Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:9][C:10]([C:12]2(OC)[CH:17]=[CH:16][CH:15]=[N+:14]([O-])[NH:13]2)=[O:11])=[CH:4][CH:3]=1.P(Br)(Br)Br.C(=O)([O-])[OH:33].[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:33])[NH:14][N:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: COC1(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)C=CC=[N+]([O-])N1
Reactant: O=C([O-])O
Agent: BrP(Br)Br
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)[nH]n1)c1ccc(Br)cc1

Procedure:
A mixture of (R)-6-(3-(3-(4-bromophenyl)-3-o-tolylpropanoyl)-3-methoxypyridazine 1-oxide (679 mg, 1.59 mmol) and phosphorous tribromide (2.58 g, 9.53 mmol) in ethyl acetate (15 mL) was heated at reflux for 30 min, then after cooling poured onto ice water, neutralized with sat. aq. sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. After chromatography (SiO2; heptane-ethyl acetate gradient) the title compound was obtained (318 mg, 50%). White semisolid, MS: 397.1 [M+H]+.
Reaction SMILES: C([OH:3])C.[F:4][C:5]([F:49])([F:48])[C:6]1[CH:7]=[C:8]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:9][N:10]([C:35]1[N:36]=[N:37][N:38]([CH3:40])[N:39]=1)[C@H:11]1[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][C@H:19]2[CH2:24][CH2:23][C@H:22]([C:25]([O:27]C)=[O:26])[CH2:21][CH2:20]2)[C:13]2[C:29]([CH3:34])=[CH:30][C:31]([CH3:33])=[CH:32][C:12]1=2.[OH-].[Na+].C(O)(=O)C>O>[OH2:3].[F:47][C:44]([F:45])([F:46])[C:42]1[CH:41]=[C:8]([CH2:9][N:10]([C:35]2[N:36]=[N:37][N:38]([CH3:40])[N:39]=2)[C@@H:11]2[C:12]3[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[C:13]=3[N:14]([CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]3)[CH2:15][CH2:16][CH2:17]2)[CH:7]=[C:6]([C:5]([F:4])([F:49])[F:48])[CH:43]=1
Reactant: CCO
Reactant: COC(=O)[C@H]1CC[C@H](CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)cc(C)c32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C)c2c(c1)[C@@H](N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)CCCN2C[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
Charge a 250 mL flask equipped with an overhead stirrer, with ethanol (100 mL), (trans)-methyl 4-(((S)-5-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)cyclohexanecarboxylate (10.0 g, 15.32 mmoles) and NaOH (2 M, 15.0 mL, 30.0 mmoles). Warm the resulting mixture to about 40° C. and stir at that temperature for about 4 hrs. Allow the reaction mixture to cool to RT. Add acetic acid (2.7 mL, 45.4 mmoles) and warm to 40° C. Add water (40 mL) slowly over 2.5 h to provide a thick, white slurry. Continue heating for an additional 1.5 h and then allow the slurry to cool to RT. Collect the solid by filtration and sequentially wash the solid with ethanol:water (20 mL, 1:1), water (20 mL). Suspend the solid in water (70 mL); collect the solid via filtration; then wash the solid with water (2×20 mL). Repeat to the water slurry two additional times. Collect the resulting solid and dry at 60° C. to provide the titled compound as a white solid (6.1 g).
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[C:14]([N:15]3[CH2:25][CH2:24][C:18]4[N:19]=[C:20]([NH2:23])[N:21]=[CH:22][C:17]=4[CH2:16]3)=[C:13]([CH3:26])[CH:12]=[CH:11][N:10]=2)=CC=1.FC(F)(F)C(O)=O>ClCCl>[NH2:23][C:20]1[N:21]=[CH:22][C:17]2[CH2:16][N:15]([C:14]3[C:9](=[O:8])[NH:10][CH:11]=[CH:12][C:13]=3[CH3:26])[CH2:25][CH2:24][C:18]=2[N:19]=1
Reactant: COc1ccc(COc2nccc(C)c2N2CCc3nc(N)ncc3C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc[nH]c(=O)c1N1CCc2nc(N)ncc2C1
Reaction time: 0.5 h

Procedure:
A solution of 6-{2-[(4-methoxybenzyl)oxy]-4-methylpyridin-3-yl}-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (3.92 g, 10.39 mmol) in dichloromethane (150 ml) was treated with trifluoroacetic acid (5.71 ml, 76.89 mmol) at room temperature. After stirring for 30 minutes, the solvent and excess acid was removed in vacuo and the residue was treated with ethyl acetate. Washing with sat'd NaHCO3(aq.) gave a yellow, amorphous precipitate. The solid was collected, washed with water, EtOAc, and dried in vacuo at 50° C. to give (1.65 g, 62%). HPLC analysis showed the compound has a purity of 97%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:46]=[CH:47][C:48]=1[F:49])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:24]=[C:25]([C:27]3[C:35]4[C:30](=[N:31][CH:32]=[CH:33][CH:34]=4)[N:29](S(C4C=CC=CC=4)(=O)=O)[CH:28]=3)[CH:26]=2)[O:19][CH2:20][C:21]([OH:23])=O)=[O:13])[C:7]1=[O:45].[Cl-].[NH4+].C[N:53](C)C=O.C(N(CC)C(C)C)(C)C.CO.C(=O)([O-])[O-].[K+].[K+]>O.CCOC(C)=O>[NH2:53][C:21](=[O:23])[CH2:20][O:19][C:18]1[CH:17]=[C:16]([CH:26]=[C:25]([C:27]2[C:35]3[C:30](=[N:31][CH:32]=[CH:33][CH:34]=3)[NH:29][CH:28]=2)[CH:24]=1)[CH2:15][NH:14][C:12]([C:8]1[C:7](=[O:45])[N:6]([CH2:5][C:4]2[CH:46]=[CH:47][C:48]([F:49])=[C:2]([F:1])[CH:3]=2)[CH:11]=[CH:10][CH:9]=1)=[O:13]
Reactant: CN(C)C=O
Reactant: O=C(O)COc1cc(CNC(=O)c2cccn(Cc3ccc(F)c(F)c3)c2=O)cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: NC(=O)COc1cc(CNC(=O)c2cccn(Cc3ccc(F)c(F)c3)c2=O)cc(-c2c[nH]c3ncccc23)c1
Reaction time: 8 h
Yield: 39.4 %

Procedure:
A mix of 2-(3-((1-(3,4-difluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)methyl)-5-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-yl)phenoxy)acetic acid (50 mg, 0.00007 mol;), Ammonium chloride (20 mg, 0.0004 mol;), and N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl) pyridin Hexafluorophosphate (0.06 g, 0.0001 mol;) in N,N-Dimethylformamide (5 mL, 0.06 mol;) N,N-Diisopropylethylamine (0.06 mL, 0.0004 mol;) was stirred for overnight and LC-MS showed complete amide formation (1.71 min, ES+/684.37). Worked up with EtOAc and water. Dried over MgSO4 and concentrated. The residue was then dissolved in Methanol (10 mL, 0.2 mol;) and added Potassium carbonate (50 mg, 0.0004 mol;) and heated to reflux for 1 h. LC-MS showed the formation of the des-PhSO2 product C (1.24 min, ES+/544.53). Evaporated off the solvents and dissolved in DMSO and water and purified on Gilson HPLC to give the desired product (15 mg, 40%) MS (ES+) m/z 544.53 4 (M+1). 1H NMR (DMSO, 400 MHz): δ 8.41 (dd, 1H), 8.29 (d, 1H), 8.27 (dd, 1H), 8.24 (dd, 1H), 7.88 (s, 1H), 7.45-7.35 (m, 2H), 7.31 (s, 2H), 7.18 (m, 2H), 7.11 (dd, 1H), 6.83 (s, 1H), 6.60 (t, 1H), 5.22 (s, 2H), 4.55 (s, 2H), 4.49 (s, 2H),
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].I[CH3:19]>C1COCC1>[C:4]([O:3][C:1](=[O:2])[N:8]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1)[CH3:19])([CH3:7])([CH3:6])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-(BOC-amino)-5-bromopyridine (3.06 g) in THF (50 mL) was added sodium hydride (538 mg) and the reaction stirred at room temperature for 20 min. Then, iodomethane (0.84 mL) was added and the reaction stirred at room temperature for 16 h. The reaction was quenched with water (30 mL) and extracted into dichloromethane (3×30 mL). The organic layers were dried (MgSO4) and reduced in vacuo to give (5-bromo-pyridin-2-yl)-methyl-carbamic acid tert-butyl ester as an oil.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([CH3:16])([CH3:15])[C:13]#[N:14])=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.C([OH:19])C.O>[OH-].[K+]>[CH:1]1([C:4]([C:6]2[CH:7]=[CH:8][C:9]([C:12]([CH3:16])([CH3:15])[C:13]([NH2:14])=[O:19])=[CH:10][CH:11]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: CCO
Reactant: CC(C)(C#N)c1ccc(C(=O)C2CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C(N)=O)c1ccc(C(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionitrile (100 mg) in aqueous ethanolic potassium hydroxide (2 mL) (prepared from ethanol (5 mL), water (5 mL) and solid potassium hydroxide (1.5 g). Stir overnight at room temperature, then heat at reflux for 6 hours. Cool and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][CH:35]=[CH:34][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][C:8]([CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=2)([CH2:11][CH2:12]OS(C)(=O)=O)[C:7]1=[O:33].I.[CH2:39]([O:41][CH2:42][CH2:43][N:44]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[N:46]=[C:45]1[N:53]1[CH2:59][CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)[CH3:40]>>[CH3:1][O:2][C:3]1[CH:37]=[CH:36][CH:35]=[CH:34][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][C:8]([CH2:11][CH2:12][N:56]2[CH2:57][CH2:58][CH2:59][N:53]([C:45]3[N:44]([CH2:43][CH2:42][O:41][CH2:39][CH3:40])[C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=4[N:46]=3)[CH2:54][CH2:55]2)([CH2:18][C:19]2[CH:20]=[C:21]([C:29]([F:31])([F:30])[F:32])[CH:22]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:24]=2)[C:7]1=[O:33]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1ccccc1CN1CCC(CCOS(C)(=O)=O)(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1=O
Agent: I
Product: CCOCCn1c(N2CCCN(CCC3(Cc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CCN(Cc4ccccc4OC)C3=O)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 7.6 using 1-(2-methoxybenzyl)-3-(3 5-di(trifluoromethyl)phenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt to give the title compound: Rf=0.54 (silica gel, 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia).
Reaction SMILES: [F:1][CH2:2][C:3]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][NH:5][CH2:4]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O1CCOCC1.O>[F:1][CH2:2][C:3]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][N:5]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:4]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1(CF)CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C1(CF)CCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
To a solution of ethyl 3-(fluoromethyl)pyrrolidine-3-carboxylate (1.86 g, 10.62 mmol) in a 1:1 mixture of 1,4-dioxane/water (18 mL) was added sodium carbonate (1.35 g, 12.74 mmol) and the mixture cooled to 0° C. in an ice bath. Benzyl chloroformate (1.79 mL, 12.74 mmol) was added dropwise and the resulting mixture was stirred at 0° C. for 30 minutes, then at ambient temperature for 18 hours. The mixture was partitioned between water and ether, and the layers separated. The organic layer was washed sequentially with water, saturated sodium bicarbonate solution and brine, then dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by chromatography (Biotage 25M; 15% ethyl acetate/hexanes) to afford 1-benzyl 3-ethyl 3-(fluoromethyl)pyrrolidine-1,3-dicarboxylate (3.3 g, 100%).
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH:8][C@@H:9]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]1[OH:11])=[O:7])[CH2:2][CH2:3][CH3:4].[N:20]([O-])=[O:21].[Na+]>O.C(O)(=O)C>[CH2:1]([N:5]([N:20]=[O:21])[C:6]([NH:8][C@@H:9]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]1[OH:11])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCN(N=O)C(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 90.6 %

Procedure:
1-n-butyl-3-(β-D-glucopyranosyl)urea (0.50 g) was dissolved in a mixture of water (2 ml) and acetic acid (2 ml), and to the resulting solution was added sodium nitrite (186 mg, 1.5 mol. equivalents). The nitrosation was conducted in the same manner as in Example 1(a). The reaction mixture was treated with Amberlite IR-120 (H+ form) for the removal of sodium cation and then freeze-dried, affording 0.5 g of the titled compound as a glassy substance of pale yellow color. [α]D26 -1.5° (c 1.0, H2O). This substance gave a single spot at Rf 0.51 in a thin layer chromatography on silica gel using chloroform-methanol (4:1 by volume) as eluent.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][C:13]([CH2:19]O)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([Cl:30])(=O)=O)=CC=1.C(N(CC)CC)C.O>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][C:13]([CH2:19][Cl:30])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1=Cc2cccc(OCc3ccccc3)c2CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: ClCC1=Cc2cccc(OCc3ccccc3)c2CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.5 %

Procedure:
Under an argon atmosphere, to a solution of 1.82 g of 5-(benzyloxy)-2-(hydroxymethyl)-3,4-dihydronaphthalene and 0.55 g of 4-(dimethylamino)pyridine in 30 ml of dichloromethane, 1.43 g of p-toluenesulfonyl chloride was added. After 1.2 ml of triethylamine was added dropwise, the mixture was stirred at room temperature for 1.5 hours. The reaction solution was poured into iced water and then extracted with diethyl ether. The extract was washed in turn with 5% hydrochloric acid, water and an aqueous saturated sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.06 g of the desired compound as a colorless oily substance.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]([O:13]C)=[O:12])[S:8][C:7]=2[CH:15]=1)#[N:2].CO.[OH-].[Na+]>O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[S:8][C:7]=2[CH:15]=1)#[N:2]
Reactant: COC(=O)c1cc2ccc(C#N)cc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc2cc(C(=O)O)sc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A round bottom flask was charged with methyl 6-cyanobenzo[b]thiophene-2-carboxylate (4.00 g, 17.9 mmol), methanol (130 mL), and sodium hydroxide (23 g, 0.58 mol) in water (200 mL). The reaction was stirred at room temperature for 20 minutes. The reaction was concentrated to half of the volume and acidified with 6 N aq. HCl. The mixture was extracted with CHCl3/i-PrOH (90:10) and the organic phase was concentrated under reduced pressure to get the title compound as a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:12]2[NH:13][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:20](=[O:28])[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:7]1)=[O:5])[CH3:2].ClOC(C)(C)C.O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:20](=[O:28])[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1c2CCCC1
Agent: CC(C)(C)OCl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1c2CCCC1
Yield: 10.6 %

Procedure:
To a solution of 3-(4-fluoro-benzoyl)-1,2,3,4,5,6,7,8,9,10-decahydro-azepino[4,5-b]indole-5-carboxylic acid ethyl ester (Example 6, 60 mg, 0.16 mmol) in DCM (2 mL) was added TEA (45 μL, 0.32 mmol) and a solution of tert-butyl hypochlorite (19.2 mL, 0.16 mmol) in DCM (1 mL) at 0° C. and the mixture was stirred for 0.5 h at 0° C. Cold water was added to quench the reaction mixture and the aqueous layer was separated and extracted with DCM. The combined organic layer was washed with water and dried over MgSO4. Evaporation of solvent gave a crude, which was purified by column chromatography on silica gel, eluting with MeOH-DCM (1:19) to give the title compound (6.5 mg) with some starting material (27 mg) recovered. 1H-NMR(CDCl3): δ 10.07 (1H, s), 7.57 (2H, m), 7.52 (1H, s), 7.10 (2H, m), 4.19 (2H, q), 4.07 (2H, t), 2.89 (2H, t), 2.62 (2H, t), 2.43 (2H, t), 1.80 (4H, m), 1.19 (3H, t). MS (ES): 383 (MH+).
Reaction SMILES: [CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH2:7][CH:6]([NH:15]C(=O)OC(C)(C)C)[C:5]1=[O:23])[CH:2]=[CH2:3].[ClH:24]>O1CCOCC1>[ClH:24].[NH2:15][CH:6]1[C:5](=[O:23])[N:4]([CH2:1][CH:2]=[CH2:3])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH2:7]1
Reactant: C=CCN1C(=O)C(NC(=O)OC(C)(C)C)CSc2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: C=CCN1C(=O)C(N)CSc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
610 mg of 56 (1.82 mmol) are taken up in a 25 ml round-bottomed flask and 15 ml of a solution of hydrogen chloride in dioxane (4M) are added. The mixture is stirred for 3 hours at room temperature under argon. After evaporating off the solvent, a gummy residue is obtained, which is triturated from isopropyl ether to give, after filtration, 441 mg of amine 57 in hydrochloride form (cream-colored solid).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C([N:12]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13]1)C1C=CC=CC=1>C(Cl)Cl>[O:17]([CH:14]1[CH2:15][CH2:16][N:12]([C:1]([Cl:4])=[O:2])[CH2:13]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(CN2CCC(Oc3ccccc3)C2)cc1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)N1CCC(Oc2ccccc2)C1
Yield: 145.7 %

Procedure:
To a solution of 9.5 g (0.097 mole) of phosgene in 200 ml of methylene chloride under nitrogen gas was added dropwise with stirring, 30.2 g (0.88 mole) of 1-benzyl-3-phenoxypyrrolidine in 100 ml of methylene chloride over a 45 minute period. The reaction mixture was stirred additionally for 20 minutes. The reaction mixture was concentrated in vacuo to give 31.9 g of oil. The oil was triturated with boiling 30/60 petroleum ether and the mixture was cooled. The ether layer was decanted off and the trituration in petroleum ether procedure was repeated 3 times. The oil contained a trace of benzyl chloride as indicated by thin-layer chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:25]2[O:29][N:28]=[C:27]([C:30]([O:32]CC)=O)[N:26]=2)([N:11]2[C:19]3[C:14](=[C:15]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[N:12]2)[CH2:9][CH3:10])=[CH:4][CH:3]=1.[NH3:35]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:25]2[O:29][N:28]=[C:27]([C:30]([NH2:35])=[O:32])[N:26]=2)([N:11]2[C:19]3[C:14](=[C:15]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[N:12]2)[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1noc(C(CC)(c2ccc(Cl)cc2)n2ncc3c(NS(C)(=O)=O)cccc32)n1
Reactant: N
Solvent: CO
Product: CCC(c1ccc(Cl)cc1)(c1nc(C(N)=O)no1)n1ncc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The product from Step E above (0.015 g, 0.030 mmol) was dissolved in a 7 N solution of ammonia in methanol (2.6 mL). After stirring at RT for 45 min, the resulting mixture was concentrated under reduced pressure. The residue was dissolved in dioxane/water, acidified with TFA, and purified directly on RP-HPLC to give the title compound. LC/MS m/z=475.0[M+H]+. 1H NMR (500 MHz, CD3OD): δ (ppm) 8.34 (s, 1H), 7.43 (d, J=8.8 Hz, 2H), 7.37 (d, J=8.8 Hz, 2H), 7.16-7.14 (m, 2H); 6.48-6.45 (m, 1H), 3.20-3.12 (m, 1H), 3.14-3.05 (m, 1H), 3.04 (s, 3H), 0.89 (t, J=7.4 Hz, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([CH2:10][CH:11]([C:13]2[N:14]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:15]=[N:16][C:17]=2[CH3:18])O)=[N:7][C:6]=1[CH3:26])=[O:4]>S(=O)(=O)(O)O>[F:25][C:22]1[CH:21]=[CH:20][C:19]([N:14]2[C:13](/[CH:11]=[CH:10]/[C:8]3[S:9][C:5]([C:3]([OH:4])=[O:2])=[C:6]([CH3:26])[N:7]=3)=[C:17]([CH3:18])[N:16]=[N:15]2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1sc(CC(O)c2c(C)nnn2-c2ccc(F)cc2)nc1C
Agent: O=S(=O)(O)O
Product: Cc1nc(/C=C/c2c(C)nnn2-c2ccc(F)cc2)sc1C(=O)O
Temperature: 160 °C
Yield: 76.9 %

Procedure:
A suspension of 2-{2-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-yl]-2-hydroxy-ethyl}-4-methyl-thiazole-5-carboxylic acid methyl ester (355 mg, 0.94 mmol) in sulfuric acid (conc, 5.9 mL) was heated at 160° C. under Ar for 30 min. After cooling to room temperature the mixture was poured into ice and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated to afford the title compound (249 mg, 77%) as an grey solid. MS: m/e=345.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([CH3:10])[N:3]=1.S(Cl)([Cl:13])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][Cl:13])[CH:5]=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1cc(CO)cc(Cl)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(CCl)cc(Cl)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(2-Chloro-6-methylpyridin-4-yl)methanol (0.212 g, 1.35 mmol) and thionyl chloride (0.12 mL, 1.62 mmol) were combined in methylene chloride (4 mL) and stirred at room temperature for 4 h. The solvents were removed and the product dried under vacuum for several hours to afford 0.24 g (quant.) as a clear oil which was used without purification. Mass spec.: 176.0 (MH)+.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:14]([C:12]1[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: C=CCCCCCCC
Reactant: c1ccc(Nc2ccccc2)cc1
Product: CCCCCCCCCc1cccc(Nc2ccccc2)c1CCCCCCCCC
Yield: 71 %

Procedure:
A commercial nonene yielded 59% dialkylate when reacted for 10 hours with diphenylamine under the conditions of Example 1. The nonene, after passing in the vapor phase over a 75 cc catalyst bed of F-24 at 650° F. for 5 seconds, was converted to a high reactivity alkene which yielded 71% dinonyl diphenylamine under the reaction conditions of Example 1 after 10 hours reaction time.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10](=[O:27])[C:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:8]2)=[O:4].[NH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39].C[O-].[Na+]>>[OH:34][C:6]1[C:5]([C:3]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:4])=[N:14][C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:12]2[C:7]=1[CH:8]=[C:9]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:10](=[O:27])[N:11]2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2-c2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2-c2ccccc2)c1O
Temperature: 25 °C
Yield: 64.9 %

Procedure:
A mixture of 5-hydroxy-2-oxo-1,3-diphenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (34 mg, 0.076 mmol), β-alanine (675 mg, 7.6 mmol) and NaOMe solution (11 mL, 5.7 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 25 mg of the title compound. MS: (+) m/z 507.30 (M+1).