Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5](=[O:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.C(NC1C=CC(S([N:33]=[N+:34]=[N-])(=O)=O)=CC=1)(=O)C>C(#N)C>[CH3:10][O:9][C:7](=[O:8])[C:6](=[N+:33]=[N-:34])[C:5](=[O:11])[CH2:4][C:3]([O:2][CH3:1])=[O:12]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: COC(=O)CC(=O)CC(=O)OC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CC(=O)C(=[N+]=[N-])C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3-ketoglutaric acid dimethyl ester 15.0 g, triethylamine 9.6 g and acetonitrile 300 ml is portionwise added 4-acetylaminobenzensulfonylazide 20.7 g at 0° C. The mixture is stirred at room temperature for 30 minutes. After removal of the precipitate by filtration the filtrate is concentrated in vacuo. The residue is diluted with a mixture of hexane and diethyl ether (1:1). The insoluble materials are removed by filtration and the filtrate is concentrated in vacuo. The residue is purified with column chromatography (silica gel 225 g, solvent; hexane:ethyl acetate=5:13:1) to give 2-diazo-3-ketoglutaric acid dimethyl ester as a pale yellow oil, 16.03 g.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[N:33](S(C)(=O)=O)[S:34]([CH3:37])(=[O:36])=[O:35])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)N(c1cnccc1OCc1ccccc1)S(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cnccc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Tetrabutylammonium fluoride 1 M in THF (12.2 ml, 42 mmol, 2.5 eq) was added to a solution of N-(4-(benzyloxy)pyridin-3-yl)-N-(methylsulfonyl)methane sulfonamide (6 g, 16.8 mmol, 1 eq) in THF at room temperature. The reaction mixture was refluxed at 60° C. for 10 h. The solution was concentrated completely and diluted with water (5 mL) and was allowed to stir for 15 minutes. The solid precipitated was filtered, washed with water and dried under vacuum yielding the expected product as a pale brown solid. 1HNMR (400 MHz, DMSO-d6): δ 3.35 (s, 3H), 5.27 (s, 2H), 7.21 (d, J=5.64 Hz, 1H), 7.36-7.54 (m, 3H), 7.54 d, J=7.28 Hz, 2H), 8.30 (s, 1H), 8.33 (d, J=5.64 Hz, 1H), 9.34 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[C:17](=O)(O)[O-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:5]([O:7][CH3:17])=[O:6]
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(C)c(O)c(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3,5-dimethyl-4-hydroxybenzoic acid (2 g, 0.012 mol) in anhydrous methanol (60 mL) was cooled in an ice-bath and thionyl chloride (5 mL) was added drop wise to this solution. The reaction was stirred in the ice-bath for one hour and was then warmed to room temperature and stirred for 16 hours. Solid sodium bicarbonate was then added to neutralize the acid and then the mixture was evaporated to dryness by rotary evaporation. The residue was partitioned between ethyl acetate and water (100 mL each). The ethyl acetate layer was separated and washed once with brine. It was then dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. Yield=2.146 g, white powder.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].Br[CH:20]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].CS(C)=O>O>[C:24]([O:23][C:21]([CH:20]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)C(Br)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)C(ON1C(=O)c2ccccc2C1=O)c1ccccc1
Reaction time: 18 h
Yield: 77.3 %

Procedure:
(a)(i) A mixture of N-hydroxyphthalimide (24.5 g), anhydrous potassium carbonate (16.5 g), t-butyl α-bromophenylacetate (41 g) and dimethylsulphoxide (225 ml) was stirred for 18 hours and was then poured into water (1.2 liters). The precipitated solid was filtered off, washed well with water, dried, and crystallised from industrial methylated spirits to give N-[α-(t-butoxycarbonyl) benzyloxy] phthalimide (41 g, 78%); m.p. 120.6°-121.5°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][CH:19]=[CH2:20]>>[CH2:20]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH2:19][CH:18]=[CH2:17]
Reactant: C=CCCBr
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCCOc1ccc(C#N)cc1
Reaction time: 1 h
Yield: 85.4 %

Procedure:
4-Cyanophenol (30 g, 250 mmol) was mixed with K2CO3 (72.5 g, 525 mmol) and stirred for 60 minutes. 4-Bromo-1-butene (50 g, 370 mmol) was added dropwise. The reaction mixture was stirred at 60° C. overnight. The solids were filtered off and the solvents were evaporated. The residue was dissolved in DCM. and washed with 1 N NaOH. The organic layer was separated, dried (Na2SO4) and evaporated to give 37 g (58%) of the sub-title compound.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C=O.O.[C:17](=O)(O)[O-:18].[Na+]>C1COCC1>[C:1]1([CH2:17][OH:18])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: O=C([O-])O
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cccc2c1Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Fluorene 60 g (0.36 mol) was dissolved in dehydrated THF 1500 ml. Subsequently, butyl lithium-hexane solution 225 ml (1.6 M) was slowly dropped in at 0° C. under argon gas atmosphere. Next, paraformaldehyde 12 g was added and the mixture was agitated at a room temperature for 5 hours. After agitation, saturated sodium bicarbonate water 600 ml was added, and extracted with diethyl ether. An organic layer was washed twice with an aqueous saturated NaCl solution, and then the solvent was evaporated off after drying using anhydrous magnesium sulfate. The obtained pasty solid matter was refined by recrystallization with a mixed solvent of hexane and ethanol to obtain a white needle crystal 50 g of fluorenyl methanol. It was determined by measurement of 1H-NMR that the obtained compound had a structure illustrated in the above-described formula (6). The melting point and the measurement result of 1H-NMR will be shown in the following paragraph.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+].O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([O:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: OCc1ccccc1
Reactant: CS(=O)(=O)c1nc(Br)cc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cc(Br)nc(OCc2ccccc2)n1

Procedure:
4,6-dibromo-2-(methysulfonyl)pyrimidine (Compound III-3) (1.5 g, 0.00476 mol) was dissolved in toluene, and benzyl alcohol (Compound II-64) (0.515 g, 0.00476×1.0 mol) was added thereto. While cooling with ice, 60% sodium hydride (0.21 g, 0.00476×1.1 mol) was added while stirring. After stirred for 6 hours, the reaction solution was poured into water and extracted with toluene. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered, and thereafter, the solvent was distilled off. The residue was purified on silica gel column chromatography (Wakogel C300, 100 ml, ethyl acetate/hexane=20 ml/400 ml) to obtain the compound (I-81) as an oily product from the fraction of 100 ml to 120 ml.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]([NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][C:19]([OH:21])=[O:20])=[O:10].O=C1CCC(=O)N1[O:29][C:30](=O)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43](=[O:46])[CH2:44][I:45].Cl>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>[I:45][CH2:44][C:43]([NH:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C:30]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]([NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][C:19]([OH:21])=[O:20])=[O:10])=[O:29])=[O:46]
Reactant: NCCOCCOCC(=O)NCCOCCOCC(=O)O
Reactant: O=C(CI)NCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(O)COCCOCCNC(=O)COCCOCCNC(=O)CCCCCCCCCCCNC(=O)CI
Reaction time: 0.75 h
Yield: 49 %

Procedure:
To a solution of [2-(2-{2-[2-(2-aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetic acid (194 mg) in 0.1 M sodium carbonate was added acetonitrile (5 ml) followed by a solution of 12-(2-Iodoacetylamino)dodecanoic acid 2,5-dioxopyrrolidin-1-yl ester (260 mg) in acetonitrile (6 ml). After stirring for 45 min, pH was adjusted to 4 with 1 N HCl and the mixture was purified by preparative HPLC: C18, 3 cm column (Gemini), A-buffer 0.1% TFA in MiliQ water, B-buffer: 0.1% TFA in AcCN, flow 20 ml/min, gradient 10-80% B over 30 min. Product containing fractions were pooled and concentrated to give the title compound in 49% yield (180 m). LC-MS, M/z: 674.3 (M+1).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]([F:24])([F:23])[S:12]([O:15]S(C(F)(F)F)(=O)=O)(=[O:14])=[O:13].[CH2:25]([C:27]([C:45]1[CH:50]=[CH:49][C:48](O)=[CH:47][CH:46]=1)([C:30]1[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38]([CH2:42][CH3:43])([OH:41])[CH2:39][CH3:40])=[C:32]([CH3:44])[CH:31]=1)[CH2:28][CH3:29])[CH3:26].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:25]([C:27]([C:45]1[CH:46]=[CH:47][C:48]([O:15][S:12]([C:11]([F:24])([F:23])[F:10])(=[O:14])=[O:13])=[CH:49][CH:50]=1)([C:30]1[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38]([CH2:39][CH3:40])([OH:41])[CH2:42][CH3:43])=[C:32]([CH3:44])[CH:31]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(O)cc2)cc1C)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(OS(=O)(=O)C(F)(F)F)cc2)cc1C)CC
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
N,N-Diisopropylethylamine (0.83 mL, 2 mmol) and trifluoromethanesulfonic anhydride (0.26 mL, 1.6 mmol) were added to a solution of 4-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-phenol (Example 39-(3); 0.52 g, 1.4 mmol) in dichloromethane (7 mL) at −78° C., and the mixture was stirred at the same temperature for 10 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (0.65 g, 92%).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:9][C:8]2[CH:7]=[C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:5]=[CH:4][C:3]1=2.Cl.[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C>[CH2:39]([O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]1[N:2]([CH3:1])[C:3]2[CH:4]=[CH:5][C:6]([N:17]([CH2:18][CH2:19][Cl:20])[CH2:21][CH2:22][Cl:23])=[CH:7][C:8]=2[N:9]=1)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: CCCCCCCCCCCCCCCO
Reactant: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCCCCCCCCCCCCCCOC(=O)CCCc1nc2cc(N(CCCl)CCCl)ccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A 250 mL three neck round bottom flask was equipped with an overhead stirrer, thermocouple, temperature controller and nitrogen sweep then charged with 10.0 g (25.34 mmol) of bendamustine hydrochloride, 5.85 g (25.6 mmol, 1.01 eq) of pentadecanol, 5.3 g (25.6 mmol, 1.01 eq) of dicyclohexylcarbodiimide (DCC), 100 mL of MDC and 0.31 g (2.54 mmol, 0.1 eq) of DMAP. The reaction was stirred at room temperature overnight at which time an in process analysis indicated the reaction was complete. Solids were removed by vacuum filtration and washed with 25 mL of MDC. The filtrate was washed with saturated aqueous sodium bicarbonate solution (2×100 mL), DI water (1×100 mL) and brine (1×100 mL) before drying over sodium sulfate, filtering and concentrating to dryness in vacuo to an off-white solid. This solid was triturated with 25 mL of MDC and the solid impurities were removed by vacuum filtration and washed with 5 mL of MDC. The filtrate was concentrated to dryness in vacuo to yield 10.8 g (19.0 mmol, 75%) of the product as an off-white solid with an HPLC purity of 94.6A %. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J=8.76 Hz, 1H), 7.08 (d, J=2.32 Hz, 1H), 6.78 (dd, J=2.4, 8.76 Hz, 1H), 4.05 (t, J=6.8 Hz, 2H), 3.72 (m, 4H), 3.69 (s, 3H), 3.63 (m, 4H), 2.91 (t, J=7.4 Hz, 2H), 2.49 (t, J=7.08 Hz, 2H), 2.18 (m, 2H), 1.60 (m, 2H), 1.32 (m, 24H), 0.88 (t, J=6.68 Hz, 3H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27](Cl)=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: C1COCCN1
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cccnc1Cl
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cccnc1N1CCOCC1

Procedure:
Using the conditions of Example 334 and 1 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-phenyl]-2-chloropyridine-3-carboxamide and 5 ml of morpholine gives 800 mg of the desired product :M+ =493.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[O:14])[N:7]2[C:15]([CH2:18]Cl)=[N:16][N:17]=[C:6]12)[CH2:2][CH2:3][CH3:4].[CH3:20][OH:21]>C[O-].[Na+].O>[CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[O:14])[N:7]2[C:15]([CH2:18][O:21][CH3:20])=[N:16][N:17]=[C:6]12)[CH2:2][CH2:3][CH3:4]
Reactant: CO
Reactant: CCCCn1c2nc[nH]c2c(=O)n2c(CCl)nnc12
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: CCCCn1c2nc[nH]c2c(=O)n2c(COC)nnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.1 %

Procedure:
The mixture of 9-butyl-3-(chloromethyl)-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (35 mg, 125 mmol) in 4 M of sodium methoxide in methanol (0.5 mL, 2 mmol) was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers was dried with sodium sulfate, filtered, and concentrated in vacuo to yield the desired product (6 mg, 17.42%). LCMS calculated for C13H19N6O2(M+H): 290.2; found 290.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([NH2:8])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([NH2:8])=[S:17]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1cc(C(N)=O)cc(OC)c1OC
Solvent: c1ccccc1
Product: COc1cc(C(N)=S)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 122.7 %

Procedure:
500 mg of 3,4,5-trimethoxybenzamide was suspended in 15 ml of benzene. Thereto was added 526 mg of phosphorus pentasulfide. The mixture was refluxed for 30 minutes with heating. The solvent was removed by distillation. To the residue were added 5 ml of 10% sodium hydroxide and 5 ml of water. The mixture was stirred for 30 minutes. The reaction mixture was filtered, and the resulting solid was washed with small amounts of water and ethanol and dried to obtain 330 mg of 3,4,5-trimethoxythiobenzamide as a yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:22])=[N:8][N:9]2[C:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:13](Br)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>[Pd].C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:22])=[N:8][N:9]2[C:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:13]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nn2c(C3CCCCC3)c(Br)cnc12
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)nn2c(C3CCCCC3)c(-c3ccc(F)cc3)cnc12
Temperature: 80 °C
Yield: 93.3 %

Procedure:
A mixture of 187 mg (0.5 mmol) of 6-bromo-7-cyclohexyl-2-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, 105 mg (0.75 mmol, 1.5 equiv) of 4-fluorophenylboronic acid, 20 mg (0.025 mmol, 5 mol %) of Pd catalyst, and 318 mg (1.5 mmol, 3 equiv) of potassium phosphate was placed into a carousel tube. After a vacuum and argon cycle, 1,4-dioxane (7 mL) was added, and the resulting mixture was heated at 80° C. under argon for 14 h. The reaction mixture was diluted with ethyl acetate, filtered through a small pad of Celite, dried over sodium sulfate and evaporated to give a brown residue which was chromatographed on silica gel (gradient elution with 2%, 5% to 10% ethyl acetate in dichloromethane) to afford 0.178 g (94%) of 7-cyclohexyl-6-(4-fluoro-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester as an off-white solid as indicated by 1H NMR; LC-MS—calcd for C22H24FN3O2 [M++H]+: 382.19, found: 382.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[NH:18][C:17]1=[O:27]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[NH:18][C:17]1=[O:27])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@@H]1CCc2ccccc2NC1=O

Procedure:
Prepared from 2-(t-butoxycarbonylamino)-2-methylpropanoic acid and 3(R)-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (Example 1, Step B) by the procedure described in Example 1, Step F. 1H NMR (200MHz, CDCl3): 1.42 (s,12H), 1.46 (s,3H), 1.90 (m,1H), 2.5-3.0 (m,3H), 4.48 (m,1H), 5.01 (br s,1H), 6.97 (d,8Hz,1H), 7.1-7.3 (m,3H), 7.9 (br s,1H). FAB=MS: calculated for C19H27N3O4 361; found 362 (M+H,30%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22](=[O:23])[C:21](=[O:24])[N:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32](Cl)=[O:33])=[CH:28][CH:27]=3)[C:19]2([CH3:36])[CH3:35])=[CH:13][CH:12]=1)=[O:10]>N1C=CC=CC=1>[O:7]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22](=[O:23])[C:21](=[O:24])[N:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([O:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:33])=[CH:28][CH:27]=3)[C:19]2([CH3:36])[CH3:35])=[CH:13][CH:12]=1)=[O:10])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)N(Cc2ccc(C(=O)Cl)cc2)C(=O)C(=O)N1Cc1ccc(C(=O)Cl)cc1
Reactant: Oc1ccccc1
Solvent: c1ccncc1
Product: CC1(C)N(Cc2ccc(C(=O)Oc3ccccc3)cc2)C(=O)C(=O)N1Cc1ccc(C(=O)Oc2ccccc2)cc1

Procedure:
To a solution of 10 g (0.106 mole) of phenol in 20 ml of pyridine are added at room temperature, with stirring, 5 g (0.0115 mole) of 1,3-bis-(4'-chlorocarbonylphenylmethyl)-2,2-dimethylimidazolidine-4,5-dione.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:44]([NH:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH3:45]>CN(C=O)C>[CH2:44]([N:46]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:15](=[O:17])[CH2:14][CH2:13][C:12](=[O:18])[C:9]1[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=1)[CH3:45]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Reactant: CCCCCCCNCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCCCCCN(CC)C(=O)CCC(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A stirred solution of 4-[(methylsulfonyl)amino]-γ-oxobenzenebutanoic acid as prepared in Preparation 2 (12.0 g, 0.044 mol) in DMF (100 ml) under N2 is cooled in an ice bath to 5° C. and treated with 1-hydroxybenzotriazole (5.94 g, 0.044 mol) and N,N'-dicyclohexylcarbodiimide (9.08 g, 0.044 mol). After 1 hour, ethylheptylamine (6.3 g, 0.044 mol) is added; after an additional 30 minutes the ice bath is removed and the mixture is kept at ambient temperature for 18 hours. The reaction mixture is filtered over a Celite filter aid and the filtrate is concentrated under vacuum. The resulting material is dissolved in CH2Cl2 ; washed with dilute HCl, NaHCO3 and brine; dried (Na2SO4) and concentrated. The residue is chromatographed over silica gel (1.25 kg) with 5% MeOH:1% NH4OH:CH2Cl2. The N-ethyl-N-heptyl-γ-oxo-4-[(methylsulfonyl)amino]benzenebutanamide thus obtained is crystallized from EtOAc:SSB to yield 10.77 g, mp 100°-102° C. and 2.32 g, mp 99°-101° C. The analytical sample has a mp 102°-103° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C@H:10]1[O:15][C@@H:14]([CH3:16])[CH2:13][N:12]([C:17]2[CH:22]=[C:21]([C:23]3[CH:27]=[CH:26][O:25][C:24]=3[CH3:28])[CH:20]=[CH:19][N:18]=2)[CH2:11]1>C(Cl)(Cl)Cl>[Br:1][C:20]1[C:21]([C:23]2[CH:27]=[CH:26][O:25][C:24]=2[CH3:28])=[CH:22][C:17]([N:12]2[CH2:11][C@H:10]([CH3:9])[O:15][C@H:14]([CH3:16])[CH2:13]2)=[N:18][CH:19]=1
Reactant: Cc1occc1-c1ccnc(N2C[C@@H](C)O[C@@H](C)C2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Cc1occc1-c1cc(N2C[C@@H](C)O[C@@H](C)C2)ncc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-Bromosuccinimide (133 mg, 0.749 mmol) was added portionwise to a solution of cis-2,6-dimethyl-4-[4-(2-methyl-3-furanyl)-2-pyridinyl]morpholine (204 mg, 0.749 mmol) in chloroform (6 mL) at 0° C. The reaction was stirred at 0° C. for 1 hour. Crude LC/MS showed desired product can be seen and no starting material left, so the reaction mixture was diluted with ethyl acetate and washed with water, brine, water and brine. The organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane (˜5 ml) and purified on silica by a Biotage SP4 chromatographic system (25+M cartridge, eluted with 0-50% ethyl acetate in isohexanes). Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound (295 mg, 0.798 mmol, 107% yield) as a colourless oil. LC/MS [M+H]+=351/353.