Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:7]=[N:8]2)=[C:4]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:3]=1.[NH2:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:6]2[C:5]3[C:9](=[N:10][C:2]([NH:33][C:34]4[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=4)=[N:3][C:4]=3[O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)=[CH:23][CH:22]=3)[N:8]=[CH:7]2)=[CH:17][CH:16]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: COc1ccc(Cn2cnc3nc(Cl)nc(Oc4ccc(-c5ccncc5)cc4)c32)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2cnc3nc(Nc4ccc(C#N)cc4)nc(Oc4ccc(-c5ccncc5)cc4)c32)cc1
Temperature: 80 °C

Procedure:
A solution of 2-chloro-7-(4-methoxybenzyl)-6-(4-(pyridin-4-yl)phenoxy)-7H-purine (48 mg, 0.11 mmol), 4-aminobenzonitrile (20 mg, 0.17 mmol), Pd(OAc)2(2 mg, 0.009 mmol), BINAP (9 mg, 0.014 mmol), and Cs2CO3 (43 mg, 0.13 mmol) in toluene (2 mL) was degassed by bubbling nitrogen for 15 min then heated at 80° C. overnight. The desired product was precipitated with EtOAc (10 mL) and saturated NaHCO3. NMR (DMSO-d6): 10.00 (s, 1H), 8.70 (d, 2H), 8.41 (s, 1H), 7.98 (d, 2H), 7.82 (d, 2H), 7.75 (d, 2H), 7.53 (m, 4H), 7.38 (d, 2H), 6.98 (d, 2H), 5.38 (s, 2H), 3.74 (s, 3H); MS (ESI): m/z 526 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][O:11][C:10](=[O:13])[N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[N:33]=[CH:32][N:31](COCC[Si](C)(C)C)[N:30]=5)=[C:25]([F:42])[CH:24]=4)=[C:16]3[N:15]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][O:11][C:10](=[O:13])[N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[N:33]=[CH:32][NH:31][N:30]=5)=[C:25]([F:42])[CH:24]=4)=[C:16]3[N:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@@H]5c5cccc(Cl)c5)nc34)cc2F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1OC[C@H](c2cccc(Cl)c2)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)c(F)c3)c2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 42 %

Procedure:
To (S)-4-(3-chlorophenyl)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (65 mg, 0.11 mmol) in DCM (5 mL) was added TFA (1 mL) and the reaction was stirred at ambient temperature for 6 hours. The reaction was concentrated to dryness and the residue dissolved in MeOH/ammonia (7N). After stirring at ambient temperature for 30 minutes, the reaction was concentrated then purified by reverse phase chromatography (SP4, 12M, water/CH3CN 100:0 to 0:100, 20 column volumes) to yield (S)-4-(3-chlorophenyl)-3-(3-(3-fluoro-4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (22 mg, 43% yield) as a pale yellow solid. LCMS (APCI+) m/z 476.3 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]2[CH2:17][CH2:16][CH2:15][C@H:14]2[OH:18])=[C:8]([Cl:19])[CH:7]=1)[CH3:5].[OH-].[Na+].Cl>CO>[Cl:19][C:8]1[CH:7]=[C:6]([CH:4]([CH3:5])[C:3]([OH:20])=[O:2])[CH:11]=[CH:10][C:9]=1[CH2:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[OH:18]
Reactant: COC(=O)C(C)c1ccc(C[C@@H]2CCC[C@H]2O)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)O)c1ccc(C[C@@H]2CCC[C@H]2O)c(Cl)c1
Yield: 84 %

Procedure:
3 g of methyl-2-[3-chloro-4-(trans-2-hydroxycyclopentane-1-yl methyl)phenyl]propionate were incorporated with 80 ml of an aqueous methanol containing 1.2 g of sodium hydroxide and then refluxed under heat for two hours. After the end of the reaction, the reaction mixture was treated to concentrate the solvent at a reduced pressure, incorporated with 50 ml of water and washed with 50 ml of ethyl acetate, after which the aqueous layer obtained was adjusted to a pH of 2 with conc. hydrochloric acid. The aqueous layer so adjusted was extracted with 50 ml of ethyl acetate, washed with water, dried and then freed of the solvent to obtain a residue. The thus obtained residue was adsorbed onto a silica gel-packed column and then eluted with chloroform methanol (10:1) to obtain 2.4 g (yield 84%) of oily 2-[3-chloro-4-(trans-2-hydroxycyclopentane-1-yl methyl)phenyl] propionic acid.
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[C:13]([O:22][CH3:23])(=[O:21])[CH:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[OH:15].C(Br)C=CC>C1COCC1>[CH3:23][O:22][C:13](=[O:21])[C@@H:14]([OH:15])[C@@H:16]([CH2:8][CH:9]=[CH:10][CH3:11])[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)CC(O)C(=O)OC
Reactant: [Li]CCCC
Agent: CC=CCBr
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC=CC[C@@H](C(=O)OC)[C@H](O)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a solution of diisopropylamine (14 mL, 100 mmol) in THF at 0° C. was added n-butyllithium (2.5 M in hexane, 40 mL, 100 mmol) over 10 min. The mixture was stirred at RT for 30 min., and then added via cannula to a −78° C. solution of dimethyl malate F-1 (7.71 g, 47.6 mmol) in THF (130 mL). The mixture was warmed to −20° C. over 2 h, and then cooled to −78° C. Crotyl bromide (8.1 g, 60 mmol) was added, then the mixture was allowed to warm to room temperature and then stirred overnight. The solution was then cooled to −10° C. and quenched with NH4Cl (10%, 100 mL). The THF was removed and the residue extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with HCl (1N, 3×50 mL), saturated aqueous sodium bicarbonate (3×50 mL), and brine, then dried over Na2SO4. The solution was filtered and concentrated to give a residue, which was purified on silica gel (ethyl acetate/hexane 1:4) to afford (2S,3R)-3-(2-butenyl)-2-hydroxysuccinic dimethyl ester F-2 (2.5 g, 24%).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]2[C:11]3[CH:18]=[C:17]([C:19]4[CH:20]=[C:21]([CH2:25]O)[CH:22]=[CH:23][CH:24]=4)[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:46]N1C(=O)CCC1=O>ClCCl>[Cl:46][CH2:25][C:21]1[CH:20]=[C:19]([C:17]2[NH:16][C:12]3[N:13]=[CH:14][N:15]=[C:10]([NH:9][C@@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH3:8])[C:11]=3[CH:18]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3cccc(CO)c3)cc12)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@@H](Nc1ncnc2[nH]c(-c3cccc(CCl)c3)cc12)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 688 mg (2 mmol) {3-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol and 578 mg (2.2 mmol) triphenylphosphine in 60 ml dichloromethane is treated at 0° C. with 293 mg (2.2 mmol) N-chlorosuccinimide. After stirring 1 h at 0° C. all the material has gone into solution. The solvent is evaporated and the title compound purified with flash chromatography using dichloromethane/ethanol 95:5 (the title compound is contaminated with a small amount of triphenylphosphine oxide); Rf (dichloromethane/ethanol 95:5)=0.35; MS-ES+: (M+H)+=363.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:21]([C:17]1[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=1)=[N:1]2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: O=Cc1cccnc1
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccnc3)nc2c1
Yield: 48 %

Procedure:
5,7-Dimethoxy-2-(pyridin-3-yl)quinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 3-pyridine carboxaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 5,7-Dimethoxy-2-(pyridin-3-yl)quinazolin-4(3H)-one (105 mg, 48%) was isolated as a white solid. Selected data: MS (m/z): 284.0; MP 257-259° C. (hydrochloride).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22](B(O)O)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1>>[NH:17]1[C:25]2[C:20](=[CH:21][C:22]([C:2]3[N:3]=[C:4]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[C:5]4[S:10][CH:9]=[CH:8][C:6]=4[N:7]=3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Product: c1cc2cc(-c3nc(N4CCOCC4)c4sccc4n3)ccc2[nH]1

Procedure:
2-Chloro-4-moropholinothieno[3.2-d]pyrimidine 4 was reacted with 5-indole boronic acid in General Procedure A on a 23.5 mmol scale to give 25.7 mg. of 271 after RP-HPLC purification. MS (Q1) 337.1 (M)+.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:25]2[CH:26]=[CH:27][C:28]3[C:39]4=[C:40]5[C:31]([CH:32]=[CH:33][CH:34]=[C:35]5[CH:36]=[CH:37][C:38]=24)=[CH:30][CH:29]=3)[CH:13]=[C:14]([CH2:16][O:17][Si](C(C)(C)C)(C)C)[CH:15]=1)(C(C)(C)C)(C)C.[C:41](Cl)([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)([C:50]1[CH:57]=[CH:56][C:53]([O:54][CH3:55])=[CH:52][CH:51]=1)[C:42]1[CH:49]=[CH:48][C:45]([O:46][CH3:47])=[CH:44][CH:43]=1>CO>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:25]2[C:38]3[C:39]4=[C:40]5[C:35](=[CH:36][CH:37]=3)[CH:34]=[CH:33][CH:32]=[C:31]5[CH:30]=[CH:29][C:28]4=[CH:27][CH:26]=2)[CH:13]=[C:14]([CH2:16][O:17][C:41]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)([C:50]2[CH:57]=[CH:56][C:53]([O:54][CH3:55])=[CH:52][CH:51]=2)[C:42]2[CH:49]=[CH:48][C:45]([O:46][CH3:47])=[CH:44][CH:43]=2)[CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CO[Si](C)(C)C(C)(C)C)cc(-c2ccc3ccc4cccc5ccc2c3c45)c1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CO
Product: COc1ccc(C(OCc2cc(CO)cc(-c3ccc4ccc5cccc6ccc3c4c56)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 27 h

Procedure:
14.5 ml of pyrizine were added to dissolve 0.932 g of Compound (14) in an Ar atmosphere, and 1.27 g (3.77 mmol, 1.3 eq) of DMTrCl was added. This was agitated for 27 hours in an Ar atmosphere. After extraction with chloroform, the organic layer was washed with H2O, sat. NaHCO3 aq and sat. NaCl aq, and dried by addition of anhydrous NaSO4. The solvent was distilled off under reduced pressure, and 0.4632 g (0.72 mmol, 3-step 30%) of Compound (14) was isolated by silica gel chromatography (chloroform only→chloroform:methanol=100:1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1>>[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:26][CH:25]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Cc1ccc(CBr)cc1
Product: Cc1ccc(CN2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)cc1

Procedure:
Compound 120 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1-(bromomethyl)-4-methylbenzene and conditions outlined in procedure V. M.p.=156-158° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 7.2 (dd, 4H), 3.55 (s, 2H), 2.9 (s, 2H), 2.75 (d, 2H), 2.5 (t, 2H), 2.35 (s, 3H), 2.1 (d, 2H), 1.85 (t, 2H); LCMS: 406 [M+H].
Reaction SMILES: [CH:1](=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[Mg].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>CCOCC>[CH2:5]=[CH:4][CH2:3][CH2:2][CH:1]([OH:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: C=CCCC=O
Reactant: CCCCCCBr
Agent: [Mg]
Solvent: CCOCC
Product: C=CCCC(O)CCCCCC
Yield: 88.1 %

Procedure:
4-pentenal (8.4 g., 0.1 mol) was added dropwise to the Grignard reagent from magnesium turnings (2.88 g., 0.12 mol) and 1-bromohexane (19.8 g., 0.12 mol) in ether (120 ml). The reaction mixture was then refluxed for 2 hours cooled, and quenched with ammonium chloride solution. After layers were separated, ether solution was evaporated and the residue distilled to give 1-undecen-5-ol (15.0 g., 88% yield, b.p. 93°-96°/1.2 torr).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]3[C:20](=[O:21])[CH2:19][O:18][C:17]3=[O:22])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.Br[Zn][CH2:25][CH:26]([CH3:28])[CH3:27].O.C(OCC)(=O)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:25]([C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]3[C:20](=[O:21])[CH2:19][O:18][C:17]3=[O:22])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: O=C1COC(=O)N1CCC1CCN(c2cccc(Br)n2)CC1
Reactant: CC(C)C[Zn]Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Cc1cccc(N2CCC(CCN3C(=O)COC3=O)CC2)n1
Reaction time: 17 h

Procedure:
2 g (5.43 mmol) of 3-{2-[1-(6-bromo-2-pyridyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione, prepared in step 13.3, and 0.20 g (0.271 mmol) of dichlorobis(triphenylphosphine)palladium (Pd(PPh3)2Cl2) suspended in 10 ml of tetrahydrofuran are introduced under an inert atmosphere. 22 ml (10.80 mmol) of a solution (0.5 M) of bromo(isobutyl)zinc in tetrahydrofuran are then added. Stirring is continued at room temperature for 17 hours. The reaction mixture is poured into water and ethyl acetate. The phases are separated by settling, the aqueous phase is extracted twice with ethyl acetate, the combined organic phases are dried over sodium sulfate and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by chromatography on silica gel, eluting with a 20/80 mixture of ethyl acetate and cyclohexane.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([O:28]C)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[OH-].[Li+].C1COCC1.Cl>C(OCC)(=O)C.O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([OH:28])=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoate (0.466 g, 1 mmol), lithium hydroxide (0.237 g, 10 mmol), THF (30 mL), and water (10 mL) were combined and stirred under argon at room temperature overnight. Solvents were pumped off, and the residue taken up in ethyl acetate and water. The mixture adjusted to pH 2.5 with HCl, and extracted with a large volume of ethyl acetate. Organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to afford the title compound as a white solid. LC-MS m/z 451.8 (M+H)+, 1.37 min (ret time).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[S:12](Cl)(=[O:14])=[O:13].Cl.CN.[CH2:19]([N:21](CC)CC)C.Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[S:12]([NH:21][CH3:19])(=[O:14])=[O:13]
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)c(F)cc1F
Agent: CN
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cc([N+](=O)[O-])c(F)cc1F
Temperature: -50 °C
Reaction time: 6 h
Yield: 39.2 %

Procedure:
A solution of 2,4-difluoro-5-nitrobenzenesulfonyl chloride (21 g, 81 mmol) in THF (400 mL) at −60° C. was treated with methylamine hydrochloride (6.6 g, 97 mmol) and then treated dropwise with triethylamine (22.6 mL, 162 mmol). After stirring for 6 hours at −60 to −40° C. the mixture was adjusted to pH 3 with the addition of 15% aqueous HCl, diluted with water, and extracted with EtOAc. The organic extracts were dried (Na2SO4), concentrated, and subjected to flash chromatography (17% EtOAc-petroleum ether) to give 2,4-difluoro-N-methyl-5-nitrobenzenesulfonamide (8 g, 38%) as a brown solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.66-8.74 (m, 1 H), 7.20-7.25 (m, 1 H), 4.81-4.91 (m, 1 H), 2.78-2.81 (m, 3 H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:27](O)=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37](=[N:39][OH:40])[NH2:38]>>[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[N:38]=[C:27]([CH:12]2[CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:26])[F:25])=[CH:18][CH:17]=3)[CH2:15][N:10]([C:8]([N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)=[O:9])[CH2:11]2)[O:40][N:39]=1
Reactant: NC(=NO)c1ccccc1F
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ccccc3F)no2)C1

Procedure:
100 mg (0.24 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 63A) and 56 mg (0.36 mmol, 1.5 eq.) of 2-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 73 mg (57% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10](OC(=O)C)(=[O:12])[CH3:11]>O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:10](=[O:12])[CH3:11])[CH:5]=[CH:4][C:3]=1[OH:9]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(O)c(Cl)c1
Solvent: O
Product: CC(=O)Nc1ccc(O)c(Cl)c1
Temperature: 25 °C

Procedure:
The mixture was heated at reflux for 6 hours, cooled to ambient temperature and filtered. The filtrate was evaporated, and the residue treated with ether to give crude 2-chloro-4-aminophenol (10 g). The crude 2-chloro-4-aminophenol (3.5 g) was added to a mixture of water (50 ml) and acetic anhydride (5.7 ml). The reaction mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to ambient temperature and the supernatant was decanted away from an oil which gave a solid on standing. The solid was purified by flash column chromatography on silica gel (Merck Art. No 9385) using a 1:2(v/v) mixture of ethyl acetate and pentane as eluent to give 2-chloro-4-acetamidophenol as an oil (1.7 g); NMR: ([CD3 ]2SO): 2.0(3H,s), 6.85(1H,d), 7.2(1H,m), 7.68(1H,m) and 9.8(2H,m).
Reaction SMILES: S1C2C=CC=CC=2N=CN1.[Cl:11][C:12]1[C:13]([S:24][CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:14][C:15]2[S:20](=[O:22])(=[O:21])[NH:19]C=[N:17][C:16]=2[CH:23]=1>>[S:20]([C:15]1[CH:14]=[C:13]([S:24][CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[C:12]([Cl:11])=[CH:23][C:16]=1[NH2:17])(=[O:21])(=[O:22])[NH2:19]
Reactant: CCC(CC)Sc1cc2c(cc1Cl)N=CNS2(=O)=O
Agent: C1=Nc2ccccc2SN1
Product: CCC(CC)Sc1cc(S(N)(=O)=O)c(N)cc1Cl

Procedure:
By replacing the 1,2,4-benzothiadiazine derivative employed in Step A-1 by an equivalent quantity of 6-chloro-7-(1-ethylpropylthio)-1,2,4-benzothiadiazine-1,1-dioxide (prepared as described in Example 7) and following substantially the same procedure described in Step A-1, there is obtained 2-sulfamoyl-4-(1-ethylpropylthio)-5-chloroaniline, m.p. 118°-120° C.
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][CH:13]=[CH:14][N:15]=2)[N:10]=[C:9]1[CH:19](Br)[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C>[N:24]([CH:19]([C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17](=[O:18])[C:16]2[C:11](=[N:12][CH:13]=[CH:14][N:15]=2)[N:10]=1)[CH:20]([CH3:22])[CH3:21])=[N+:25]=[N-:26]
Reactant: CC(C)C(Br)c1nc2nccnc2c(=O)n1Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(N=[N+]=[N-])c1nc2nccnc2c(=O)n1Cc1ccccc1

Procedure:
Formula 106 where R2 and R3 are H; R5 is Benzyl; R6 is Isopropyl; R6′ is H; X and Y are —C═; and W and Z are —N═: A DMF (50 mL) solution of 3-benzyl-2-(1-bromo-2-methyl-propyl)-3H-pteridin-4-one (1.4 g, 3.75 mmol) and sodium azide (0.488 g, 7.50 mmol) was stirred at 60° C. for two hours and concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed with water and brine, dried over sodium sulfate and concentrated in vacuo to give desired azido product of Formula 106, 2-(1-azido-2-methyl-propyl)-3-benzyl-3H-pteridin-4-one, which was taken on without further purification. MS (Cl) M/E: 336.1.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([F:7])=[C:4]([F:6])[F:5].[CH:10]([O:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]1)=[CH2:11].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:5][C:4]([F:6])([O:21][CH2:20][CH:17]1[CH2:18][CH2:19][CH:14]([CH2:13][O:12][CH:10]=[CH2:11])[CH2:15][CH2:16]1)[CH:3]([F:7])[C:2]([F:9])([F:8])[F:1]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: C=COCC1CCC(CO)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=COCC1CCC(COC(F)(F)C(F)C(F)(F)F)CC1
Temperature: 25 °C
Yield: 75.9 %

Procedure:
Hexafluoropropene (264 g, 1.76 mol) was added dropwise to a mechanically stirred mixture of 1,4-cyclohexanedimethanol vinyl ether (300 g, 1.76 mol), acetonitrile (600 mL), and K2CO3 (121 g, 0.88 mol), at 0° C. under N2. The reaction flask was placed in an ice bath to moderate the exothermic reaction during the addition of hexafluoropropene. After complete addition of hexafluoropropene, the reaction mixture was stirred for an additional hour at room temperature and filtered. The filtrate w as added to 1.5 L water and mixed well. The lower layer formed was separated, washed with water (3×300 mL), and concentrated under reduced pressure (approximately 0.05 mm Hg) to afford 1,1,2,3,3,3-hexafluoro-1-{[4 (vinyloxymethyl)cyclo-hexyl]methoxy} propane(cis/trans mixture) as a colorless liquid (428 g, 76% yield); b.p. 55-60° C./0.05 mm Hg; Refractive Index 1.4145 at 23.7° C.; GC/MS: m/z at 320 for M+; 19F and 1H NMR spectral data are consistent with the structure.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[OH:6][N:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH:10]([OH:15])[CH2:9][C:8]1([CH3:17])[CH3:16]>ClCCCl>[CH2:1]([NH:3][C:4](=[O:5])[O:15][CH:10]1[CH2:11][C:12]([CH3:13])([CH3:14])[N:7]([O:6][C:4](=[O:5])[NH:3][CH2:1][CH3:2])[C:8]([CH3:17])([CH3:16])[CH2:9]1)[CH3:2]
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: CCN=C=O
Solvent: ClCCCl
Product: CCNC(=O)OC1CC(C)(C)N(OC(=O)NCC)C(C)(C)C1
Temperature: 70 °C
Reaction time: 30 h
Yield: 78.7 %

Procedure:
20 ml (0.26 mol) of ethyl isocyanate are added dropwise under nitrogen to 10.0 g (0.058 mol) of 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine, prepared as described by Paleos C. M. et al., loc. cit., in 100 ml of 1,2-dichloroethane. The mixture is stirred at 70° C. for 30 hours and then evaporated to dryness on a rotary evaporator. Recrystallization of the residue from xylene gives 14.4 g (77%) of the compound 117 as colourless crystals; melting point: 149-151° C.