Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1.[Br:20][C:21]1[CH:22]=[N:23][C:24](Cl)=[N:25][CH:26]=1.BrC1C=NC(N2C3C(=CC=C(C(N4CCOCC4)=O)C=3)C(SC)=C2)=NC=1>>[Br:20][C:21]1[CH:22]=[N:23][C:24]([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([C:12]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)=[O:13])[CH:7]=3)[C:3]([CH2:2][OH:1])=[CH:4]2)=[N:25][CH:26]=1
Reactant: O=C(c1ccc2c(CO)c[nH]c2c1)N1CCOCC1
Reactant: Clc1ncc(Br)cn1
Agent: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Product: O=C(c1ccc2c(CO)cn(-c3ncc(Br)cn3)c2c1)N1CCOCC1

Procedure:
Prepared from 27b) (700 mg, 2.69 mmol, 1.0 eq) and 5-bromo-2-chloropyrimidine (520 mg, 2.69 mmol, 1.0 eq) in an analogous manner to the procedure of 1c). The raw product was purified by column chromatography [100-200 mesh; ethyl acetate/petrolether=7:3]. White solid. Yield: 400 mg (35% of theory).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=2)=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH2:21][C@H:22]([C:24]1[N:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:32](=[O:40])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[Cl:41])[N:25]=1)[CH3:23].[F-].[K+].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=2)=[C:6]([NH:21][C@H:22]([C:24]2[N:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:32](=[O:40])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[Cl:41])[N:25]=2)[CH3:23])[N:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(C#Cc2c(N)ncnc2Cl)nc1
Reactant: C[C@H](N)c1nc2cccc(Cl)c2c(=O)n1-c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(C#Cc2c(N)ncnc2N[C@@H](C)c2nc3cccc(Cl)c3c(=O)n2-c2ccccc2)nc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To methyl 6-((4-amino-6-chloropyrimidin-5-yl)ethynyl)nicotinate (50 mg, 0.17 mmol) (prepared according to the procedure in Example 3 above) in NMP (5 mL) was added (S)-2-(1-aminoethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (62 mg 0.21 mmol) (prepared according to the procedure in Example 2A above), KF (33 mg 0.35 mmol), and Hunig's base (0.15 ml, 0.21 mmol). After stirring overnight at 120° C. the reaction was cooled to rt. Water was added. The precipitate was filtered, and then dissolved in DCM. Purification on silica with 0 to 100% EtOAc in hexanes then 0 to 20% MeOH in EtOAc gave material that required further purification. Purification on a reverse phase system run from 0 to 95% ACN in water (0.1% TFA) gave (S)-methyl 6-((4-amino-6-(1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidin-5-yl)ethynyl)nicotinate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:5][C@@H:6]1[CH2:11][C@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][N:7]1C(OC)=O.Br>>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:24]=1)[CH2:5][C@@H:6]1[CH2:11][C@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][NH:7]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@H]1Cc1cc(F)cc(C(F)(F)F)c1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@H](Cc3cc(F)cc(C(F)(F)F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
(2S,4R)-Methyl 2-(3-fluoro-5-(trifluoromethyl)benzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.675 g, 1.68 mmol) (from example 137, step 3) was dissolved in hydrogen bromide (33% in AcOH, 5 mL, 71.37 mmol) and stirred at room temperature overnight. The solvents were evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4R)-2-(3-fluoro-5-(trifluoromethyl)benzyl)-piperidin-4-yl)isoxazol-3(2H)-one (443 mg, 77%). 1H NMR (600 MHz, dmso) δ 1.08 (q, 1H), 1.31 (qd, 1H), 1.75 (t, 2H), 2.48-2.54 (m, 1H), 2.64-2.79 (m, 4H), 2.96 (d, 1H), 5.65 (s, 1H), 7.38-7.46 (m, 3H). HRMS Calculated for [C16H16F4N2O2+H]+: 345.1226. Found: 345.1212.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.C([Li])CCC.[C:20](=[O:22])=[O:21]>C1COCC1.O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]([C:20]([OH:22])=[O:21])[C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)Cc1ccccc1-2
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(c1)C(C(=O)O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
A solution of 2-methylfluorene (6 g, 33.2 mmol) in 100 ml of THF at -78° C. was charged with butyl lithium (2.18 g, 34.0 mmol). The reaction mixture was stirred for 15 min then CO2 gaseous (5 g, 113.6 mmol) was introduced via a cannula over a period of 15 min at -78° C. The reaction mixture was warmed up to room temperature and stirred for additional 2 hr until colorless. The reaction mixture was diluted with 250 mL of water and 100 mL of ethyl acetate, the layers were separated, the aqueous phase was washed with ethyl acetate (3×50 mL) and acidified to pH 2 with conc. HCl. The precipitate was filtered off, washed with water and dried to afford 6.1 g (81.9%) of 2-methyl-9-fluorenecarboxylic acid.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10](I)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[CH2:17]([Sn](CCCC)(CCCC)C=C)[CH2:18]CC>C1(C)C=CC=CC=1.CN(C)C=O.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:17]=[CH2:18])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(I)ccc2[nH]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=Cc1ccc2[nH]c(CCCC)nc(=O)c2c1
Yield: 53.3 %

Procedure:
A mixture of 12.28 g of 2-butyl-6-iodo-4(1H)-quinazolinone 0.866 g of tetrakis (triphenylphosphine)palladium, 0.015 g of 2,6-di-t-butyl-4-methylphenol in 75 ml of toluene and 20 ml of N,N-dimethylformamide is treated with 13.06 g of tri-n-butyl vinyltin followed by heating at reflux for 4 hours. The reaction mixture is cooled and concentrated in vacuo. The residue is diluted with hexanes and filtered. The filter cake is washed with hexanes and the remaining tacky solid dissolved in 100 ml of chloroform-methanol (8:2) and purified by chromato- graphy on silica gel with 1:3 ethyl acetate-hexanes to afford 4.55 g of the desired product as a yellow solid. CI MASS SPEC 229(MH+).
Reaction SMILES: N#N.[C:3]1(C)[CH:8]=CC=C[CH:4]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[O:12].C(Br)C#C>C1COCC1.CCOCC.[Zn].C(Br)C#C>[CH2:15]([O:14][C:10](=[O:13])[CH:11]([OH:12])[CH2:8][C:3]#[CH:4])[CH3:16]
Reactant: CCOC(=O)C=O
Reactant: Cc1ccccc1
Agent: C#CCBr
Agent: N#N
Agent: [Zn]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CCC(O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
Propargyl bromide (˜10 g) was added under a blanket of N2 to a 3-L round bottom flask containing 350 mL anhydrous THF and Zn (230 g, 3.5 mol). The mixture was stirred at room temperature for 30 min and then cooled in an ice bath. A toluene solution of ethyl glyoxylate (51 wt %, determined by NMR, 473 g, 2.36 mol) and a toluene solution of propargyl bromide (80 wt %, 352 g, 2.36 mol) were combined in 500 mL dry THF and 700 mL dry ether. This mixture was then added dropwise to the stirred slurry. After the addition was complete, the mixture was stirred at 0° C. overnight. The reaction mixture was then poured into a 4-L Erlenmeyer flask containing 1 L of ice-cold 3M HCl. After separation of the organic layer, the aqueous layer was extracted with ether (3×300 mL) and the combined organic layers were dried over MgSO4. Filtration and removal of the solvents by rotary evaporation gave a dark blue oil, which was purified by column chromatography using silica gel with EtOAc/hexanes (30/70) as the eluent. Vacuum distillation of the resulting material (50-55° C./100 mTorr) gave the ester 2 as a colorless oil (170 g, 51%). 1H NMR δ 4.25 (m, 3H), 3.11 (d, 1H, J=6.4 Hz), 2.65 (m, 2H), 2.03 (t, 1H, J=2.7 Hz), 1.28 (t, 3H, J=7.2 Hz). 13C NMR δ 172.99, 78.53, 71.25, 68.64, 62.11, 24.81, 14.13.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[NH2:6])[CH3:2].[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:15])[C@@H:5]([NH:6][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
L-Tyrosine ethyl ester (0.28 g, 1.35 mmol) was dissolved in DMF (9 mL). Benzoic acid (1 eq, 1.35 mmol, 0.17 g) was added, followed by N-methylmorpholine (3 eq, 4.06 mmol, 0.45 mL), 1-hydroxybenzotriazole hydrate (1.2 eq, 1.62 mmol, 0.22 g), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.2 eq, 1.62 mmol, 0.31 g). The yellow solution was allowed to stir at room temperature under nitrogen for three days. The DMF was then removed by rotary evaporation and the resulting residue partitioned between ethyl acetate and water. The organic portion was separated and washed 3×H2O and 1×aq. saturated NaHCO3. It was dried over MgSO4, filtered, and concentrated to an oil. Trituration with diethyl ether induced formation of a white powder (0.32 g, 76%). MS (ES+) m/e 314 [M+H]+, 627.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].F[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1
Reactant: Oc1c(F)cccc1F
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2c(F)cccc2F)cc1
Temperature: 25 °C

Procedure:
A slurry of 2,6-difluorophenol (1.0 g, 8 mmol), potassium carbonate (3.29 g, 24.2 mmol) and 4-fluoro benzaldehyde (1.36 g 10.4 mmol) in dry DMF (50 mL) was stirred at 100° C. overnight under nitrogen atmosphere. After the reaction is completed it was cooled to room temperature and poured in to ice cold water. The mixture was extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with water (50 mL×2), brine, then dried over anhydrous sodium sulphate and concentrated. The resulting residue was purified by column chromatography using 3% ethyl acetate in hexane to obtain the title compound.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].Cl[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]2[O:24][C:25]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:26]=3[N:27]=2)=[CH:17][CH:16]=1>>[CH2:1]([N:5]([CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18](/[CH:21]=[CH:22]/[C:23]2[O:24][C:25]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:26]=3[N:27]=2)=[CH:19][CH:20]=1)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCCCC
Reactant: COc1ccc2nc(/C=C/c3ccc(OCCCCl)cc3)oc2c1
Product: CCCCN(CCCC)CCCOc1ccc(/C=C/c2nc3ccc(OC)cc3o2)cc1
Yield: 8 %

Procedure:
Reaction of this product (2.4 g, 6.9 mmol) with dibutylamine produced 0.20 g (8% yield) of the named compound as the HCl salt, mp 151°-152° C. IR(KBr): 1600 cm-1. MS: 437(MH+). 1H NMR (CDCl3): δ 8.31-6.91 (m, 9H), 4.18 (t, J=5.1 Hz, 2H), 3.91 (s, 3H), 3.09 (m, 4H), 2.67-0.82 (m, 18H).
Reaction SMILES: [Br-].[C:2]1([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH2:33]1[O:43][C:36]2([CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]2)[O:35][CH2:34]1>>[C:2]1([CH:8]=[C:39]2[CH2:40][CH2:41][C:36]3([O:43][CH2:33][CH2:34][O:35]3)[CH2:37][CH2:38]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: C(=C1CCC2(CC1)OCCO2)c1ccccc1

Procedure:
For example, when n is the bridging group --CH2 --, an appropriately substituted or unsubstituted phenylmethyl bromide, for example, 2-chlorophenylmethyl bromide, is reacted with triphenylphosphine in toluene, affording the corresponding phenylmethyltriphenylphosphonium bromide. The so-prepared phosphonium bromide is then treated with n-butyllithium, and reacted with 1,4-cyclohexanedione mono-ethylene ketal, yielding the appropriate 8-phenylmethylene-1,4-dioxaspiro[4.5]-decane. The 8-phenylmethylene-1,4-dioxaspiro[4.5]-decane is in turn reduced with hydrogen gas in the presence of 10% palladium on charcoal, giving the corresponding 8-phenylmethyl-1,4-dioxaspiro[4.5]-decane. The 1,4-dioxaspiro functional group is then cleaved from the so-prepared molecule with acetic acid and water, affording the corresponding 4-phenylmethylcyclohexanone. The 4-phenylmethylcyclohexanone is then reacted with cyanoguanidine, as previously described, yielding the targeted 2,4-diamino-6-phenylmethyl-5,6,7,8-tetrahydroquinazoline. Example 2 provides a detailed description of how this reaction is conducted.
Reaction SMILES: N1C=CC=CC=1.[SH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[Cl:14][C:15](=[CH:19][C:20]1[CH:25]=[C:24]([C:26]2[C:30]([Cl:31])=[C:29]([O:32][CH:33]([F:35])[F:34])[N:28]([CH3:36])[N:27]=2)[C:23]([Cl:37])=[CH:22][C:21]=1[Cl:38])[C:16](Cl)=[O:17]>O1CCCC1>[Cl:14][C:15](=[CH:19][C:20]1[CH:25]=[C:24]([C:26]2[C:30]([Cl:31])=[C:29]([O:32][CH:33]([F:35])[F:34])[N:28]([CH3:36])[N:27]=2)[C:23]([Cl:37])=[CH:22][C:21]=1[Cl:38])[C:16]([S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:17]
Reactant: Cn1nc(-c2cc(C=C(Cl)C(=O)Cl)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Reactant: CCOC(=O)CS
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)CSC(=O)C(Cl)=Cc1cc(-c2nn(C)c(OC(F)F)c2Cl)c(Cl)cc1Cl
Reaction time: 8 h

Procedure:
0.95 g (7.3 mmol) of pyridine and 0.88 g (7.3 mmol) of ethyl mercaptoacetate were added to a solution of 3.3 g (6.7 mmol) of 2-chloro-3-(2,4-dichloro-5-{4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)phenyl)propenoyl chloride in 70 ml of tetrahydrofuran. The reaction mixture was stirred for 8 hours and then concentrated. The crude product was purified by chromatography on silica gel (eluent: hexane/ethyl acetate =1:1). Yield: 2.1 g.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[C:16]([CH3:17])=[CH:15][N:14]=[C:13](Cl)[CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1.C(OCC)(=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>[NH2:10][C:11]1[C:16]([CH3:17])=[CH:15][N:14]=[C:13]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=1
Reactant: Cc1cnc(Cl)cc1N
Reactant: OB(O)c1ccccc1
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: CCOC(C)=O
Solvent: c1ccccc1
Product: Cc1cnc(-c2ccccc2)cc1N
Yield: 62.1 %

Procedure:
Phenylboronic acid (188 mg, 1.5 mmol, 1.1 equiv.) and 11 (200 mg, 1.4 mmol, 1.0 equiv.) were dissolved in benzene (5 mL). Aqueous Na2CO3 (1 mL) was then added, followed by Pd(PPh3)4 (324 mg, 0.28 mmol, 0.2 equiv.). The resulting mixture was refluxed for 16 hours. The reaction mixture was dissolved in ethyl acetate and washed with water. The organic extract was dried over Na2SO4 and the solvent evaporated. The crude material was purified by reverse phase HPLC (Acetonitrile/water/TFA), to give 12 as a colorless solid (160 mg, 0.87 mmol, HPLC Rt3.373 minutes; FIA ES+ 185.1, ES− not observed).
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[N:7]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=1.CN1CCCC1=O>ClCCl>[Br:8][C:6]1[N:7]=[C:2]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: Cn1cc(Br)nc(Br)c1=O
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: Cn1cc(Br)nc(Nc2ccc(CCO)cc2)c1=O
Temperature: 120 °C
Yield: 84.5 %

Procedure:
A mixture of 3,5-dibromo-1-methyl-2(1H)pyrazinone (2.0 g; 7.5 mmol), 2-(4-Amino-phenyl)-ethanol (1.0 g; 7.3 mmol), and 1-methyl-2-pyrrolidinone (1 mL) was heated at 120° C. for 1 hr. The mixture was cooled to room temperature, diluted with dichloromethane and filtered to give a dull brown oil. This was dissolved in CH2Cl2 and washed with 0.01N NaOH, and dried over solid sodium sulfate. After filtration and evaporation of the CH2Cl2 layer, the resulting brown solid was chromatographed on silica using methanol/CH2Cl2 (1:9) as eluent to provide 2.0 g of 5-bromo-3-[4-(2-hydroxy-ethyl)-phenylamino]-1-methyl-1H-pyrazin-2-one (1) as a light tan solid. MS 324.23 (M+H).
Reaction SMILES: [CH3:1][C:2]([NH:4][C@@H:5]1[C:21]2[C:14](=[CH:15][CH:16]=[C:17]([S:22][CH3:23])[C:18]([CH:20]=2)=[O:19])[C:13]2[C:8](=[CH:9][C:10]([OH:28])=[C:11]([O:26][CH3:27])[C:12]=2[O:24][CH3:25])[CH2:7][CH2:6]1)=[O:3].[CH2:29]([O:33][C:34](Cl)=[O:35])[CH2:30][CH2:31][CH3:32].Cl>N1C=CC=CC=1>[CH3:32][CH2:31][CH2:30][CH2:29][O:33][C:34]([O:28][C:10]1[CH:9]=[C:8]2[CH2:7][CH2:6][CH:5]([NH:4][C:2]([CH3:1])=[O:3])[C:21]3[C:14]([C:13]2=[C:12]([O:24][CH3:25])[C:11]=1[O:26][CH3:27])=[CH:15][CH:16]=[C:17]([S:22][CH3:23])[C:18](=[O:19])[CH:20]=3)=[O:35]
Reactant: COc1c(O)cc2c(c1OC)-c1ccc(SC)c(=O)cc1[C@@H](NC(C)=O)CC2
Reactant: CCCCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCCOC(=O)Oc1cc2c(c(OC)c1OC)-c1ccc(SC)c(=O)cc1C(NC(C)=O)CC2
Reaction time: 1 h

Procedure:
3-demethylthiocolchicine (100 mg) in pyridine (3 ml) is added with butylchloroformate (0.2 ml) under ice cooling. After 1 hour standing, the reaction mixture is adjusted to pH 5 by addition of 2N HCl and extracted with chloroform. After washing and drying as described in Example 5, 108 mg of 3-butoxycarbonyl-3demethylthiocolchicine is obtained as a yellow powder. mp 212°-215° C.; [α]D =-110.8° (c=0.3, CHCl3).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].IC.Cl[CH2:18]Cl>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:18])[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][CH:7]=1
Reactant: ClCCl
Reactant: CS(=O)(=O)Nc1ccc(I)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CN(c1ccc(I)cc1)S(C)(=O)=O
Reaction time: 2 h

Procedure:
A mixture of N-(4-iodophenyl)methanesulphonamide (4.3 g), 50% aqueous sodium hydroxide (25 ml), iodomethane (5 ml), dichloromethane (10 ml) and tetrabutylammonium bisulphate (0.5 g) was stirred vigorously for 2 h. Water (50 ml) was added and the mixture was extracted with ether (3×50 ml). The organic extracts were washed with water and brine, dried and concentrated to a solid which was triturated with hexane to give the title compound as white crystals (4.1 g) m.p. 106°-107°.
Reaction SMILES: [Na].Br[C:3]12[CH2:12][C:7]3([CH3:13])[CH2:8][CH:9]([CH2:11][C:5]([CH3:14])([CH2:6]3)[CH2:4]1)[CH2:10]2.O>CCCCCCCC>[CH3:9][C:3]12[CH2:10][CH:9]3[CH2:8][C:7]([CH3:13])([CH2:6][C:5]([C:14]45[CH2:14][C:5]6([CH3:11])[CH2:4][CH:3]([CH2:12][C:7]([CH3:13])([CH2:6]6)[CH2:8]4)[CH2:10]5)([CH2:11]3)[CH2:4]1)[CH2:12]2
Reactant: CC12CC3CC(C)(C1)CC(Br)(C3)C2
Agent: [Na]
Solvent: O
Solvent: CCCCCCCC
Product: CC12CC3CC(C)(C1)CC(C14CC5CC(C)(CC(C)(C5)C1)C4)(C3)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 159.6 %

Procedure:
A four-neck 1000 ml flask provided with a thermometer, stirrer, and reflux tube was charged with metal sodium 14 g (0.6 mol) and n-octane 600 ml and was cooled to an inside temperature of 0° C. While vigorously stirring, 1-bromo-3,5-dimethyl adamantane 73.0 g (0.3 mol) previously dissolved in n-octane 300 ml was gradually added dropwise. While dropping, the inside temperature was kept at 0° C. to 5° C. After the end of the dropwise addition, when the temperature no longer rose, the reaction was continued for 1 hour. After that, the reactant was poured into cold water 1500 ml, then the crude product was separated by filtration, rinsed with pure water, and dried. Further, the crude product was recrystallized by hot hexane. The obtained recrystallized product was dried under reduced pressure to obtain the product 78.2 g.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[C:22]([C:30](O)=[O:31])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CC(OC)(C)C>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[C:30](=[O:31])[C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: Cc1ccc(NCCc2ccc(C(F)(F)F)nc2)cc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: COC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)C(=O)c2ccccc2)cc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.4 %

Procedure:
To a solution of (3,4-dimethyl-phenyl)-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amine (172 mg, 0.58 mmol) in DMF (4 mL) was added under a nitrogen atmosphere at 0° C. benzoylformic acid (105 mg, 0.70 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-uronium tetrafluoroborate (280 mg, 0.88 mmol) and N,N-diisopropyl ethyl amine (299 μl, 1.75 mmol). The resulting solution was stirred for 18 h at ambient temperature. It was diluted with TBME (15 mL) and washed with aqueous hydrochloric acid (1 M, 15 mL), water (15 mL), aqueous Na2CO3 (saturatedm, 15 mL) and brine (15 mL). The combined aqueous layers were extracted with TBME (15 mL) and the combined organic layers dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (132 mg, 53%) as a light brown oil. MS m/e: 427.2 [M+H]+.