Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14](OC)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].CO.[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([CH2:14][OH:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(CO)CC1
Yield: 68.8 %

Procedure:
17.6 g of methyl 1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro-4-pyridinecarboxylate was dissolved in 300 ml of tetrahydrofuran. After adding 4.77 g of lithium tetrahydroborate and then 20 ml of methanol, the resulting mixture was stirred at room temperature for 20 minutes. Saturated ammonium chloride was added to the reaction mixture under ice-cooling and the resulting mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate followed by filtration. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 10.7 g of the title compound as a colorless oily substance.
Reaction SMILES: OC[C@@H](N)C(C)CC.COC(=O)[C@H]([C@H](CC)C)N.OCCN.[CH3:23][C:24]1[CH:31]=[C:30]([N+:32]([O-])=O)[C:29]([CH3:35])=[CH:28][C:25]=1[C:26]#[N:27].NC1C=CC=CC=1.C([C:45]1C(C)=[CH:49][C:48]([N:52]=[C:53]=[S:54])=[C:47]([CH3:55])[CH:46]=1)#N>>[C:26]([C:25]1[C:24]([CH3:23])=[CH:31][C:30]([N:32]=[C:53]2[NH:52][C@@H:48]([CH:47]([CH2:46][CH3:45])[CH3:55])[CH2:49][S:54]2)=[C:29]([CH3:35])[CH:28]=1)#[N:27]
Reactant: Cc1cc(N=C=S)c(C)cc1C#N
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1C#N
Agent: CCC(C)[C@H](N)CO
Agent: CC[C@H](C)[C@H](N)C(=O)OC
Solvent: NCCO
Solvent: Nc1ccccc1
Product: CCC(C)[C@H]1CSC(=Nc2cc(C)c(C#N)cc2C)N1

Procedure:
(1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 2,5-Dimethyl-4-nitrobenzonitrile was converted to 4-cyano-2,5-methylaniline according to Method A1a. The aniline was converted to 4-cyano-2,5-dimethylphenyl isothiocyanate as described in Method A2a, Step 3. 4-Cyano-2,5-dimethylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-2-methylbutanammonium chloride to Method C1a to give (4S)-2-(4-cyano-2,5-dimethylphenylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-cyano-2,5-dimethylphenylimino)-4-butyl-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: [Cl-].[C:2]([O:7][C@H:8]1[C@H:16]([CH3:17])[O:15][C:14](=[O:18])[C@@H:13]([NH3+:19])[CH2:12][O:11][CH2:10][C@@H:9]1[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:6])[CH:3]([CH3:5])[CH3:4].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[OH:64][C:65]1[C:66]([C:73](O)=[O:74])=[N:67][CH:68]=[CH:69][C:70]=1[O:71][CH3:72].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[C:2]([O:7][C@@H:8]1[C@@H:9]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)[CH2:10][O:11][CH2:12][C@H:13]([NH:19][C:73](=[O:74])[C:66]2[C:65]([OH:64])=[C:70]([O:71][CH3:72])[CH:69]=[CH:68][N:67]=2)[C:14](=[O:18])[O:15][C@H:16]1[CH3:17])(=[O:6])[CH:3]([CH3:5])[CH3:4]
Reactant: COc1ccnc(C(=O)O)c1O
Reactant: CC(C)C(=O)O[C@@H]1[C@@H](Cc2cccc3ccccc23)COC[C@H]([NH3+])C(=O)O[C@H]1C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](Cc3cccc4ccccc34)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1O
Reaction time: 0.17 h
Yield: 88 %

Procedure:
To a suspension of (3S,7S,8R,9S)-8-(isobutyryloxy)-9-methyl-7-(naphthalen-1-ylmethyl)-2-oxo-1,5-dioxonan-3-aminium chloride in CH2Cl2 (2 mL) were added PyBOP (248 mg, 0.477 mmol) and 3-hydroxy-4-methoxypicolinic acid (81 mg, 0.477 mmol) followed by the dropwise addition of N-ethyl-N-isopropylpropan-2-amine (249 μL, 1.43 mmol). After 10 min everything solubilized and stirring was continued for 2 h. The reaction was treated with Celite®, the solvent removed under reduced pressure, and the resulting adsorbed crude material was purified by flash chromatography (SiO2, 0→100% EtOAc/hexanes) to provide (3S,6S,7R,8S)-3-(3-hydroxy-4-methoxypicolin-amido)-6-methyl-8-(naphthalen-1-ylmethyl)-4-oxo-1,5-dioxonan-7-yl isobutyrate as a white powder (210 mg, 88%): mp 139-142° C.; 1H NMR (400 MHz, CDCl3) δ 11.91 (s, 1H), 8.50 (d, J=8.3 Hz, 1H), 8.01-7.92 (m, 2H), 7.89-7.82 (m, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.49 (dddd, J=14.7, 8.1, 6.9, 1.5 Hz, 2H), 7.40 (dd, J=8.2, 7.0 Hz, 1H), 7.30 (dd, J=6.9, 1.2 Hz, 1H), 6.84 (d, J=5.2 Hz, 1H), 5.20-5.02 (m, 3H), 4.04 (dd, J=11.7, 7.3 Hz, 1H), 3.92 (s, 3H), 3.60 (d, J=4.1 Hz, 2H), 3.43 (dd, J=11.7, 7.1 Hz, 1H), 3.23 (dd, J=14.2, 3.2 Hz, 1H), 2.79-2.64 (m, 2H), 2.36-2.23 (m, 1H), 1.43-1.37 (m, 3H), 1.29 (dd, J=7.0, 3.6 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 176.37, 171.12, 168.88, 155.32, 148.71, 140.60, 134.68, 133.97, 131.94, 130.09, 128.97, 127.76, 127.35, 126.02, 125.57, 125.37, 123.45, 109.55, 76.95, 74.38, 72.09, 56.07, 51.42, 44.93, 34.37, 32.19, 19.14, 19.07, 18.26; HRMS-ESI (m/z) [M+H]+ calcd for C30H35N2O8 expected, 551.2388. found 551.2388.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].Br[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][C:27]=1[O:36][CH3:37].C(=O)([O-])[O-].[K+].[K+]>>[CH3:33][O:32][C:30](=[O:31])[C:29]1[CH:34]=[CH:35][C:26]([CH2:25][O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:2]([Cl:1])[CH:3]=2)=[C:27]([O:36][CH3:37])[CH:28]=1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(COc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)c(OC)c1

Procedure:
In analogy to Example 1, step 7, (3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (Example 19, Step 5) was reacted with methyl 4-(bromomethyl)-3-methoxy-benzoate and potassium carbonate to give the title compound as a colorless viscous oil. MS (m/e, ISP neg. ion)=542.1 [M−H+].
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([O:17][CH3:18])[C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:5]=2[N:4]=1.[NH:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:8][N:7]1[C:6]2[CH:9]=[C:10]([O:17][CH3:18])[C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:5]=2[N:4]=[C:3]1[CH2:2][N:19]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:2][C:3]2[N:7]([CH3:8])[C:6]3[CH:9]=[C:10]([O:17][CH3:18])[C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:5]=3[N:4]=2)[CH2:21][CH2:20]1
Reactant: COc1cc2c(nc(CCl)n2C)c(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc2c(nc(CN3CCCN(Cc4nc5c(OC)c(OC)c(OC)cc5n4C)CC3)n2C)c(OC)c1OC

Procedure:
2-Chloromethyl-1-methyl-4,5,6-trimethoxy-benzimidazole (75 mg) and homopiperazine (11 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].C1(C)C=CC=CC=1.[CH2:18]1[O:28][C:27]2[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][C:20]=2[O:19]1>O.C(Cl)Cl.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:23][C:22]2[CH:25]=[CH:26][C:27]3[O:28][CH2:18][O:19][C:20]=3[CH:21]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S)cc1
Reactant: ClCc1ccc2c(c1)OCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccc(SCc2ccc3c(c2)OCO3)cc1
Temperature: 25 °C

Procedure:
To a solution of 28.5 g of p-thiocresol in 250 mL of water is added 8.8 g of sodium hydroxide. The solution is heated on a steam bath briefly with vigorous stirring and then cooled to room temperature. To this solution is added 250 of toluene, 39.7 g of a 50% by weight solution of 3,4-methylenedioxybenzyl chloride in methylene chloride and 3.3 g of tetrabutylammonium chloride. This solution is stirred at room temperature for one hour and then 4.4 g of sodium hydroxide is added. The resulting solution is stirred at room temperature overnight and then partitioned. The organic layer is washed with 1N sodium hydroxide, brine, and dried over sodium sulfate. The solvent is removed at reduced pressure and the residual brown oil is purified via column chromatography using hexane/chloroform (2:1). This affords 24 g of the desired product as a clear oil. MS (CI): m/z 259 (MH+). Calcd for C15H14O2S: C=69.74, H=5.46, S=12.41 Found C=69.53, H=5.36, S=12.69
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])#[CH:20].C1(C)C=CC=CC=1>C(#N)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:19]#[C:20][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(F)cc1F
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1nc(C#Cc2ccc(F)cc2F)ccc1[N+](=O)[O-]
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
6-Chloro-3-nitro-pyridin-2-ylamine (1254 g, 7.23 mol), triethylamine (1510 mL, 10.84 mol) and acetonitrile (10 L) are charged into a 20 L, 4-neck round bottom flask equipped with a mechanical stirrer under nitrogen. To the resulting yellow suspension, copper(I) iodide (13.9 g, 72.3 mmol) and bis(triphenylphosphine)palladium (II) chloride (50.72 g, 72.3 mmol) are added. The resulting pale orange suspension is cooled to 0-5° C. and then degassed during 10 min with nitrogen. A solution of 1-ethynyl-2,4-difluoro-benzene (1100 g, 7.95 mol) dissolved in acetonitrile (2.5 L) is added dropwise during 60 min. The resulting mixture is left stirring at RT (30° C.) overnight. The mixture is cooled to 0-5° C. Toluene (6 L) is added to the suspension and the mixture is stirred for 45 min and filtered though a frit. The solid is washed with toluene (3×3 L), water (2×3 L) and is dried overnight in a vacuum oven, to obtain the title compound as a yellow solid (1750 g, 92%). LC-ES/MS m/z 276 (M+1).
Reaction SMILES: [CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:14])=[C:3]1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+].[C:30]([O:39][CH2:40]Cl)(=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].CC(C)=O>C1(C)C=CC=CC=1.CCCCCC>[C:30]([O:39][CH2:40][O:14][C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11](=[O:13])(=[O:12])[N:2]([CH3:1])[C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16])(=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Reactant: CCCCCCCC(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCCCCCCC(=O)OCOC1=C(C(=O)Nc2ccccn2)N(C)S(=O)(=O)c2ccccc21

Procedure:
To a round bottomed flask equipped with a reflux condenser and a stirring bar were added piroxicam (1.00 g, 3.0 mmol), potassium carbonate (840 mg, 6.0 mmol), chloromethyl octanoate (870 mg, 4.5 mmol) and acetone (15 mL). The heterogenous reaction mixture was heated to reflux under a nitrogen atmosphere. After 6 hours additional chloromethyl octanoate (250 mg, 0.75 mmol) and additional potassium carbonate (210 mg, 1.5 mmol) were added and reflux continued for an additional hour. Chromatographed title product was isolated, according to the method of Example 5, as a yellow foam which oiled from toluene/hexane, but crystallized from the oil upon refrigeration (690 mg white crystals, 1.4 mmol, 47%); mp 98°-99° C.; IR (KBr) 1766, 1683 cm-1 ; 1H NMR (CDCl3) delta 0.87 (t, J=8 Hz, 3H), 1.02-1.48 (m, 10H), 2.19 (t, J=6 Hz, 2 H), 3.12 (s, 3H), 5.70 (s, 2H), 7.08-7.17 (m, 1H), 7.67-7.98 (m, 5H), 8.30-8.45 (m, 2H), 9.32 (br s, 1H); precise mass calcd for C24H30N3O6S m/e (P+ +H) 488.1859, found 488.1794.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C)C=O>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cc2ccccc2)cc1
Reactant: OCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCCCCCOc1ccc(Cc2ccccc2)cc1
Temperature: 100 °C

Procedure:
A mixture of 40.0 g (0.217 mole) of p-benzylphenol (Eastman) and 29.7 g (0.217 mole) of 6-chlorohexan-1-ol (MCB) in 500 ml of dry dimethylformamide is stirred and heated to about 100° C., after which 33.1 g (0.24 mole) of potassium carbonate is added, and the mixture refluxed for 2.5 hours. The mixture is cooled, poured into ice-water, and 50 ml of 10% NaOH is added. The mixture is extracted with ether, the ether extracts washed with water and brine, dried (Mg2SO4), and the ether evaporated. The resultant oil is redistilled to give the product as a water-white oil fraction distilling at 140-175° C., 0.05 mmHg.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[Mg]Br.[Sn:12](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16]>C1COCC1>[CH2:21]([Sn:12]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:17][CH2:18][CH2:19][CH3:20])[C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=1[CH3:9])[CH2:22][CH2:23][CH3:24]
Reactant: Cc1cc(C)c([Mg]Br)c(C)c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1c(C)cc(C)cc1C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To 2,4,6-trimethylphenylmagnesium bromide (1.0 M in THF, 10.0 mL, 10 mmol, 1.0 equiv) in THF (30 mL) at −78° C. was added nBu3SnCl (3.25 g, 10.0 mmol, 1.00 equiv). After stiffing for 1.0 hr at 23° C., the solvent was removed in vacuo and the residue was purified by fractional distillation to afford 3.68 g of the title compound as a colorless oil (90% yield).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH:13]([N+:16]([O-])=O)[CH2:14][CH3:15])[CH2:9][C:8]2=[O:19])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Ni].O>[NH2:16][CH:13]([CH:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:20]=[CH:21][C:2]([F:1])=[CH:3][CH:4]=2)[C:8](=[O:19])[CH2:9]1)[CH2:14][CH3:15]
Reactant: [H][H]
Reactant: CCC(C1CCN(Cc2ccc(F)cc2)C(=O)C1)[N+](=O)[O-]
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: CCC(N)C1CCN(Cc2ccc(F)cc2)C(=O)C1
Reaction time: 24 h

Procedure:
To a solution of 1-(4-fluorobenzyl)-4-(1-nitropropyl)piperidin-2-one (2.8 g, 9.51 mmol) in ethanol (50 mL) was added Raney Nickel (2 grams of a 50% by weight slurry in water). The reaction mixture was shaken under 55 psi of hydrogen. After 24 hours, the reaction mixture was filtered through a bed a celite, then concentrated under vacuum to afford the title compound as a mixture of diastereomers. The first diastereomer has a retention time of 2.05 min and the second diastereomer has a retention time of 2.10 min. The HPLC method was performed on a Hewlett-Packard Zorbax SB-C8 column (75×4.6 mm, 3.5 micron) eluting with 5%-100% CH3CN (0.1% TFA) in H2O (0.1% TFA). ES MS M+1=265.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:15]N(C)CCN(C)C.C([Li])(CC)C.CI>C1COCC1.O>[CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)CCN(C)C
Reactant: CCCCOc1ccc(C(=O)O)cc1
Agent: [Li]C(C)CC
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: CCCCOc1ccc(C(=O)O)c(C)c1
Temperature: -90 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-butoxybenzoic acid (10 g), N,N,N′,N′-tetramethylethylenediamine (13.2 g) and THF (75 mL) was cooled to −90° C., and sec-butyllithium (81 mL; 1.4 M in hexane) was added over the course of 30 minutes. After a further 30 minutes, the mixture was warmed to −78° C., and a solution of methyl iodide (12.8 mL) in THF (10 mL) was added dropwise. The reaction solution was allowed to warm to room temperature and the mixture was hydrolyzed with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel. The product with the molecular weight of 208.26 (C12H16O3) was obtained in this way; MS (ESI): 209 (M+H+).
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[O:4][CH:5]=[C:6]([CH:8]=[O:9])[CH:7]=1.[CH2:12]([Mg]Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>O1CCCC1>[OH:9][CH:8]([C:6]1[CH:7]=[C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])[O:4][CH:5]=1)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: CCCCCCCCCCCC[Mg]Br
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Reaction time: 2 h

Procedure:
A solution of 2-trimethylsilyl-4-furaldehyde (0.5 g, 2.97 mmol) in tetrahydrofuran (5 ml) was added to a solution of dodecyl magnesium bromide (5.95 mmol; prepared from 1.48 g dodecyl bromide and 146 mg magnesium turnings in 30 ml tetrahydrofuran) at room temperature. After 2 hours, the mixture was quenched with ammonium chloride solution and extracted thoroughly with ethyl ether. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was flash chromatographed on silica using 10% ethyl ether/hexane. Fractions with Rf about 0.13 gave, after evaporation, the title alcohol as a pale yellow oil.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][CH2:14][CH2:15][CH2:16]Br.C(N(CC)CC)C.[Cl-].[Na+]>CN(C)C=O>[Cl:13][CH2:14][CH2:15][CH2:16][N:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: ClCCCBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: ClCCCN1CCC(c2ccccc2)CC1
Reaction time: 1 h

Procedure:
24 Grams of 4-phenylpiperidine, 24 g of 1-chloro-3-bromopropane and 15 g of triethylamine were mixed with 100 ml of dimethylformamide and stirred at 50°-60° C. for 1 hour. The reaction mixture was poured into 200 ml of saturated sodium chloride aqueous-solution and the organic layer was extracted with chloroform. Then the chloroform layers was washed with water, dried and the chloroform was removed by distillation. The residue thus obtained was purified by a silica-gel column chromatography (to obtain only the main product at the upper-most portion in the column). 15.3 Grams of 1-chloro-3-(4-phenylpiperidinyl)propane was obtained as in the form of colorless oily substance. Then this oily substance was distilled under a reduced pressure to obtain 11 g of a fraction of distillate having the boiling point of 112°-115° C. (0.1 mmHg). A part of this distillate was made as in the form of hydrochloride and recrystallized from ethanol to obtain 1-chloro-3-(4-phenyl-1-piperidyl)propane monohydrochloride having the melting point of 167°-169° C. as in the form of colorless needle-like crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12](=O)[CH2:13]Br)=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[C:16]([NH2:19])(=[S:18])[CH3:17]>COCCOC.C(O)C>[NH2:1][C:2]1[S:3][C:4]([C:12]2[N:19]=[C:16]([CH3:17])[S:18][CH:13]=2)=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1nc(N)sc1C(=O)CBr
Reactant: CC(N)=S
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)c1nc(N)sc1-c1csc(C)n1
Yield: 64.8 %

Procedure:
A solution of ethyl 2-amino-5-(2-bromoacetyl)-4-thiazolecarboxylate (2.35 g) and thioacetamide (1.8 g) in a mixture of 1,2-dimethoxyethane (70 ml) and ethanol (70 ml) was refluxed for 7 hours and the reaction mixture was evaporated in vacuo. To the residue was added water, and the resulting mixture was adjusted to pH 8.0 with 20% aqueous potassium carbonate and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was washed with diethyl ether and recrystallized from ethyl acetate to give ethyl 2-amino-5-(2-methyl-4-thiazolyl)-4-thiazolecarboxylate (1.4 g). mp 197°-199° C. (dec.).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH2:7][CH:6]3[CH2:22][O:23][CH2:24][CH2:25][N:5]3[C:4]=2[N:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][CH:40]=[C:39]3[C:35]=2[CH:36]=[CH:37][NH:38]3)O1>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:38]1[C:39]2[C:35](=[C:34]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([S:12]([C:15]5[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=5)(=[O:14])=[O:13])[CH2:7][CH:6]5[CH2:22][O:23][CH2:24][CH2:25][N:5]5[C:4]=4[N:3]=3)[CH:42]=[CH:41][CH:40]=2)[CH:36]=[CH:37]1
Reactant: Cc1ccc(S(=O)(=O)N2CC3COCCN3c3nc(Cl)ncc32)cc1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)N2CC3COCCN3c3nc(-c4cccc5[nH]ccc45)ncc32)cc1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 3 using 2-chloro-5-tosyl-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x11, 68 mg, 0.179 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (87 mg, 0.357 mmol) and PdCl2(dppf) (6.53 mg, 8.93 μmol) in dioxane (2 mL) and aqueous saturated NaHCO3 (0.4 mL). 1H NMR (400 MHz, DMSO-d6) δ 2.35-2.41 (m, 3H), 2.55-2.66 (m, 1H), 2.68-2.76 (m, 1H), 2.97-3.09 (m, 1H), 3.17-3.27 (m, 1H), 3.82-3.98 (m, 2H), 4.16-4.27 (m, 1H), 4.53-4.63 (m, 1H), 4.57-4.57 (m, 1H), 7.14-7.24 (m, 1H), 7.23-7.31 (m, 1H), 7.38-7.50 (m, 3H), 7.51-7.63 (m, 3H), 8.00-8.10 (m, 1H), 8.48-8.58 (m, 1H), 11.19-11.35 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C24H23N5O3S, 462.15. found 462.4.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:16]=[C:17]2[C:24]([CH3:25])=[N:23][N:22]([CH3:26])[C:18]2=[N:19][C:20]=1Cl)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.CC(C)([O-])C.[K+].[CH:42]1([CH2:45][NH2:46])[CH2:44][CH2:43]1>CC([O-])=O.CC([O-])=O.[Pd+2].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(OCC)(=O)C>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:16]=[C:17]2[C:24]([CH3:25])=[N:23][N:22]([CH3:26])[C:18]2=[N:19][C:20]=1[NH:46][CH2:45][CH:42]1[CH2:44][CH2:43]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cc1nn(C)c2nc(Cl)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)cc12
Reactant: NCC1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Product: Cc1nn(C)c2nc(NCC3CC3)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)cc12
Temperature: 25 °C
Yield: 97.4 %

Procedure:
A mixture of (3,5-bis-trifluoromethyl-benzyl)-(6-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-ylmethyl)-(2-methyl-2H-tetrazol-5-yl)-amine (0.5 g, 0.9 mmol), potassium tertiary butoxide (0.43 g, 3 mmol), cyclopropylmethyl amine (0.275 g, 3 mmol), and Pd(OAc)2 (0.01 g, 0.004 mmol), BINAP (0.03 g, 0.04 mmol) was prepared in a 10 mL pressure vial. The pressure vial was placed in the focused microwave oven (CEM Discovery) and irradiated for 20 min at 110° C. by using 250 Watt microwave power. After this mixture was cooled to RT, ethyl acetate (100 mL) was added to the vial. The organic layer was washed with water (3×100 mL) and dried and concentrated. The resultant oil was purified by column chromatography using silica gel (230-400 mesh) and eluting the column with 10% ethyl acetate in hexane afforded a colorless solid (0.485 g), yield: 90%.