])=O.[K+].[K+].COCCOC>CCOC(C)=O.O>[CH:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH:35]=3)=[CH:3][CH:4]=2)[CH:12]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:10]=1)([CH3:25])[CH3:24]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)c1ccccc1-c1nc(C(C)(C)O)cn1-c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CC(C)c1ccccc1-c1nc(C(C)(C)O)cn1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
To a 50 mL round bottom flask attached with Vigreux column and magnetic stir bar was added 2-[1-(4-Bromo-phenyl)-2-(2-isopropyl-phenyl)-1H-imidazol-4-yl]-propan-2-ol (297 mg, 743 μmol), 3-methylsulfonylphenyl boronic acid (193 mg, 968 μmol), PdCl2dppf (60 mg, 10 mol %), K2CO3 (310 mg, 2.23 mmol), 1,2-dimethoxyethane (14 mL) and H2O (4 mL). The reaction solution was allowed to stir at 80° C. for 2 hrs. The reaction solution was diluted with EtOAc (150 mL) and filtered through a Celite padded Buchner funnel to remove spent Pd. The filtrate was transferred to a separatory funnel and washed with aq NH4Cl (100 mL) and aq NaCl (100 mL). The organic phase was dried over Na2SO4, filtered, concentrated on the Rotavapor and chromatographed through a 25 g SiO2 column using a mobile phase gradient of 100% Hx to 90% EtOAc to afford 303 mg (86% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 8.14 (s, 1H), 8.02 (d, 1H), 7.89 (d, 1H), 7.89 (d, 1H), 7.78 (d, 2H), 7.72 (t, 1H), 7.37-7.34 (m, 3H), 7.26 (d, 2H), 7.18-7.16 (m, 2H), 4.84 (s, 1H), 3.26 (s, 3H), 2.85 (sept, 1H), 1.50 (6H), 0.96 (d, 6H); MS (ES): 475.4 [M+H]+, 497.5 [M+Na]+.
Reaction SMILES: C([N:4]1[C:16]2[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=O)C.[C:18]1([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:31][CH:30]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>[Cu]=O>[CH:6]1[C:5]2[NH:4][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[C:8]([N:28]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[C:29]2[CH:34]=[CH:33][C:32]([N:35]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:31][CH:30]=2)[CH:7]=1
Reactant: CC(=O)n1c2ccccc2c2cc(Br)ccc21
Reactant: c1ccc(N(c2ccccc2)c2ccc(Nc3cccc4ccccc34)cc2)cc1
Agent: O=[Cu]
Product: c1ccc(N(c2ccccc2)c2ccc(N(c3ccc4[nH]c5ccccc5c4c3)c3cccc4ccccc34)cc2)cc1
Temperature: 170 °C
Yield: 69.6 %

Procedure:
A mixture of 1.2 g of 9-acetyl-3-bromocarbazole and 2.2 g of N′-1-naphthyl-N,N-diphenyl-1,4-benzenediamine were stirred together in 20 ml N,N′-dimethylacetamide. To this was added 0.8 g of copper oxide and heated to 170° C. for 24 h. The reaction was quenched with water and the solid was filtered, washed with methanol, and dried under vacuum. The solid was then taken up for further deprotection using 0.6 g KOH with TI-IF (3 ml), methanol (6 ml) and water (6 ml) at reflux temperature. The reaction mixture was then extracted using ethyl acetate; and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. Subsequent silica gel column chromatography using toluene/hexane (½) as eluent, yielded 1.6 g of N-(9H-carbazol-3-yl)-N-(naphthalen-1-yl)-N′,N′-diphenylbenzene-1,4-diamine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[O:11])=[CH:6][CH:7]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(CCc1ccc(OCc2ccccc2)cc1)OCc1ccccc1
Yield: 89.3 %

Procedure:
3-(4-Hydroxyphenyl)propionic acid (5 g), potassium carbonate (16 g) and tetrahydrofuran (50 ml) were placed in a three-necked flask, 8.5 ml of benzyl bromide was added dropwise through a syringe under stirring, and the mixture was heated under reflux overnight. After filtering off the solid matters, the solvent was distilled off, and the residue was purified by column chromatography on silica gel (50 g), affording 9.25 g (89.3%) of pure benzyl 3-(4-benzyloxyphenyl)propionate.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([NH2:16])[C:9]=2[CH3:17])[CH2:5][C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][CH3:22].Cl.[CH2:25]([O:27][NH2:28])[CH3:26]>>[CH2:25]([O:27][N:28]=[C:19]([C:3]1[C:4](=[O:18])[CH2:5][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([NH2:16])[C:9]=2[CH3:17])[CH2:7][C:2]=1[OH:1])[CH2:20][CH2:21][CH3:22])[CH3:26]
Reactant: CCON
Reactant: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)c(N)c2C)CC1=O
Agent: Cl
Product: CCCC(=NOCC)C1=C(O)CC(c2c(C)cc(C)c(N)c2C)CC1=O

Procedure:
Reaction of 3-hydroxy-5-(3-amino-2,4,6-trimethylphenyl)-2-butyrylcyclohex-2-en-1-one with ethoxyamine hydrochloride following essentially the same procedure as described in Example 1 part (iv) gave 2-[1-(ethoxyimino)butyl]-3-hydroxy-5-(3-amino-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (8) as a pale orange oil. The compound was characterized by its proton magnetic resonance spectrum which is given in Table 5, Example 37.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([NH2:27])[C:24]([N+:28]([O-])=O)=[CH:23][C:22]=3[F:31])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(#N)C.[OH-].[Na+].O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([NH2:27])[C:24]([NH2:28])=[CH:23][C:22]=3[F:31])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(N)c([N+](=O)[O-])cc3F)CC2)CC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(N)c(N)cc3F)CC2)CC1
Reaction time: 20 h

Procedure:
60a obtained in the previous step was dissolved in acetonitrile (4 mL) and treated with Na2S2O3 (0.42 g) in 1N NaOH (4 mL). After 20 h, the mixture was poured in water and extracted with EtOAc twice. The combined extracts were dried and concentrated to afford the crude 60b.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4](/[CH:13]=[CH:14]/[C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[N:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)[N:5]=[C:4](/[CH:13]=[CH:14]/[C:15]2[CH:22]=[CH:21][CH:20]=[C:17]([C:18]3[N:23]=[N:24][NH:25][N:19]=3)[CH:16]=2)[N:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(N2CCCC2)nc(/C=C/c2cccc(C#N)c2)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(N2CCCC2)nc(/C=C/c2cccc(-c3nn[nH]n3)c2)n1
Temperature: 70 °C
Yield: 17.6 %

Procedure:
A mixture of 100 mg (0.34 mmol) of (E)-3-[2-(4-methyl-6-pyrrolidin-1-yl-pyrimidin-2-yl)-vinyl]-benzonitrile, 448 mg (6.9 mmol) NaN3 and 368 mg (6.9 mmol) NH4Cl in 10 ml DMF was heated at 70° C. for 20 h until completion of the reaction according to TLC analysis. The reaction mixture was cooled to RT, concentrated in vacuo and then partitioned between 1N HCl and CH2Cl2. The organic layer was separated and the aqueous layer extracted several times with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crystalline solid which formed was filted off by suction and dried in a high vacuum to give ((E)-4-methyl-6-pyrrolidin-1-yl-2-{2-[3-(2H-tetrazol-5-yl)-phenyl]-vinyl}-pyrimidine (20 mg, 17.4%) as an off-white solid. ISP mass spectrum, m/e: 334.3 (M+1 calculated for C18H19N7: 334).
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[O:10][C:9]=2[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([N:31]([CH3:30])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:26])=[CH:23][CH:22]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: Cc1oc(-c2ccncc2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccncc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
A solution of 4-({cyclohexyl[2-methyl-5-(pyridin-4-yl)furan-3-yl]methyl}amino)benzoic acid (390 mg), ethyl 3-(methylamino)propanoate (157 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (230 mg), hydroxybenzotriazole monohydrate (184 mg) and triethylamine (116 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (3 mL), tetrahydrofuran (3 mL) and 1N lithium hydroxide (2.0 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (400 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[O:10](C(OC(C)(C)C)=O)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=O>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])[N:3]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Product: Cc1cc(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1

Procedure:
Method 24 was followed using 4-chloro-6-methylpyrimidin-2-amine (1.0 equiv.), BOC2O (2.0 equiv.), and DMAP (cat.) to afford 4-chloro-N,N-di-BOC-6-methylpyrimidin-2-amine in 71%. LCMS (m/z): 344.2 (MH+); LC Rt=4.3 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][CH2:16][C:17]1[CH:27]=[C:26]([OH:28])[C:20]2[O:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1.N1C=CC=CC=1.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>CN(C)C=O>[CH:35]1([C:38]([O:28][C:26]2[C:20]3[O:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=3[CH:18]=[C:17]([CH2:16][NH:15]/[CH:14]=[C:5]3\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]4[C:4]\3=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=4)[CH:27]=2)=[O:39])[CH2:37][CH2:36]1
Reactant: O=C(Cl)C1CC1
Reactant: CC1(C)Oc2cc(CN/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc(O)c2O1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC1(C)Oc2cc(CN/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc(OC(=O)C3CC3)c2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4Z)-6-bromo-4-({[(7-hydroxy-2,2-dimethyl-1,3-benzodioxol-5-yl)methyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione (30 mg, 67 μmol) in dimethylformamide (0.5 mL) is added pyridine (12 μL, 0.17 mmol) and cyclopropanecarbonyl chloride (10 μL). The reaction mixture is shaken overnight at room temperature and then purified by reverse-phase high performance liquid chromatography to give 6-({[(Z)-(6-bromo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)-2,2-dimethyl-1,3-benzodioxol-4-yl cyclopropanecarboxylate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:25])[CH2:16][NH:17]C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:26]>CO.O1CCOCC1>[Cl:26][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:25])[CH2:16][NH2:17])[CH2:10][CH2:9]2)=[CH:3][CH:4]=1
Reactant: Cl
Reactant: CC(C)(C)OC(=O)NCC(=O)NC1CCN(Cc2ccccc2)CC1
Solvent: C1COCCO1
Solvent: CO
Product: NCC(=O)NC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 1-benzyl-4-{N-(tert-butoxycarbonyl)glycyl}aminopiperidine (6.59 g) in methanol (80 mL) was added 4 N HCl in dioxane (19 mL). The solution was stirred at room temperature for 2 h. The reaction mixture was concentrated and 2 N aqueous NaOH solution (20 mL) was added. The mixture was extracted with dichloromethane (40 mL×3), and the combined extracts were dried over anhydrous sodium sulfate and concentrated. Column chromatography (SiO2, AcOEt/MeOH/Et3N=85/12/3) gave 1-(4-chlorobenzyl)-4-(glycylamino)piperidine (3.91 g, 83%): 1H NMR (CDCl3, 400 MHz) d 1.47-1.59 (m, 2 H), 1.59 (br, 2 H), 1.76-1.96 (m, 2 H), 2.10-2.19 (m, 2 H), 2.75-2.87 (m, 2 H), 3.29 (s, 2 H), 3.50 (s, 2 H), 3.65-3.89 (m, 1 H), 7.15-7.23 (m, 1 H), 7.23-7.33 (m, 5 H).