Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[S:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][C:17]=3[N:22]=2)[C:9]([NH2:23])=[CH:8][CH:7]=1.[OH-].[Na+]>O.CC(O)=O>[Cl:5][C:6]1[N:11]=[C:10]2[N:12]([CH2:13][C:14]3[S:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][C:17]=4[N:22]=3)[N:1]=[N:23][C:9]2=[CH:8][CH:7]=1
Reactant: Nc1ccc(Cl)nc1NCc1nc2cnccc2s1
Reactant: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc2nnn(Cc3nc4cnccc4s3)c2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of NaNO2 (42.5 mg, 0.62 mmol) in H2O (0.5 mL) was added dropwise to a solution of 6-chloro-N2-(thiazolo[4,5-c]pyridin-2-ylmethyl)pyridine-2,3-diamine (90 mg, 0.31 mmol) in AcOH (1 mL) and H2O (1 mL) at 0° C. The reaction solution was stirred at 0° C. for 1 h, then basified with 30% aqueous NaOH to pH ˜9. The resulting precipitate was collected by filtration to afford the title compound. MS (m/z): 303 (M+1)+.
Reaction SMILES: C([O:14][C:15]([C:17]1[O:18][C@@H:19]([C:45](=[O:53])[N:46]([CH2:50][CH2:51][CH3:52])[CH2:47][CH2:48][CH3:49])[C@H:20]([NH:41][C:42](=[O:44])[CH3:43])[C@@H:21]([NH:23][C:24]([NH:33]C(OC(C)(C)C)=O)=[N:25]C(OC(C)(C)C)=O)[CH:22]=1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.[F:54][C:55]([F:60])([F:59])[C:56]([OH:58])=[O:57]>ClCCl>[F:54][C:55]([F:60])([F:59])[C:56]([OH:58])=[O:57].[C:42]([NH:41][C@H:20]1[C@H:19]([C:45](=[O:53])[N:46]([CH2:50][CH2:51][CH3:52])[CH2:47][CH2:48][CH3:49])[O:18][C:17]([C:15]([OH:16])=[O:14])=[CH:22][C@@H:21]1[NH:23][C:24]([NH2:33])=[NH:25])(=[O:44])[CH3:43]
Reactant: CCCN(CCC)C(=O)[C@@H]1OC(C(=O)OC(c2ccccc2)c2ccccc2)=C[C@H](NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)[C@H]1NC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(CCC)C(=O)[C@@H]1OC(C(=O)O)=C[C@H](NC(=N)N)[C@H]1NC(C)=O
Reaction time: 2 h

Procedure:
(4S,5R,6R)-5-Acetylamino-4-[2,3-bis(tert-butoxycarbonyl)-guanidino]-6-dipropylcarbamoyl-5,6-dihydro-4H-pyran-2-carboxylic acid benzhydryl ester (0.32 g) was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (2 ml) and left to stand at 23° C. for 2 hours. The solvent was removed in vacuo and the residue triturated with diethyl ether (20 ml). The resulting solid was collected by filtration and dried to give the title compound as an off-white solid. (0.158 g)
Reaction SMILES: [Br:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH:3]1[OH:13].FC(S(O[Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])(=O)=O)(F)F.N1C(C)=CC=CC=1C>C(Cl)Cl>[Br:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH:3]1[O:13][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)N1CCC(Br)C(O)C1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCOC(=O)N1CCC(Br)C(O[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-bromo-3-hydroxypiperidine-1-carboxylate (Preparation: Izamanishi, T. et al; 1982, Chem. Pharm. Bull., 30: 3617-3623) (10.17 g) was dissolved in anhydrous DCM (100 mL) under an argon atmosphere and cooled to 0° C. tert-Butyldimethylsilyl trifluoromethylsulfonate (10.2 mL) was added dropwise via syringe, followed by 2,6-lutidine (4.7 mL), also added dropwise via syringe. The reaction was stirred overnight, slowly warming to room temperature, then diluted with DCM (200 mL) and washed with saturated aqueous NaHCO3 (150 mL), saturated aqueous NH4Cl ((150 mL), brine (100 mL), dried over anhydrous MgSO4 and concentrated in vacuo, yielding the title compound as a crude product (15.1 g, 102%). MS (GC-EI)[(M-C4H7)+]: 310, 312 for C14H28BrNO3Si; NMR (CDCl3): 0.10 (s, 3H), 0.12 (s, 3H), 0.88 (s, 9H), 1.24 (t, 3H), 1.87 (m, 1H), 2.34 (m, 1H), 2.84-3.40 (m, 2H), 3.69 (m, 2H), 3.93 (m, 2H), 4.13 (q, 2H).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][NH:6][CH2:5][C:4]1=[O:9].C(N(CC)C(C)C)(C)C.[CH3:19][C:20]([O:23][C:24]([N:26]1C(C2C=CC(C#N)=CC=2)O1)=[O:25])([CH3:22])[CH3:21]>ClCCl>[C:20]([O:23][C:24](=[O:25])[NH:26][N:6]1[CH2:7][CH2:8][N:3]([CH3:2])[C:4](=[O:9])[CH2:5]1)([CH3:22])([CH3:21])[CH3:19]
Reactant: CN1CCNCC1=O
Reactant: CC(C)(C)OC(=O)N1OC1c1ccc(C#N)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(NC(=O)OC(C)(C)C)CC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 16.3 %

Procedure:
Methyl-2-piperazinone hydrochloride (1:1) (300 mg, 1.99 mmol) was combined with dichloromethane (20 mL) to give a light yellow suspension. N,N-Diisopropylethylamine (309 mg, 417 μl, 2.39 mmol) was added at 0° C. Subsequently 3-(4-cyanophenyl)-2-oxaziridinecarboxylic acid 1,1-dimethylethyl ester (441 mg, 1.79 mmol) in dichloromethane (10 mL) was added during 35 min at 0° C. and the reaction mixture was stirred for 1 h at 0° C. Afterwards the reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 20 g, 0% to 100% ethyl acetate in n-heptane) to deliver an oil contaminated with 4-cyano-benzaldehyde. This material was purified by a second chromatography (aminophase 5 g, ethyl acetate/n-heptane 1/1) to give the title compound (67 mg, 15%) as white solid; GC-MS (EI) 229.0 (M)+.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.CN(C=O)C.[CH:11]1([C:14]2[CH:15]=[C:16]([CH:19]=[C:20]([O:23][CH2:24][CH3:25])[C:21]=2[OH:22])[CH:17]=[O:18])[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>O>[CH:11]1([C:14]2[CH:15]=[C:16]([CH:19]=[C:20]([O:23][CH2:24][CH3:25])[C:21]=2[O:22][CH2:2][CH:3]2[CH2:5][CH2:4]2)[CH:17]=[O:18])[CH2:12][CH2:13]1
Reactant: BrCC1CC1
Reactant: CCOc1cc(C=O)cc(C2CC2)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)cc(C2CC2)c1OCC1CC1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
(Bromomethyl)cyclopropane (0.781 mL) was added to a DMF (10 mL) suspension of 3-cyclopropyl-5-ethoxy-4-hydroxybenzaldehyde (830 mg) and potassium carbonate (1.11 g), and the mixture was stirred at 70° C. for 5 hours. The reaction mixture was allowed to cool to room temperature, and then, water was added thereto, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.03 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9]2(O)[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1>FC(F)(F)C(O)=O>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCCN1CCC(O)(c2cccc(SC)c2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCCN1CC=C(c2cccc(SC)c2)CC1
Temperature: 25 °C

Procedure:
4-(3-Methylsulfanyl-phenyl)-1-propyl-piperidin-4-ol (1) (100 mg, 0.38 mmol) was dissolved in 2 mL of trifluoroacetic acid (TFA) in a 50 mL flask while stirring in a nitrogen atmosphere. The reaction mixture was heated to reflux on an isomantle. After 15 minutes the reaction mixture was cooled to room temperature. The TFA was removed by distillation under reduced pressure. The remaining brown oil was dissolved in diethyl ether, washed 3 times with water and once with brine. The aqueous layers and brine layer were collected, basified with Na2CO3 and extracted with diethyl ether twice. The organic layers were collected, dried on MgSO4, filtered and the solvent was evaporated under reduced pressure using a rotavapor. Yield: 103 mg (111%). GCMS (EI): m/z 247 (M+), 218 (M−29); GC (100-320° C., 15° C./min): 7.6 min.
Reaction SMILES: Cl.[Br:2][C:3]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:6]2[N:7]([CH:13]([CH3:15])[CH3:14])[C:8]([CH2:10][CH2:11]Cl)=[N:9][C:5]=2[CH:4]=1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O>C(OCC)(=O)C>[Br:2][C:3]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:6]2[N:7]([CH:13]([CH3:15])[CH3:14])[C:8]([CH2:10][CH2:11][N:31]3[CH2:32][CH2:33][N:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:29][CH2:30]3)=[N:9][C:5]=2[CH:4]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC(C)n1c(CCCl)nc2cc(Br)c3ccccc3c21
Agent: Cl
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Solvent: CCOC(C)=O
Product: CC(C)n1c(CCN2CCN(c3ccccc3)CC2)nc2cc(Br)c3ccccc3c21

Procedure:
By following the procedure described in Example 16 but condensing 5-bromo-2-(2-chloroethyl)-1-(1-methylethyl)-1H-naphth[1,2-d]imidazole hydrochloride with 1-phenylpiperazine, the compound of the title is obtained. M.p. 211°-213° C. (from ethyl acetate). The corresponding citrate melts at 169°-171° C. with decomposition.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH3:21])=[CH:8][C:7](=[O:22])[CH2:6][CH2:5]1.C(O)C.O.[BH4-].[Na+]>O1CCCC1>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH3:21])=[CH:8][C:7](=[O:22])[CH2:6][CH2:5]1
Reactant: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F
Temperature: -55 °C
Reaction time: 1.5 h
Yield: 45.7 %

Procedure:
A solution of 500 mg of 11β-fluoro-7α-methylestr-4-ene-3,17-dione (B′) in 10 ml of tetrahydrofuran, 5.8 ml of ethanol and 1.15 ml of water was stirred at −55° C. with 175.6 mg of sodium borohydride for 2.5 hours. After another 351.2 mg of sodium borohydride was added, it was stirred for another 1.5 hours at −55° C., then added to ice water, extracted three times with ethyl acetate, washed neutral, dried on sodium sulfate and concentrated by evaporation in a vacuum. Then, it was chromatographed on silica gel with hexane/ethyl acetate. 230 mg of pure 11β-fluoro-17β-hydroxy-7α-methylestr-4-en-3-one (I) with a melting point of 126.7° C. was obtained ([α]D20=+79.9° (c=0.53% in chloroform)).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH:2]=[CH2:3].C(O)(=O)C1C=CC=CC=1.[C:19]([C:23]1[CH:28]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:26]=[C:25]([CH2:33]OCCCC)[C:24]=1[OH:39])([CH3:22])([CH3:21])[CH3:20]>C(O)CCC>[C:29]([C:27]1[CH:26]=[C:25]2[C:24](=[C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:28]=1)[O:39][CH:2]([C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])[CH2:3][CH2:33]2)([CH3:31])([CH3:32])[CH3:30]
Reactant: C=CC(=O)OCCCC
Reactant: CCCCOCc1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Agent: O=C(O)c1ccccc1
Solvent: CCCCO
Product: CCCCOC(=O)C1CCc2cc(C(C)(C)C)cc(C(C)(C)C)c2O1
Temperature: 157.5 °C
Yield: 87 %

Procedure:
Butyl acrylate (771.2 g, 6.02 mol) and benzoic acid (12.26 g, 0.10 mol) were added to 2,4-di-t-butyl-6-butoxymethyl-1-hydroxybenzene (665.2 g, net 586.71 g, 2.01 mol) obtained in Example 1, and the mixture was stirred while heating at 150-165° C. for 30 h. 1-Butanol produced by the reaction was removed. After the completion of the reaction, the reaction mixture was quantitatively analyzed by liquid chromatography according to the internal standard method. As a result, 6,8-di-t-butyl-2-butoxycarbonylchroman was obtained in a yield of 87% (1.74 mol). At this time, 6,8-di-t-butyl-3-butoxycarbonylchroman (a position isomer) was produced in about 8%. For use in the next step, excess butyl acrylate was distilled away under reduced pressure, toluene was added to the residue, and benzoic acid was removed with aqueous sodium hydrogen carbonate solution. The 1H-NMR data of the obtained 6,8-di-t-butyl-2-butoxycarbonylchroman are shown below.
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[CH:7][NH:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[H-].[Na+].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl>CN(C=O)C>[C:1]([C:4]1[C:8]([CH3:9])=[CH:7][N:6]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(=O)c1c(C)c[nH]c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1c(C)cn(COCC[Si](C)(C)C)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a stirred solution of 3-acetyl-2,4-dimethyl-1H-pyrrole (commercially available from Aldrich Chem. Co. Inc., 1.50 g, 10.6 mmol) in DMF (40 mL) was added NaH (60% oil dispersion, 0.85 g, 21.2 mmol) at room temperature under nitrogen. After stirring for 30 minutes at room temprature the resulting suspension was cooled to 0° C. and added 2-(trimethylsilyl)ethoxymethyl chloride (3 mL, 15.9 mmol). The reaction mixture was warm to room temperature and stirred for 3 hours. The mixture was quenched with aqueous saturated NaHCO3 solution, and the whole extracted with diethyl ether (100 mL×2). The combined organic layers were washed with brine (50 mL), dried over MgSO4, concentrated iii vaciio. Chromatographic purification of the crude product eluting ethyl acetate-hexane (1:10) gave the subtitle product (2.32 g, 82% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5]1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([N:22]2[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH:4]3[O:8][C:7](=[O:9])[N:6]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH2:5]3)[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C1OC(CCCl)CN1c1ccccc1
Product: O=C1OC(CCN2CCN(c3ccccc3)CC2)CN1c1ccccc1

Procedure:
Following the procedure of Example 2, the title compound was prepared from 5-(2-chloroethyl)-3-phenyl-2-oxazolidinone and 1-phenylpiperazine.
Reaction SMILES: [N:1]1([C:5]2[N:10]=[CH:9][C:8]([NH:11][C:12]([C:14]3[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[C:16]4[C:21]([CH:22]=3)=[CH:20][C:19](Br)=[CH:18][CH:17]=4)=[O:13])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:32]([SiH:34]([CH2:37][CH3:38])[CH2:35][CH3:36])[CH3:33].[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+]>CN1CCCC1=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N:1]1([C:5]2[N:10]=[CH:9][C:8]([NH:11][C:12]([C:14]3[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[C:16]4[C:21]([CH:22]=3)=[CH:20][C:19]([Si:34]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:32][CH3:33])=[CH:18][CH:17]=4)=[O:13])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC[SiH](CC)CC
Reactant: O=C(Nc1ccc(N2CCC2)nc1)c1cc2cc(Br)ccc2n1Cc1cccc(F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC[Si](CC)(CC)c1ccc2c(c1)cc(C(=O)Nc1ccc(N3CCC3)nc1)n2Cc1cccc(F)c1
Yield: 16.3 %

Procedure:
Compound No. 17 was prepared according to a process similar to that described in stage 8.4, by reacting 0.15 g (0.31 mmol) of N-[6-(azetidin-1-yl)pyridin-3-yl]-5-bromo-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in stage 17.3, with 110 mg (0.93 mmol) of triethylsilane in the presence of 0.2 g (0.94 mmol) of potassium triphosphate and of 16 mg (0.03 mmol) of bis(tri-tert-butylphosphine)palladium in 2 ml of dry 1-methyl-2-pyrrolidinone (NMP). 26 mg of the expected product are obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[CH:21][C:5]=1[O:6][C:7]1[C:8]([NH2:20])=[N:9][C:10]([NH:13][CH:14]2[CH2:19][CH2:18]S[CH2:16][CH2:15]2)=[N:11][CH:12]=1)([CH3:3])[CH3:2].O[O:30][S:31]([O-:33])=O.[K+].[ClH:35].CCOCC>CO.O>[ClH:35].[O:30]=[S:31]1(=[O:33])[CH2:18][CH2:19][CH:14]([NH:13][C:10]2[N:9]=[C:8]([NH2:20])[C:7]([O:6][C:5]3[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:4]=3[CH:1]([CH3:3])[CH3:2])=[CH:12][N:11]=2)[CH2:15][CH2:16]1
Reactant: COc1cc(Oc2cnc(NC3CCSCC3)nc2N)c(C(C)C)cc1OC
Reactant: O=S([O-])OO
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: COc1cc(Oc2cnc(NC3CCS(=O)(=O)CC3)nc2N)c(C(C)C)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(2-isopropyl-4,5-dimethoxy-phenoxy)-N*2*-(tetrahydro-thiopyran-4-yl)-pyrimidine-2,4-diamine (0.19 g, 0.46 mmol) in 25 mL of methanol and 25 mL of water was added the OXONE (1.73 g, 1.4 mmol). This mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The organic solution was washed with Brine, dried over MgSO4. The solution was filtered and concentrated. The residue was purified on one preparative TLC plate (20×40 cm) eluting with EtOAc. Product recovered was stirred with 1.5 eq of 1M HCl/ether to afford 25 mg of N*2*-(1,1-dioxo-hexahydro-1lambda*6*-thiopyran-4-yl)-5-(2-isopropyl-4,5-dimethoxy-phenoxy)-pyrimidine-2,4-diamine HCl salt): MS (M+H); 441: MP; 255.1-257.8° C.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([O:10][CH2:11][C:12]([O:14]CC)=[O:13])=[C:8]([Cl:17])[C:7]([Cl:18])=[C:6]([C:19]([C:21]2[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=2)=[O:20])[CH:5]=1)[CH:2]=[CH2:3].CCOCC>CCCCCC>[CH2:1]([C:4]1[C:9]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[C:8]([Cl:17])[C:7]([Cl:18])=[C:6]([C:19]([C:21]2[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=2)=[O:20])[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C(=O)c2ccnn2C)c(Cl)c(Cl)c1OCC(=O)OCC
Solvent: CCCCCC
Solvent: CCOCC
Product: C=CCc1cc(C(=O)c2ccnn2C)c(Cl)c(Cl)c1OCC(=O)O
Yield: 88.9 %

Procedure:
1.44 g of ethyl [6-allyl-2,3-dichloro-4-(1-methyl-5-pyrazolylcarbonyl)phenoxy]acetate are treated in the same manner as described in Example 18 except that a mixture of ether and hexane is used as the crystallization solvent. 1.19 g of [6-allyl-2,3-dichloro-4-(1-methyl-5-pyrazolylcarbonyl)phenoxy]acetic acid are obtained as crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]([O:22][CH3:23])[N:9]([C:12]3[CH:13]=[N:14][N:15]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH:16]=3)[C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[C:31]([O:32][CH3:33])=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:33][O:32][C:31]1[CH:30]=[C:29]([C:2]2[N:7]=[C:6]3[CH:8]([O:22][CH3:23])[N:9]([C:12]4[CH:13]=[N:14][N:15]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH:16]=4)[C:10](=[O:11])[C:5]3=[CH:4][CH:3]=2)[CH:28]=[N:27][C:26]=1[O:25][CH3:24]
Reactant: COC1c2nc(Cl)ccc2C(=O)N1c1cnn(CC(F)(F)F)c1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2ccc3c(n2)C(OC)N(c2cnn(CC(F)(F)F)c2)C3=O)cnc1OC
Temperature: 110 °C
Reaction time: 0.67 h

Procedure:
As shown in step 17-v of Scheme 17, to Compound 2058 (293 mg, 0.85 mmol), 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (269 mg, 1.01 mmol), Na2CO3 (179 mg, 1.69 mmol), and Pd(PPh3)4 (98 mg, 0.085 mmol) was added DMF (10 mL), followed by the addition of water (2 mL). The reaction vessel was evacuated, placed under an atmosphere of nitrogen, then warmed to 110° C. (sand bath). After 16 hours the reaction mixture was partitioned between EtOAc and water (100 mL each). The organics were washed with water (70 mL), brine (70 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was dissolved/suspended in EtOAc (7 mL) and heated with swirling in a water bath at 50° C. for 40 minutes. The resulting mixture was treated with hexanes (5 mL) and swirled an additional 5 minutes at 50° C. After cooling to 23° C., the resulting solid was collected by filtration and washed with 1:1 (EtOAc:hexanes, 5 mL) to give 2-(5,6-dimethoxypyridin-3-yl)-7-methoxy-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 256) as a mixture of enantiomers: ESMS (M+H) 450.44; 1H NMR (CDCl3, 300 MHz) δ 8.57 (d, J=3 Hz, 1H), 8.35 (s, 1H), 8.27 (s, 2H), 7.99 (d, J=3 Hz, 1H), 7.93 (s, 1H), 6.40 (s, 1H), 5.22 (q, J=9 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 3.13 (s, 3H).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[O:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[CH2:33][C:34](O)=[O:35]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:34](=[O:35])[CH2:33][CH:28]3[CH2:29][O:30][CH2:31][CH2:32][O:27]3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)CC1COCCO1
Agent: Cl
Product: O=C(CC1COCCO1)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, white solid (60 mg, 53%), MS (ISP) m/z=455.3 [(M+H)+], mp 172° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and (RS)-2-[1,4]dioxan-2-yl-acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][C:3]=1[CH3:21].[CH3:22][N:23]1[CH2:28][CH2:27][O:26][C:25]2[CH:29]=[C:30]([C:33](O)=[O:34])[CH:31]=[N:32][C:24]1=2>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:33]([C:30]3[CH:31]=[N:32][C:24]4[N:23]([CH3:22])[CH2:28][CH2:27][O:26][C:25]=4[CH:29]=3)=[O:34])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:4][C:3]=1[CH3:21]
Reactant: CN1CCOc2cc(C(=O)O)cnc21
Reactant: Cc1cc(-c2cc(N)cnc2OCC(F)(F)F)ccc1Cl
Product: Cc1cc(-c2cc(NC(=O)c3cnc4c(c3)OCCN4C)cnc2OCC(F)(F)F)ccc1Cl

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-3-methyl-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example 57 a) and 3,4-dihydro-4-methyl-2H-pyrido[3,2-b]-1,4-oxazine-7-carboxylic acid (CAN 915707-58-3) as starting materials; MS (EI) 493.1(M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:17]S(C1C=CC=CC=1)(=O)=O)[CH2:3][CH:4]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=O.C(C1CCCCCCCCCCC1=O)C(=C)C.C1(S)C=CC=CC=1.C1(S(CCCC2CCCCCCCCCCC2=O)(=O)=O)C=CC=CC=1>>[CH3:17][CH:2]1[CH2:3][C:4]2[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=2)=[CH:1]1
Reactant: CC(CC1CCCCCCCCCCC1=O)CS(=O)(=O)c1ccccc1
Agent: C=C(C)CC1CCCCCCCCCCC1=O
Agent: O=C1CCCCCCCCCCC1CCCS(=O)(=O)c1ccccc1
Agent: Sc1ccccc1
Product: CC1C=C2CCCCCCCCCC=C2C1
Yield: 86 %

Procedure:
2-(2-Methyl-3-phenylsulfonyl-prop-1-yl)-cyclododecanone used hereinabove (Examples 3 and 4) as starting material was prepared as follows: 235 g (1 mole) of 2-methallyl-cyclododecanone--Chem. Comm. 1976, 1021--in admixture with 132 g (1.2 mole) of thiophenol and 3.0 g (0.018 mole) of α,α'-azoisobutyronitrile were heated at 115° for 32 hours and subsequently subjected to oxidation in accordance with the method described in Example 2 for 2-(3-phenylsulfonyl-prop-1-yl)-cyclododecanone to afford, after the above mentioned treatments of extraction and purification, 325 g (86% yield) of the desired compound, m.p. 98°-103°.