Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C@@H:9]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)=[N:6][CH:7]=1.Cl.O1CCOCC1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C@@H:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc(F)cn2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Fc1ccc(N[C@@H]2CCNC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 139.8 %

Procedure:
Crude (R)-tert-butyl 3-(5-fluoropyridin-2-ylamino)pyrrolidine-1-carboxylate (85 mg, 0.3 mmol) was dissolved in CH2Cl2 (3 mL) and 4 M HCl in dioxane (1 mL, 4 mmol) was added. The mixture was stirred overnight at rt and concentrated to afford crude (R)-5-fluoro-N-(pyrrolidin-3-yl)pyridin-2-amine (76 mg, quant) which was used without further purification. LC-MS Method 1 tR=0.42 min, m/z=182.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:34]([C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)=[O:41])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C(Cl)c1cccnc1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cccnc4)c3C2=O)C(=O)N1
Yield: 64.7 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.98 g, 6.48 mmol) was added to stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, nicotinoyl chloride (0.41 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by flash chromatography (SiO2, CH2Cl2: CH3OH 97.5:2.5) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}-3-pyridylcarboxamide (0.47 g, 64%) as a white solid: mp 148-151° C.; 1H NMR (DMSO-d6) δ d 11.16 (s, 1H), 9.36 (t, J=5.6 Hz, 1H), 9.09 (d, J=1.25 Hz, 1H), 8.75-8.73 (m, 1H), 8.25 (d, J=8.0 Hz, 1H), 7.84-7.76 (m, 3H), 7.57-7.52 (m, 1H), 5.22-5.15 (dd, J=5.4 and 12.7 Hz, 1H), 4.96 (d, J=5.6 Hz, 2H), 2.92-2.85 (m, 1H), 2.65-2.50 (m, 2H), 2.11-2.06 (m, 1H); 13C NMR (DMSO-d6) δ d 172.72, 169.80, 167.51, 166.94, 165.23, 152.02, 148.44, 138.86, 135.10, 134.83, 133.20, 131.55, 129.48, 127.20, 123.49, 121.95, 48.89, 38.33, 30.93, 21.98; Anal. Calcd. For C20H16N4O5+0.28H2O: C, 60.45; H, 4.20; N, 14.10. Found: C, 60.29; H, 4.28; N, 13.82.
Reaction SMILES: I.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8](=[NH:11])SC.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.C(O)C>O>[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[NH:11]
Reactant: NCc1ccncc1
Reactant: CSC(=N)NN=Cc1c(Cl)cccc1Cl
Agent: I
Solvent: O
Solvent: CCO
Product: N=C(NCc1ccncc1)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 5.85 g. of methyl 3-(2,6-dichlorobenzylidene)thiocarbazimidate hydriodide and 3.24 g. of 4-(aminomethyl)pyridine in 25 ml. of absolute ethanol is heated under reflux for 24 hours and then diluted with 75 ml. of water, causing the separation of an oil. On standing, the oil crystallizes. Filtration and recrystallization from aqueous ethanol gives the desired product as colorless crystals, m.p. 159°-161° C.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[I:12]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>FC(F)(F)S(O)(=O)=O>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccc(F)c1F
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: O=C(O)c1cc(I)cc(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.6 %

Procedure:
2,3-Difluorobenzoic acid (5.0 g, 31.6 mmol) was dissolved in trifluoromethanesulfonic acid (25 ml), and N-iodosuccinimide (8.55 g, 38.0 mmol) was added by portions at 0° C. under an argon stream. The mixture was stirred at room temperature for 3 hrs., and the reaction solution was poured into sodium sulfite in ice water. The mixture was stirred and the precipitate was collected by filtration, washed with water and vacuum-dried to give an object product (7.5 g, yield 84%) as a pale-pink solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:10].[C:11](OC)(OC)(OC)C>S(=O)(=O)(O)O>[O:9]1[C:8]2=[CH:7][CH:6]=[CH:5][C:4]([OH:10])=[C:3]2[N:2]=[CH:11]1
Reactant: COC(C)(OC)OC
Reactant: Nc1c(O)cccc1O
Agent: Cl
Agent: O=S(=O)(O)O
Product: Oc1cccc2ocnc12
Reaction time: 8 h
Yield: 51 %

Procedure:
A mixture of 2-amino-benzene-1,3-diol hydrochloride (2.00 g, 12.4 mmol) and trimethyl orthoacetate (15 mL) was treated with concentrated sulfuric acid (5 drops) and the resulting mixture heated at reflux for 3 h, cooled and allowed to stand at room temperature overnight. The resulting mixture was concentrated in vacuo and the residue treated with ethyl acetate (200 mL), washed with water (200 mL) and brine (100 mL). The combined aqueous phases were extracted with ethyl acetate (200 mL) and the combined organic phases washed with brine and dried over sodium sulfate. The mixture was filtered and concentrated in vacuo which afforded benzooxazol-4-ol (0.94 g, 51%) as a yellow solid.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]([CH2:36][CH3:37])[CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][CH2:30][N:31]([CH3:33])[CH3:32])=[CH:24][CH:23]=3)=[N:20][S:21][C:17]=2[CH:16]=1)(C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:33][N:31]([CH3:32])[CH2:30][C:29]#[C:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]2[C:18]3[CH:34]=[CH:35][C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][N:9]([CH2:36][CH3:37])[CH2:8][CH2:7][OH:6])=[CH:16][C:17]=3[S:21][N:20]=2)=[CH:23][CH:24]=1
Reactant: CCN(CCCCOc1ccc2c(-c3ccc(C#CCN(C)C)cc3)nsc2c1)CCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCN(CCO)CCCCOc1ccc2c(-c3ccc(C#CCN(C)C)cc3)nsc2c1
Yield: 66.1 %

Procedure:
350 mg (0.62 mmol) (3-{4-[6-(4-{[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amino}-butoxy)-benzo[d]isothiazol-3-yl]-phenyl}-prop-2-ynyl)-dimethyl-amine in 5 ml THF were treated with 0.92 ml 1M Bu4NF in THF at RT for 1 h. The solution was concentrated and the residue was purified by column chromatography on silica gel to give 185 mg (66%) 2-[(4-{3-[4-(3-Dimethylamino-prop-1-ynyl)-phenyl]-benzo[d]isothiazol-6-yloxy}-butyl)-ethyl-amino]-ethanol as light brown oil, MS: 452 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:24][C:25](=[O:27])[NH2:26])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:35][C:36]([CH3:41])([CH3:40])[C:37](Cl)=[O:38]>CC(C)=O.O>[C:25](=[O:27])([O:24][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:37](=[O:38])[C:36]([CH3:41])([CH3:40])[CH3:35])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)[NH2:26]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NC(=O)OC(CCN1CCN(c2ccc(O)cc2)CC1)c1ccc(F)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)Oc1ccc(N2CCN(CCC(OC(N)=O)c3ccc(F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The compound ‘carbamic acid 1-(4-fluoro-phenyl)-3-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-propyl ester (2 mmol) prepared in Example 88 was dissolved in acetone (15 mL), and triethylamine (2.4 mmol) was added and trimethyl acetylchloride (2.4 mmol) was added dropwise, and the resulting mixture was then stirred at a room temperature for 5 hours. The reaction mixture was diluted with water, and extracted several times with ethyl acetate to obtain an organic phase. The prepared organic phase was dried over magnesium sulfate, and concentrated under a reduced pressure. The resulting pellet was purified with column chromatography (hexane:ethyl acetate=1:1) to obtain a title compound.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[Br:10][C:11]1[N:16]=[C:15]([C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[N:21]=2)(O)[CH3:18])[CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:10][C:11]1[N:16]=[C:15]([C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[N:21]=2)([F:7])[CH3:18])[CH:14]=[CH:13][CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(O)(c1cccc(Br)n1)c1cccc(Br)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(F)(c1cccc(Br)n1)c1cccc(Br)n1
Temperature: 20 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
117.3 ml (888 mmol) of DAST were added dropwise over the course of 30 min. to a solution, cooled to 10° C., of 105.9 g (296 mmol) of 1,1-bis(6-bromo-2-pyridyl)ethan-1-ol in 1500 ml of chloroform at such a rate that the temperature did not exceed 20° C. The reaction mixture was stirred at 20° C. for 1 h and then hydrolysed dropwise with 500 ml of ice-water (care: highly exothermic reaction) with ice cooling and subsequently with 1000 ml of aqueous 3M NaOH. The organic phase was separated off, the aqueous phase was extracted twice with 100 ml of chloroform, and the combined organic phases were washed once with 500 ml of water and dried over calcium chloride. After the desiccant had been filtered off, the brown organic phase was concentrated to 200 ml and filtered through a silica-gel column. The yellow solution obtained in this way was evaporated to dryness, and the yellow, viscous oil remaining was recrystallised from 200 ml of n-heptane, giving 78.6 g (218 mmol) of the product, corresponding to a yield of 73.7%, in the form of colourless crystal needles—purity according to 1H-NMR>99.0%.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:6][CH2:7][C:8]#[N:9])#[N:2].[H][H]>O1CCOCC1>[NH2:2][CH2:1][CH2:3][CH2:4][N:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:6][CH2:7][CH2:8][NH2:9]
Reactant: CCCCCCCCCCCCCCCCCCN(CCC#N)CCC#N
Reactant: [H][H]
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCCCN(CCCN)CCCN
Yield: 98.4 %

Procedure:
42.1 g of N,N-bis(2-cyanoethyl)octadecylamine, 3.26 g of RaneyCo, 150 ml of 1,4-dioxane was charged to an autoclave, and hydrogen addition reaction was carried out by supplying hydrogen at an initial pressure of 8.0 MPa at 110° C. for 2 hours. After removing a catalyst by filtration, the obtained filtrate was concentrated and dried to obtain 42.3 g of a target compound as a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([OH:21])[CH3:20]>>[CH2:19]([O:21][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:20]
Reactant: CCO
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Product: CCOC(=O)NC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 133° C. and MS: m/e=284.2 (M+H+) was prepared in accordance with the general method of example 1 from diphenyl-acetyl isocyanate and ethanol.
Reaction SMILES: [Sn](Cl)Cl.[N:4]([C:7]1[C:8]([C:14]#[N:15])=[C:9]([Cl:13])[CH:10]=[N:11][CH:12]=1)=[N+]=[N-]>C(O)C.O>[NH2:4][C:7]1[C:8]([C:14]#[N:15])=[C:9]([Cl:13])[CH:10]=[N:11][CH:12]=1
Reactant: N#Cc1c(Cl)cncc1N=[N+]=[N-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: N#Cc1c(N)cncc1Cl
Reaction time: 1 h

Procedure:
Tin (II) chloride (1.42 g, 7.5 mmol) was added to a solution of 5-azido-3-chloro-4-cyanopyridine (0.9 g, 5 mmol) in ethanol (20 ml) and water (0.3 ml). Bubbling ensued. The mixture was stirred for 1 h. and then extracted twice with ethyl acetate. The extracts were washed twice with saturated aqueous sodium bicarbonate and dried over sodium sulphate. Evaporation of the solvent gave the product as an oil, which was purified by flash column chromatography on silica gel, eluting with dichloromethane/metahnol (10:1) to afford the product. MS (+CI) m/z 152 [M−H]+; 1H NMR (d6-DMSO) 8.15 (1H, s), 7.87 (1H, s), 6.88 (2H, s).
Reaction SMILES: ClC(Cl)(Cl)COC([N:7]1[CH2:26][CH2:25][C@@:14]23[C:15]4[CH:16]=[C:17]([C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][C:20]=4[CH2:21][C@@H:8]1[C@@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13]3)=O>C(O)(=O)C.[Zn]>[CH:19]1[C:20]2[CH2:21][C@H:8]3[NH:7][CH2:26][CH2:25][C@:14]4([C@H:9]3[CH2:10][CH2:11][CH2:12][CH2:13]4)[C:15]=2[CH:16]=[C:17]([C:22](=[O:24])[CH3:23])[CH:18]=1
Reactant: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(=O)OCC(Cl)(Cl)Cl)CC3
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.8 %

Procedure:
To a solution of 2.4 g of (-)-3-acetylmorphinan-17-carboxylic acid (trichloroethyl)ester in 40 ml of 90% acetic acid was added portionwise, 2.5 g of zinc-dust. The mixture was stirred at room temperature for 16 hours and filtered. The filtrate was concentrated in vacuo and the residue was partitioned between 40 ml ether and dilute ammonium hydroxide. The ether solution was extracted with 60 ml of 4 N hydrochloric acid. The acidic solution was basified with concentrated ammonium hydroxide and extracted with ether (2×30 ml). The ether solution was dried over magnesium sulfate and removal of the solvent gave 1.0 g (71%) of crude (-)-1-(morphinan-3-yl)ethanone. For analysis, a sample of this compound was distilled, bp 165°-175° (0.1 mm), [α]25D-24.77° (c 1.06, MeOH).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:20]=[CH:19][C:18]2[NH:17][C:16]3[C:11](=[CH:12][C:13]([NH:21][C:22](=[O:26])[CH2:23][CH2:24]Cl)=[CH:14][CH:15]=3)[C:10](=[O:27])[C:9]=2[CH:8]=1)=[O:5].[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([CH2:2][CH2:3][C:4]([NH:6][C:7]2[CH:20]=[CH:19][C:18]3[NH:17][C:16]4[C:11](=[CH:12][C:13]([NH:21][C:22](=[O:26])[CH2:23][CH2:24][N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)=[CH:14][CH:15]=4)[C:10](=[O:27])[C:9]=3[CH:8]=2)=[O:5])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(CCCl)Nc1ccc2[nH]c3ccc(NC(=O)CCCl)cc3c(=O)c2c1
Reactant: C1CCNC1
Product: O=C(CCN1CCCC1)Nc1ccc2[nH]c3ccc(NC(=O)CCN4CCCC4)cc3c(=O)c2c1

Procedure:
Chloroamide 13 (400 mg, 1.0 mmol) was treated with pyrrolidine (3 mL) according to the general aminolysis procedure to give the desired product BR-ACO-16 (348.mg, 74.4%) as a dark yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:11]([C:19]2[CH:28]=[CH:27][C:22]3[B:23]([OH:26])[O:24][CH2:25][C:21]=3[CH:20]=2)C(=O)OC(C)(C)C)=[N:7][C:8]=1[O:9][CH3:10])#[N:2].[OH-].[Na+].O>Cl.O1CCOCC1>[OH:26][B:23]1[C:22]2[CH:27]=[CH:28][C:19]([NH:11][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[C:8]([O:9][CH3:10])[N:7]=3)=[CH:20][C:21]=2[CH2:25][O:24]1
Reactant: COc1nc(N(C(=O)OC(C)(C)C)c2ccc3c(c2)COB3O)ccc1C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1nc(Nc2ccc3c(c2)COB3O)ccc1C#N
Yield: 12.3 %

Procedure:
A solution of tert-butyl 5-cyano-6-methoxypyridin-2-yl(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)carbamate (0.944 g, 2.48 mmol) in 4 mol/L hydrogen chloride in dioxane (20 mL) was stirred at room temperature for three hours. The solution was then neutralized with 6 mol/L sodium hydroxide until pH=6 to 7. Water was added and the solution was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure. The aqueous layer contained precipitate, which was collected by filtration and dried under reduced pressure. The residue was purified by Combiflash to give 6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-ylamino)-2-methoxynicotinonitrile (0.086 g, 9.1%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.95 (s, 2H), 6.50 (d, J=8.4 Hz, 1H), 7.52 (d, J=1.4 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 9.00 (s, 1H), 9.94 (s, 1H).
Reaction SMILES: C([N:9]1[CH2:14][CH2:13][C:12]2([CH2:19][CH2:18][C:17]3[CH:20]=[C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:22]=[CH:23][C:16]=3[O:15]2)[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[ClH:29]>CO>[ClH:29].[CH3:28][S:25]([NH:24][C:21]1[CH:22]=[CH:23][C:16]2[O:15][C:12]3([CH2:13][CH2:14][NH:9][CH2:10][CH2:11]3)[CH2:19][CH2:18][C:17]=2[CH:20]=1)(=[O:26])=[O:27]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)CCC1(CCN(C(=O)c3ccccc3)CC1)O2
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)Nc1ccc2c(c1)CCC1(CCNCC1)O2
Yield: 83 %

Procedure:
1'-Benzoyl-3,4-dihydro-6-methanesulfonamido-spiro[(2H)-1-benzopyran-2,4'-piperidine] (5.44 g, 13.6 mmol) was dissolved in methanol (70 ml) and aqueous HCl (6N, 105 ml) was added. The mixture was heated under reflux for 24 hr, then the volume was reduced to 50 ml by distillation. Ethanol (200 ml) was added and the volume was reduced to 50 ml. Further ethanol (200 ml) was added, the volume was reduced to 100 ml and the mixture was cooled. The precipitate was collected and dried in vacuo to give the hydrochloride as a white solid (3.77 g, 83%). A sample was recrystallized from ethanol to give the hydrochloride as a white solid, m.p.=282°-285° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:10][C:9]2=[O:23])=[CH:4][C:3]=1[NH:24][CH3:25].[CH2:26]([C:28]1[N:29]=[CH:30][O:31][C:32]=1[C:33](O)=O)[CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:26]([C:28]1[N:29]=[CH:30][O:31][C:32]=1[C:33]1[N:24]([CH3:25])[C:3]2[CH:4]=[C:5]([N:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]4[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=4)=[CH:10][C:9]3=[O:23])[CH:6]=[CH:7][C:2]=2[N:1]=1)[CH3:27]
Reactant: CNc1cc(-n2ccc(OCc3ccc(F)cc3)cc2=O)ccc1N
Reactant: CCc1ncoc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1ncoc1-c1nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.7 %

Procedure:
A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (67.9 mg), 4-ethyl-1,3-oxazole-5-carboxylic acid (28.2 mg), HATU (80.0 mg), N,N-diisopropylethylamine (0.105 ml) and DMF (2.0 ml) was stirred at room temperature for 2 h. The mixture was poured into saturated NaHCO3 solution and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated in vacuo. The residue was dissolved in AcOH (1.5 ml), and the mixture was stirred at 80° C. for 1 h. The mixture was concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOAc-hexane to give the title compound (15.7 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.S(=O)(=O)(O)O.[C:24](=O)(O)[O-].[Na+]>CO.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([O:11][CH3:24])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C(C)c1ccc(-c2ccccc2)c(F)c1
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
2-(2-Fluoro-biphenyl-4-yl)-propionic acid (104.2 g) was dissolved in methanol (410 ml) and then conc. sulfuric acid (60.2 g) was added, after which the resulting mixture was stirred at 40° C. for 2.5 hours. The mixture was cooled to room temperature, diluted with toluene, then neutralized with a saturated aqueous sodium bicarbonate solution, and thereafter subjected to extraction with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure, to obtain methyl 2-(2-fluoro-biphenyl-4-yl)-propionate (110.2 g).
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]2[S:14][C:15]([C:24]([O-:26])=O)=[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:5]=2[CH:4]=[CH:3]1.[NH4+].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:42][CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>C(Cl)Cl>[O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]2[S:14][C:15]([C:24]([NH:42][CH2:43][CH2:44][N:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)=[O:26])=[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:5]=2[CH:4]=[CH:3]1
Reactant: NCCN1CCCCC1
Reactant: O=C([O-])c1sc2c(ccc(=O)n2-c2ccccc2)c1Nc1ccccc1
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(NCCN1CCCCC1)c1sc2c(ccc(=O)n2-c2ccccc2)c1Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21.2 %

Procedure:
To a suspension of the compound of Example 14 (90 mg, 0.23 mmol) in DCM (2 mL) was added EDC (60 mg, 0.30 mmol) and HOBT (41 mg, 0.30 mmol) and the mixture stirred at r.t. for 15 minutes. A solution 1-(2-aminoethyl)piperidine (45 mg, 0.35 mmol) in DCM (0.5 mL) was added and the reaction stirred at r.t. for 18 h. The reaction mixture was diluted with DCM (10 mL), washed with water (2×5 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on silica (0-20% THF in DCM) to give the title compound as an off-white solid (23 mg). δH (CDCl3) 8.61 (1H, s), 7.61-7.43 (3H, m), 7.40-7.27 (2H, m), 7.25-7.13 (3H, m), 7.00-6.89 (3H, m), 6.50 (1H, bs), 6.33 (1H, d, J 9.7 Hz), 3.43-3.25 (2H, m), 2.47-2.32 (2H, m), 2.31-2.11 (4H, m), 1.50-1.40 (4H, m), 1.39-1.25 (2H, m). LCMS (ES+) RT 2.40 minutes, 473 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][C:6]([CH2:7][N:8]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:23][N:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]4)[CH:19]=[N:20][C:21]=3F)[N:10]=2)=[CH:5][CH:4]=1.[CH3:48][O:49][C:50]1[N:55]=[CH:54][C:53]([NH2:56])=[CH:52][N:51]=1.O1CCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>>[CH3:1][O:2][C:3]1[CH:47]=[CH:46][C:6]([CH2:7][N:8]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:23][N:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]4)[CH:19]=[N:20][C:21]=3[NH:56][C:53]3[CH:52]=[N:51][C:50]([O:49][CH3:48])=[N:55][CH:54]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ncc(N)cn1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)cnc3Nc3cnc(OC)nc3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
A solution of tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate (0.500 g, 0.777 mmol) and 2-methoxypyrimidin-5-amine (0.117 g, 0.932 mmol) (ACES PHARMA) in tetrahydrofuran (10 mL, 123 mmol) was stirred at 0° C. and treated dropwise via syringe with lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran; 2.330 mL, 2.330 mmol). The solution was stirred at 0° C. for 1 h. The solution was quenched with water (10 mL) and diluted with water (15 mL) and EtOAc (100 mL). The organic layer was separated and dried over Na2SO4, filtered and concentrated in vacuo to give tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(2-methoxypyrimidin-5-ylamino)pyridin-3-yl)methyl)piperazine-1-carboxylate (0.420 mg, 0.561 mmol, 72% yield). m/z (ESI, +ve ion) 749.4 (M+H)+.